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When you slice a thyroid, you can see that the thyroid is made up of a lot of follicles, and it is very vascularized. The thyroid is made up of follicles filled with colloids. The colloid is surrounded by epithelial cells known as follicular cells. The cells are responsible for transporting iodine and using it to produce the thyroid hormone. They are also secretory cells. They can secret their own content into the colloid. There are also c cells. They produce another hormone. The thyroid gland produces 3 hormones. The C cells produce calcitonin. Calcium along with vitamin D and parathyroid hormone regulate bone metabolism. Calcitonin reduces the level of calcium when it is high.
1. Uptake of plasma iodide by the follicle cells
2. Oxidation of iodide & iodination of tyrosine residues of thyroglobulin
3. Secretion of thyroid hormone.
- Follicular cells have Na/I symporter. On the other side we have Pendrin that pushes the Iodine into the cytoplasm. Iodine is then oxidized into iodide. It is then used to iodinate tyrosine moieties. This results in monoiodination and diiodination. Then there is proteolysis. Eventually, we will have T4,T3 released by exocytosis into the bloodstream.
2. Oxidation of iodide & iodination of tyrosine residues of thyroglobulin
3. Secretion of thyroid hormone.
- Follicular cells have Na/I symporter. On the other side we have Pendrin that pushes the Iodine into the cytoplasm. Iodine is then oxidized into iodide. It is then used to iodinate tyrosine moieties. This results in monoiodination and diiodination. Then there is proteolysis. Eventually, we will have T4,T3 released by exocytosis into the bloodstream.
T3 & T4 - transported reversibly bound to plasma proteins (>99%):
- Protect hormone from premature metabolism & excretion
- Prolongs its t1/2 in circulation; T4 ∼7 - 10 days & T3∼ 24 h
- Allows thyroid hormone to reach its site of action
- thyroxine-binding globulin (TBG) ∼80%, transthyretin (∼15%), & albumin (∼5%)
- Free form - ∼0.04% of total T4 & 0.4% of T3
T4 & T3 are lipophilic molecules; cross the cell membrane easily; iodothyronine transporters facilitate transportation
- Protect hormone from premature metabolism & excretion
- Prolongs its t1/2 in circulation; T4 ∼7 - 10 days & T3∼ 24 h
- Allows thyroid hormone to reach its site of action
- thyroxine-binding globulin (TBG) ∼80%, transthyretin (∼15%), & albumin (∼5%)
- Free form - ∼0.04% of total T4 & 0.4% of T3
T4 & T3 are lipophilic molecules; cross the cell membrane easily; iodothyronine transporters facilitate transportation
Peripheral metabolism of thyroid hormones- Primary pathway is deiodination by 5′deiodinase enzymes ; Deiodination of T4 → T3 (3-4X more potent)
- 5′-deiodinase inhibitors - amiodarone, iodinated contrast media, β blockers, & corticosteroids; severe illness or starvation
- T4 is a pro hormone. Through diiodination it can be converted to T3. Removal of one of the I from the outside ring will convert it to T3.Thyroid and pituitary relationship- Hypothalamic cells secrete thyrotropin-releasing hormone (TRH)
- TRH stimulates synthesis & release of thyrotropin (thyroid-stimulating hormone, TSH).
- TSH stimulates ↑ synthesis & release of T4 & T3.
- T4 & T3 act in -ve feedback on pituitary & hypothalamus to block the action of TRH
- Other hormones/drugs may affect release of TRH or TSH.
- Defective regulation can lead to thyroid disordersThe thyroid hormone is released under the regulation of the hyperpituitary axis.- A lot of physiological factors can stimulate or inhibit the thyroid hormone release. Severe stress can inhibit the release of the hypothalamic hormone responsible for the release of TRH. When TRH is released, it stimulates the anterior pituitary gland to release thyroid stimulating hormone (TSH). TSH works to release T3,T4.
- Excess T3 and T4 beyond the normal values will inhibit the AP by short loop or the hypothalamus by long loop. This is a negative feedback loop. For the positive feedback, the AP plays a big role. Hypothalamus will release TRH, and so on.
- Excess I- can induce or inhibit the release of T3,T4.mechanism of action of T4 and T3- Free T4 & T3, dissociate from TBG & actively transported into the cell
- 5′-deiodinase converts T4 to T3
- T3 enters the nucleus, binds to T3 thyroid receptor which is coupled to RXR.
- T3-receptor complex interacts with specific sequences of DNA - stimulate or inhibit transcription of specific genes. (After T3 binds to the receptor it binds to Thyroid hormone response element. This causes gene transcription which causes the synthesis of new proteins. The proteins will regulate growth, CNS development, CV, metabolism, and many other systems.)Effects of the thyroid hormones- All cells are targets for thyroid hormones - affect dev., growth, & metabolism.
- Growth & dev. - regulate long bone growth & affect protein synthesis, CNS dev.
- Metabolic effects - ↑ BMR → ↑ body heat, O2 use, carb/lipid metabolism.
- Calorigenesis -↑ BMR
- Cardiovascular system - ↑ BMR, which ↑ blood flow, cardiac
- Musculature - cause a fine tremor
- Sleep - induce wakefulness in hyperthyroidism; somnolence with hypothyroidism
- Lipid metabolism - ↑ lipid mobilization & degradationEpidemiology of thyroid disorders- Thyroid diseases are prevalent endocrinologic disorders
- ∼ 12% of the U.S. population will suffer from a thyroid disorder in their lifetime
- ∼ 15 - 20 million Americans have diagnosed thyroid disease
- Relatively more common in women ∼ 10 x > men
- Worldwide - iodine deficiency is the most common cause of hypothyroidism
- Autoimmune diseases are common in areas with sufficient dietary iodine intake.What are goitrogens?Now iodine deficiency isn't that common in developed countries due to the combination with salt. Although there are agent known as goitrogens. They are found in many plant based foods such as cabbage. They are naturally occurring substances that interfere with the function of the thyroid gland. Excess cabbage intake can cause goiter, the enlargement of the thyroid gland. It can happen in hyper and hypothyroidism.What are the risk factors for thyrotoxicosis and hypothyroidism?- Age - common in middle-aged individuals; ↑ risk in those aged >50 y
- Gender - more likely to occur in women than men
- Stress
- Family history - autoimmune thyroid disease may have a genetic/familial link
- Thyroid surgery or medical treatment - can result in hyper- or hypothyroidism
- Radiation exposure
- Pregnancy - alterations in hormone levels
- Diet - dietary iodine intake and foods containing goitrogens
- Smoking - can exacerbate thyroid disease & ↑ the risk of autoantibody dev.HypothyroidismTSH: >4.5µIU (increased)
Total thyroxine (T4): <5mcg/dL (decreased)
Total triiodothyronine (T3): <80 ng/dL (decreased)
Free T3 (FT3): <169ng/dL (decreased)
Free T4 (FT4): <0.8 ng/dL (decreased)
Serum resin T3 uptake (TT3U): <35% (decreased)HyperthyroidismTSH: <0.4 µIU/mL (decreased)
Total thyroxine (T4): >12 mcg/dL (increased)
Total triiodothyronine (T3): >180 ng/dL (increased)
Free T3 (FT3): >317 ng/dL (increased)
Free T4 (FT4): >1.4 ng/dL (increased)
Serum resin T3 uptake (TT3U): >45% (increased)Why is TSH high in hypothyroidism?The pituitary tries to make more TSH to help trigger the thyroid to produce more thyroid hormone (T3 & T4). This is the pituitary's effort to return the system to "normal" and normalize thyroid functionWhy is TSH low in hyperthyroidism?High T3 and T4 increases negative feedback for its productionWhat is the effect of thyroid function on drugs?- Anticoagulation - ↓ doses of warfarin required in hyperthyroidism; ↑ doses in hypothyroidism
- Glucose control - ↑ hepatic glucose production & glucose intolerance in hyperthyroidism; impaired insulin action & glucose disposal in hypothyroidism
- Cardiac drugs - ↑ doses of digoxin required in hyperthyroidism; ↓ doses in hypothyroidism
- Sedatives & opioid analgesics - ↑ sedation & respiratory depression in hypothyroidism; ↓ in hyperthyroidismWhat are the effects of drugs on thyroid function?- ↓ thyroid hormone synthesis or release - Iodides, amiodarone, Li, thioamides
- ↑ TBG - Estrogens, tamoxifen, heroin; ↓ TBG - Androgens, anabolic steroids, glucocorticoids
- ↑ hepatic metabolism of T3 & T4 - phenytoin, rifampin carbamazepine, phenobarbital
- Inhibition of 5′-deiodinase (↓ T3) - amiodarone, β-blockers, corticosteroids, PTU
- Interference with T4 absorption - cholestyramine, colesevelam, colestipol, charcoal, sucralfate, etc.
- Induction of autoimmune thyroid disease (hypo/hyperthyroidism - Interferons, IL-2, Li, amiodarone, tyrosine kinase inhibitors e.g. sunitinibWhy is amiodarone so important in this lecture?It is an antiarrhythmic. When you look at its structure it has a lot of iodine. That release of iodine can cause hyperthyroidism. The structure is also closely related to the thyroid hormone. This means it can also act as an inhibitor of the receptor. This can cause hypothyroidism.What is hypothyroidism? What are the key symptoms?- Syndrome resulting from thyroid hormones deficiency
- Manifested by reversible slowing down of all body functions
- Can occur with or without thyroid enlargement (goiter)
Key symptoms:
- Weight gain; Cold intolerance; yellowish skin & face; Lethargy/fatigue; Muscle weakness
- Memory & mental impairment;
- Bradycardia
Drooping of eyelids; large tongue
- ↓ appetite; constipation; ↓ erythropoiesis
- ↓ libido; impotence; oligospermiaWhat are the complications of hypothyroidism?- Goiter - enlargement of the thyroid gland
- Heart problems - ↑ cholesterol & BP, and heart failure
- Depression
- Peripheral neuropathy
- Infertility and birth defects, if occurring during pregnancy
- Myxedema and myxedema coma, a rare but potentially life-threatening disorderWhat is a goiter? What causes it?- An enlarged, palpable thyroid gland
+ ↓ thyroid hormone → release of excess TSH → thyroid hypertrophy (nontoxic goiter).
Frequently caused by:
- ↓dietary iodide
- Hashimoto's thyroiditis
- Prolonged intake of goitrogensWhat is cretinism?- congenital hypothyroidism
- severe and devastating hypothyroidism in infants and children
- growth retardation and dev. leading to dwarfism (result of lack of growth hormone from the pituitary gland)
- irreversible mental retardation (there is no thyroid hormone to enhance the brain's development)
- pathogenesis: athyreosis or ectopic thyroid, iodine deficiency; TSH receptor blocking antibodies
- Goiter: absent or present
- degree of hypothyroidism: severeetiology of hypothyroidismWhat is myxedema?- hypothyroidism in adults
- Severe hypothyroidism after infancy
- Cardinal features - hypothermia (cold intolerance), resp. depression, & ↓consciousness, lethargy, fatigue, weakness, hair loss, & reproductive failure
Myxedema coma
- medical emergency
- progressive weakness, hypothermia, hypoventilation, hypoglycemia, hyponatremia, shock, & death.What is hyperthyroidism?- Hyperthyroidism (thyrotoxicosis) -clinical syndrome resulting from high levels of thyroid hormone
Caused by either
1. the overproduction of endogenous hormone
2. exposure to excess exogenous hormoneWhat are the causes of hyperthyroidism?- Excess exogenous thyroid hormone
- Diffuse toxic goiter (Graves' disease)
- Hyperfunctioning adenoma (toxic nodule)
- Toxic multinodular goiter
- Painless thyroiditis; Subacute thyroiditis
- Thyroid-stimulating hormone (TSH)-secreting adenoma
- Drug - induced - Amiodarone, Interferon alfaWhat is Grave's disease?- Diffuse toxic goiter
- Most common form of hyperthyroidism
- Autoimmune disorder (genetic)
- Lymphocytes secrete antibodies (TSH-R Ab [stim] or TSI) against TSH receptor site on the thyroid cells → stimulate growth & biosynthetic activity.
- ↑ levels of TSI stimulates TSH receptors in orbital fibrocytes → ophthalmopathy.
Laboratory diagnosis - ↓ TSH;↑T3, T4, FT4, & FT3 ; ↑ radioiodine uptake; Anti-TBG, TPO, & TSH-R Ab [stim]What is the management and complications of Grave's disease?Management:
Three primary methods
- Surgical thyroidectomy
- Destruction of the gland with radioactive iodine
- Anti-thyroid drug therapy
If left untreated:
- Heart problems - atrial fibrillation & heart failure
- Osteoporosis
- Graves' ophthalmopathy & eye problems
- Graves' dermopathy, or skin changes
- Thyrotoxic crisis or thyroid stormWhat is thyroid storm?- thyrotoxic crisis
- Life-threatening medical emergency - sudden exacerbation of hyperthyroidism - rapid release of thyroid hormone
Fatal if not treated rapidly - hyper-metabolism → dehydration, shock, & death.
- Precipitating factors - thyroid trauma or surgery, RAI therapy, infection, severe emotional stress, & sudden discontinuation of antithyroid therapy.
- Symptoms - severe hyperpyrexia, tachycardia, agitation, delirium, psychosis, stupor, or coma (some symptoms can be managed with beta blocks e.g. propranolol)ophthalmopathy in thyroid disease- Protruding eyeballs
- Rare but difficult to treat - exacerbations may occur with RAI, esp. in smokers
- The Thyroid stimulating antibody will act on the fibroblast in the periorbital space causing increase in the matrix causing protrusion of the eyeballs. The eyelids cannot easily cover the eyeballs.
Management
- Treat the thyroid disease - total surgical excision or 131I ablation of the gland
- Oral prednisone therapy
- Local therapy eg, elevation of the head, & artificial tears
- Smoking cessationDesiccated Thyroid (Armour Thyroid, Nature-throid, Westhroid)- Source - hog or beef thyroid glands (is likely to cause an allergic rxn); standardized to 0.17% - 0.25% iodine.
- Release T4, T3, DIT, and MIT via proteolytic activity of GI tract enzymes.
- Variable hormone concs., potency & ratios of T4:T3, protein antigenicity, product instability
- Difficulty in lab monitoring >>> advantage of lower cost.
- C/I in patients hypersensitive to beef or pork.
- Not well studiedthyroid supplements- May contain undisclosed amounts of levothyroxine
- ineffective and possibly toxic for weight reductionLevothyroxine - T4
Levoxyl, Levo-T, Levothroid, Levolet, Novothyrox, Synthroid, Tirosint, Unithroid
Indication - Drug of choice for HRT in hypothyroidism & suppression therapy
(stable, content uniformity, low cost, lack allergenic foreign protein, easy lab measurement of serum levels, & long t1/2 ∼ 7 days)
Pharmacokinetics
- Oral bioavailability ∼ 50% to 80%; ↓ by food; Protein binding ∼ 99%.
- Duration of action is several weeks.
- t1/2 ∼ 7 days; peak onset ∼ 9 days; 50% feces, 50% urine
MOA - Levothyroxine is converted to T3 in vivo.
Tablet colors are standard according to the strength.
- Recommended for use by AACE guidelinesLevothyroxine - T4
Levoxyl, Levo-T, Levothroid, Levolet, Novothyrox, Synthroid, Tirosint, Unithroid ADRs- C/I: avoid in thyrotoxicosis; acute MI and other CVD
- Adverse effects - Arrhythmias, tachycardia, anginal pain, cramps, headache, restlessness, sweating, weight loss, ↓ bone density → osteoporosis
- Average adult maintenance dose is 75 to 150 mcg QD (↓ in the elderly or those with CVD)
FDA pregnancy category ALiothyronine (T3, Cytomel)Synthetic form of T3 - average adult maintenance dose is 75 - 150 mcg QD
Indications
- used when rapid onset & cessation of action is required, e.g. in heart disease
- IV form - useful for rapid emergency treatment of myxoedema coma
Pharmacokinetics
- Oral bioavailability is 95%; Weakly bound to protein.
- DOA - several days; t1/2 ∼ 1-2 days; peak onset ∼ 1-2 days; 100% via the urine.
Adverse effects - arrhythmias, tachycardia, anginal pain, cramps, headache, restlessness, sweating, weight loss
- increase risk in cardiac effectsLiotrix (Thyrolar)- A mixture of T4 and T3 in a ratio of 4:1.
- No advantage over levothyroxine & costs more.
- Possible benefit in specific genotype
- possible increased mood
- similar efficacy to levothyroxineIf T3 is the active hormone, why use T4?The only advantage of T3 is if the pts lack 5'-DI. Although, it does not have much advantage. The only other advantage is quick onset of action and short duration of action. Most of the properties are similar to T4.Metabolism of T3, and T4T4 is a pro-hormone → the active T3 form
Deiodination by 5′ deiodinase:
- outer ring of T4 → T3 (∼33%)
- inner ring of T4 → rT3 (∼40%) - no known biological fxn
- Sulfonation & glucuronide conjugation of the outer ring phenolic hydroxyl group.
- Cleavage of the ether bond
- Decarboxylation & oxidative deamination at the alanine side chain.PK of T4 and T3- Good oral bioavailability; T4 ∼ 70% & T3 ∼ 95%
- Food, Ca2+ prep, & Al-containing antacids - ↓ T4 absorption
- Metabolic clearance of T4 & T3 ↑ & t1/2 ↓ in hyperthyroidism; the opposite is true with hypothyroidism.
- Hepatic enzyme inducers - rifampin, phenobarbital, carbamazepine, phenytoin, tyrosine kinase inhibitors, HIV protease inhibitors ↑metabolism of both T4 & T3
- Pregnancy, estrogens, or oral contraceptives ↑TBG sites but the conc. of free hormone & the steady-state elimination will remain normal.DI of synthetic thyroid hormones?- Bile acid sequestrants - Cholestyramine & colestipol - ↓thyroxine bioavailability; Admin. at least 6 h after thyroxine.
- Calcium carbonate - ↓ thyroxine bioavailability by adsorption.
- Estrogens (Estrace, Premarin) & SERMs - tamoxifen or raloxifene may ↓ FT4 & ↑TSH levels → requiring ↑levothyroxine dose.
- Raloxifene cause malabsorption of levothyroxine → hypothyroidism; Separate admin. times by 12 h
- Ciprofloxacin interact with levothyroxine → ↓ FT4 & ↑TSH levels; Separate admin. times by 6 h.What does the BBW on thyroid hormones say?Do not use thyroid hormones either alone or with other therapeutic agents, for the treatment of obesity or for weight loss.
They are ineffective for weight reduction in euthyroid patients, and may produce serious or even life-threatening manifestations of toxicity, particularly when given in association with sympathomimetic amines such as those used for their anorectic effectsWhat are the antithyroid drugs?- Thioamides - Methimazole (Tapazole); Propylthiouracil - used the most
- Iodines - Lugol's solution, saturated solution of potassium iodide
- Anion Inhibitors
- Radioactive iodine
- Beta blockers - propranolol, nadolol, metoprolol, atenolol
- Thyroid gland remains intact but req. long period of treatment; 50-70% incidence of relapse.
- The best clinical guide to remission is reduction in the size of the goiter.
- Monitor the course of therapy (Lab tests for serum TSH, FT3 & FT4 levels).What are thioamides?- Cyclic derivatives of thiourea - thioureylenes
- 5- & 6-membered heterocyclic derivatives - thioimidazoles & thiouracil
- Potent inhibitors of TPO → prevent iodination of tyrosine residues on TG & the coupling reactions that form iodothyronines.
- Thiouracils also inhibit peripheral deiodination of T3 & T4 by the enzyme 5′-DI.What is the SAR of thioamides?Thiouracils:
- inhibitors of peripheral deiodination
- C2 thioketo/enol & unsubstituted N1 are essential for activity.
- Activity is ↑ by a C4 enol & alkyl groups at C5 & C6.
- 6 membered ring
Thioimidazoles:
- more inhibitory of TPO & longer acting > thiouracils.
- Methyl group at N1 of thioimidazoles → lack inhibition of peripheral deiodination
- 5 membered ring
- Only Propylthiouracil (PTU) & Methimazole (MMI) are useful clinically.
- In thioamides, the C2 position must remain unsubstituted, and the nitrogen at position 1 must be unsubituted as well.What are the pharmacodynamic parameters of thioamides?Thioamides act by multiple mechanisms:
1. Major action - prevent hormone synthesis by inhibiting TPO-catalyzed reactions & blocking iodine organification.
2. Block coupling of the iodotyrosines.
3. Propylthiouracil (not methimazole) inhibits peripheral deiodination of T4 & T3
Slow onset of action:
- agents affect synthesis rather than the release of hormones
- often require 3-4 weeks before stores of T4 are depletedPropylthiouracil (PTU) pk- Take with food to ↓ GI upset.
- Readily absorbed ∼ 50% - 80% bioavailability - variable due to a large 1st pass effect.
- Plasma t1/2 ∼ 1.5 h - no change in DOA/dosing interval - accumulates in the thyroid gland.
- ∼ 80% - 90% plasma bound; PTU is preferred in 1st trimester due to ptn binding
- Excretion via the kidney as the inactive N1-glucuronide
FDA pregnancy category DMethimazole (MMI) - Tapazole pk- rapidly absorbed orally with 93% bioavailability.
- Plasma t1/2 ∼ 5 to 6 h- no change in DOA/dosing interval - accumulates in the thyroid gland.
- does not bind to serum albumin
- extensively metabolized in the liver to 3-methyl-2-thiohydantoin.
- excretion is primarily via the kidney.
- **MMI (preferred - lower risk of liver injury & once daily admin.) to PTU (except in pregnancy & thyroid storm) - Both MMI and PTU can cause liver damage, but it is more likely to happen with PTU. Any other time the preferred agent is MMI except in pregnancy.
FDA pregnancy category DThioamides ADRs- Occur in 3% to 12% of treated patients
- Nausea, GI distress & commonly maculopapular pruritic rash.
- Agranulocytosis and neutropenia - are but serious ADR
- MMI - altered sense of taste or smell, cholestatic jaundice
- FDA black box warning for PTU: Severe, sometimes fatal liver injury & acute liver failureAnion Inhibitors: Perchlorate, Pertechnetate, Thiocyanate- Block uptake of iodide - competitive inhibition of transport mechanism. (anions bind to prevent iodine from binding to receptor)
- Large doses of iodides overcome their effects - unpredictable effectiveness
- Major clinical use for KClO4 - block thyroidal re-uptake of I− in iodide-induced hyperthyroidism (eg, amiodarone-induced hyperthyroidism).
-Rarely used due to aplastic anemia.Iodides:
- Oral solution (SSKI) - Thyroshield, Lugol's solution
- Oral potassium iodide tablets - IOSAT, Thyro-Block, Thyro-SafePharmacologic actions
- Pharmacologic doses (> 6 mg/day): Inhibit organification, thyroglobulin proteolysis & hormone release
- Useful therapy in thyroid storm - improve symptoms within 2-7 days
- Pre-operative preparation (removal of thyroid) - ↓vascularity, size, & fragility of a hyperplastic gland
- Can induce hyperthyroidism or precipitate hypothyroidism.Iodides Disadvantages- ↑ intraglandular stores of iodine (can increase changes of hyperthyroidism)
- may delay onset of thioamide therapy; initiate iodides after onset of thioamide therapy;
- may prevent use of radioactive iodine therapy - avoid
avoid in pregnancy → fetal goiter
Toxicity:
- Iodism is rare & reversible upon discontinuance
- acneiform rash, swollen salivary glands, mucous membrane ulcerations, conjunctivitis, rhinorrhea, drug fever, metallic taste, bleeding disorders, anaphylaxis.Radioactive iodine
Iodotope, Sodium Iodide I131 Therapeutic- 131I - the only isotope used for treatment of thyrotoxicosis
- Admin. orally as Na131I soln; dose (80-120 μCi/g)
- rapidly absorbed & conc. by the thyroid
- incorporated into storage follicles
MOA:
- emission of β particles (t1/2 ∼ 5 days) destroys the thyroid parenchyma within a few weeks
- 6 - 12 wks of treatment shrink gland size → euthyroid or hypothyroid (80%) → HRT with levothyroxine; Monitor serum FT4 & TSH levels
Advantages
- easy admin., effectiveness, less expensive, & absence of pain.
- Avoid in pregnant women or nursing mothersBeta adrenoceptor blocking agents in thyroid disease- β-adrenoceptor-blocking agents without intrinsic sympathomimetic activity (eg, metoprolol, propranolol, atenolol) are effective therapeutic adjuncts in the management of thyrotoxicosis
Propranolol (Inderal)
- 20 - 40 mg, 4 qid reduces some of the thyrotoxic manifestations (e.g., tachycardia, sweating, severe tremor, nervousness) of hyperthyroidism.
- high doses (>160 mg/day) inhibit peripheral conversion of T4 to T3
- β blockers - primary adjunct therapy to RAIWhat is the reference range in hypothyroidism?- TSH: 0.4-4.5 mIU/mL
- Free T4: 0.8-1.4 ng/dL
- If your lab says differently use your lab.When should you treat hypothyroidism?- TSH ≥ 10 mIU/L: treat
- TSH 4.5 - 10 mIU/L: ?
- Recommendation: Treat levels ≥ 10 mIU/L and only treat levels 4.5 - 10 mIU/L if symptomatic or have CVD, ACS or HFWhat medications should you treat a pt with hypothyroidism?LevothyroxineFor a healthy patient who is <50yo with hypothyroidism, what dose should you use?1.6mcg/kg/day
Dose titration: 12.5-25 mcgFor a patient with subclinical hypothyroidism, CVD or is Elderly with hypothyroidism, what dose should you use?25-75 mcg/day
Dose titration: 12.5-25 mcgWhen and what should you measure for a patient with hypothyroidism?Hypothyroidism:
TSH:
- 6-12 weeks to normalize
- Annually at minimum
Free T4:
- For diagnosis
w/ dose changes
Hyperthyroidism:
Initial: T4 q 4 weeksWhat are some pt counseling points when using Synthroid?- In the morning 30-60 minutes before any consumption(HOWEVER: If pt. is not compliant, they are asymptomatic and have normal levels, they can continue.)
Many DI's - take at least 4 hours after levothyroxine:
- Calcium-containing products: Tums, dairy products, supplements
- Aluminum-containing products
- Multivitamins
- Iron-containing products
- Many various drugs (E.g. ciprofloxacin)What is used for symptomatic treatment in hyperthyroidism?Beta blockers. They treat:
- Muscle Weakness
- Tremor
- Irritability
- Emotional Lability
- Exercise Intolerance
e.g. propranolol, atenolol, metoprololWhat is the dose for propranolol in hyperthyroidism?- 10-40 mg TID-QID
Considerations:
- Nonselective
- Longest experience
- May block T4 to T3 conversion at ↑ dose
- Preferred agent for nursing mothersWhat is the dose for atenolol in hyperthyroidism?- 25-100mg QD-BID
Considerations:
- Relative beta-1 selectivity
- ↑ complianceWhat is the dose for metoprolol in hyperthyroidism?- 25-50 mg QID
Considerations:
- relative beta 1 selectivityWhat is the dose for methimazole?Initial Treatment: 10-20 mg daily
Maintenance Dose: 5-10 mg dailyWhat is the dose for PTU?Initial Treatment: 50-150 mg TID
Maintenance Dose: 50 mg BID-TIDWhat are some patient counseling points with PTU or MMI?- Adherence is very important. #1 reason patients do not achieve euthyroid!
- If GI upset, take with food
- Signs of liver damage (especially with PTU)
- 12-18 months of treatment (regardless of how they feel)While the overall use of specialty pharmacy is less than 2% of the US population, specialty drugs accounted for _____________________.55% of the US drug spend in 2021What is specialty pharmacy?Pharmacies that focus on medications that are high in cost, for complex disease, have high touch therapy, and are cutting edge products.What are specialty drugs?- Require special handling, preparation & storage
- Expensive! - CMS threshold is $670 per month
- Restricted access - limited distribution networks - manufacture can pick and chose who carries their medication
- REMS programsWhat are specialty diseases?Autoimmune conditions:
- Ankylosing spondylitis
- Atopic dermatitis/eczema
- Crohn's disease
- Lupus
- Multiple sclerosis
- Psoriasis
- Rheumatoid arthritis
- Ulcerative colitis
- Asthma
- Cancer
- Epilepsy
- Fertility
- Hemophilia
- Hepatitis C
- HIV
- Migraines
- Organ transplant
- Rare genetic disorders
All speciality pharmacist will serve a mix of the conditions above. Most do something in the autoimmune category.Specialty pharmacy typesPayer/PBM owned: (biggest majority in US - PBM own 60%+ of the Market share)
- CVS Specialty
- Accredo
- Optum
- AllianceRx Walgreens - Prime
- Acaria
- Humana
Ultra specialized:
- PANTHERx Rare (rare genetic diseases)
- Onco360
- Diplomat (oncology)
Health system owned:
- most major healthy systems
Everyone else:
("independent specialty pharmacy bc they aren't owned by PBM or health systems)
- Amber Pharmacy/ Hy-Vee
- Meijer
- Walmart
- Kroger
- US Bioservices
- SenderraWhat is vertical integration?the combination in one company of two or more stages of production normally operated by separate companies. This allows the company to keep the money in their own pockets.What is the centralized services hub in specialty pharmacy?This is where most of the patient. contact happens. It consists of call center staff. This is typically where all insurance and billing takes place. Financial assistance team works here as well. Most hubs also have clinical pharmacist to counsel pts.
- Patient contact
- Insurance authorization
- Financial assistance
- Clinical interventionsWhat are dispensing sites at specialty pharmacies?These sites are responsible for shipping and fulfillment. mostly techs and pharmacist work here. Prescriptions are mailed out from here. Pharmacist also do clinical interventions as well here.
- Product fulfillment
- Shipping
- Clinical interventions
- Typically not open to the publicWho is apart of the interdisciplinary team in specialty pharmacy?- Pharmacist
- RN (mostly do insurance things)
- Registered dietitians (because we are not only focusing on meds eps in autoimmune diseases)
- Pharmacy techs
- Patient services coordinators
- Financial aid coordinators
- Shipping techs
- Social workersWhat are the five groups at the core of speciality pharmacy?Patient
Prescriber
Pipeline
Pharma
PayerHow is patient intake handled in specialty pharmacy?Prescription received via:
- E-prescription
- Paper prescription
- Verbal order
- Referral form - are usually done by disease state
Includes clinical information - chart notes, diagnostic tests, imaging results, etc.Benefits investigation in specialty pharmacyPA - Providing additional clinical information to the insurance company to justify the patient's use of a non-formulary medication.
Appeals: Providing EVEN MORE clinical information to justify the patient's use of a non-formulary medication (after a PA is denied)What is a copay card?- Typically only for commercial coverage (no Medicare/Medicaid)
- Lower copays/out-of-pocket costs
- Paid for by drug manufacturers
- Have annual $ limitsWhat is a bridge program?- Provide free or low-cost medication while insurance coverage is being secured
- Paid for by drug manufacturers
- Have lifetime limits
Con: When pt hits lifetime limit, even if the medication is working, the insurance can say no to covering the med.What are grants/foundations in specialty pharmacy?- Advocacy groups that provide funding to qualifying patients
- Typically for low-income patients
- Limited funding available - first
come, first served
- Not funded by manufactures, but independent groups
- funds are usually used up within a couple of hrsRx interventionsWhat is first fill counseling?In-depth session, covering:
- Disease education
- Medication, dose, proper use & self-administration instructions
- Duration of therapy
- Timely administration or intake
- Adverse events & mitigation strategies
- Warnings, precautions & contraindications
- New or changed medications
- Safe handling, proper storage & disposal
- Expectations & possible outcomes of therapy
- VaccinesWhat is disease activity monitoring?used to make sure pts are being treated properly and to make interventions prnWhat is holistic care interventions?- Drug therapy is a big piece of treatment, but it is not the only piece. We lean into having registered dietitian on board esp to help with autoimmune conditions.
- Pharmacologic interventions paired with nutrition interventions to support symptom management for patients with specific chronic illnesses treated through specialty pharmacies
Focus on anti-inflammatory diet:
- Rich in fruits, vegetables, whole grains, nuts, beans & fish
- Contains healthy fats
- High in omega-3 fatty acids
- Low in saturated and trans fats
- Has adequate fiber
- Low levels of added sugars
- Encourages intake of probiotics and prebiotics
- Limits processed foods, red meats and alcoholShipment of specialty drugs- Strict temperature and time requirements
- Requires weather monitoring: Summer and winter protocols
- Many specialty pharmacies contract with rescue services to recover packages delivered to the wrong address or otherwise lost
- Pack outsWhat are Limited distribution drugs?Therapies only made available to a small number of pharmacies.
Why?
- Greater control & oversight from manufacturers
- Closer patient relationships with prescribers and pharmacists
- Ensures only highly-trained clinical staff are dispensing medications and supporting patientsHow do manufacturers choose pharmacies to be part of their LDD network?- Clinical expertise
- Disease-specific care coordinators
- National accreditation
- Medication adherence tools and support services
- Insurance coverage services
- Ability to provide data
- Payer accessWhat is pipeline monitoring?- Monitoring pipeline to identify opportunities for preferred drug strategies based on the likely place in therapy of a new product.
- Looking at: Will the medication get approved? and What drug class and disease will this medication treat?Enhanced services programs: ServicesProviding additional services (outside of the pharmacy's normal operating procedures) for an additional monetary fee
- Bridge enrollment/dispensing
- Drug start programs
- Adherence programs
- Manufacturer HUB enrollment
- Pharmacy transfer follow-upEnhanced services programs: Data- Providing in-depth data reporting to a manufacturer
- Manufacturers want to track trends with their products to enhance profits (and patient care)
- All data is deidentified and aggregated
Data:
- time on therapy and time to fill
- Patient demographics
- Insurance info and copays
- Prior authorization and requirements
- Reasons for discontinuing therapyWhat are the five social determinants of health in diabetes?1. Socioeconomic status (education, income, and occupation)
2. living and working conditions
3. multisector domains (housing, education, criminal justice system)
4. sociocultural content (shared cultural values, practices, experiences
5. sociopolitical content (societal and political norms that are root-cause ideologies and policies underlying health disparities)What is the diabetes diagnostic criteria?- FPG ≥ 126 mg/dL on two separate tests (same sample ok)
- Symptoms of hyperglycemia and a casual plasma glucose ≥ 200mg/dL
- A1C ≥ 6.5%, confirmed with repeat test (same sample ok)
Clinical lab test ( preferred over POC)
- 2hr plasma glucose ≥ 200 during OGTT*
Gestational DM uses OGTTWhat are the normal, prediabetic, and diabetic A1C scores?- Normal is < 5.7%
- Prediabetes 5.7-6.4%
- Diabetic ≥ 6.5What are the diagnostic parameters of prediabetes?- Pts with FBG (100-125) or PPG (2hr between 140-199) or A1c 5.7-6.4%
- Re-test A1c annuallyHow much should a person with pre diabetes diet and exercise?- Target 5-15% body weight loss
- 150 minutes/week moderate activity
- Resistance training 2 x per week
- Limit sugar beverages
- Fiber 14g/1000kcal
- Limit sedentary time (up every 30 min)
Follow-up counseling important
for success
Self-management goalsWhat considerations should be taken in pre diabetics who are high risk?- Metformin may be considered in "high risk" pts. Although, it is not as effective as lifestyle changes in preventing diabetes, but the most benefit is seen in high risk pre diabetics.
High risk individuals:
- BMI >35
- Age < 60 yrs
- Hx of GDMWhat are the goals for T2DM patients?Before meals: 80-130 mg/dl (ADA)
2 HR PP: <180mg/dL (ADA)
A1C: <7% (ADA)
Need to individualize:
Pregnancy
Elderly
Children
Hypoglycemia unawareness
Poor control (hypo/hyperglycemia)
- If a patient's A1C is close to 7, our target is PPG. If pt's A1C is significantly higher, we target FBG.Therapy for Type 2 DM: At time of diagnosis- Metformin (unless CI) + lifestyle (Medical Nutrition Therapy and exercise)
- Consider combination therapy with A1c >1.5% over target
- If comorbidities, use appropriate agents regardless of A1cTherapy for Type 2 DM: Newly diagnosed with symptoms and marked elevated BG or A1cInsulin therapy +/- additional agentsTherapy for Type 2 DM: If non-insulin monotherapy at max dose does not achieve A1c target over 3 months, add:- Second oral agent
- GLP-1 agonist (preferred injectable over insulin)
- InsulinMetformin pharmacotherapy in T2DM- Metformin is the preferred initial pharmacologic agent for the treatment of type 2 diabetes
- Once initiated, metformin should be continued as long as it is tolerated and not contraindicated; other agents, including insulin, should be added to metformin.
- Early combination therapy can be considered in some patients at treatment initiation to extend the time to treatment failureWhen should the early introduction to insulin be considered?The early introduction of insulin should be considered if there is evidence of ongoing catabolism (weight loss), if symptoms of hyperglycemia are present, or when A1C levels (>10%) or blood glucose levels (≥300 mg/dL) are very high.Metformin- Traditionally recommended as first-line glucose-lowering therapy for type 2 diabetes, because of its high efficacy in lowering HbA1c, minimal hypoglycaemia risk when used as monotherapy, potential for some modest weight loss, good safety profile, low cost
- MOA: insulin sensitivity,Lowers the production of glucose made in the liver (decrease gluconeogenesis)Metformin PharmacotherapyEfficacy: High
Hypoglycemia: No
Weight Change: Neutral - potential for modest loss (2-5kg loss)
Effect on MACE: Potential benefit
HF benefit: neutral
Progession of DKD(Diabetic kidney disease): neutral
Renal dose considerations: CI with eGFR <30ml/min per 1/73m^2
Route: Oral
Cost: low
Lipid Levels: ↓TG, LDL, ↑HDL
Consult on: Diarrhea, nausea, flatulence, bloating (If these problems are too much, try XR (remember to titrate dose to max dose).)
- Lactic acidosis 0.03 per 1000 pt/years (pts with low eGFR or liver issues are at risk)What is the starting dose of metformin?Start 500 QD or BID, titrate weekly. Max effective dose is 2g per day.
- take with meals, divide doseMetformin side notes- Stop before surgery or x-ray studies with iodinated contrast (radio contrast dye). Resume in 48 hours after checking creatinine (after SCr returns to normal)
- Particularly, for people with an eGFR Less than sixty, you are supposed to stop metformin prior to having any contrast.
- Use XR for patients who have quit it previously due to GI side effects or pts suffering from the GI side effects (XR may decrease side effect 40-50%)
- Side effects: metallic taste, B12 deficiency
- BMP annually (Scr, GFR) or q3 (eGFR is close to 45 or 30) to 6(if eGFR < 60), Vitamin B12 every 1 to 3 years (unless they have symptoms of anemia or neuropathy), A1c q 3(if A1C is not at goal) to 6 (if A1C is at goal) mo, fasting glucose periodicallyMetformin pros and consPros:
- Oral (First line)
- A1c reduction 1.5-2% (High)
- FBG control
- No hypoglycemia
- Durable action
- Weight neutral/ loss
- Clinical benefits:
Decrease macrovascular risk
Improved lipids
- Low Cost
Cons:
- SE's: Diarrhea, nausea, bloating
- Renal accumulation
- B12 deficiency
- Pts at risk for acidosis
- Additional Concerns (heavy alcohol use, uncomp HF)What are the renal adjustments for metformin?- Normal eGFR <60: 2g (no benefit in going higher)
- eGFR = 30 - 45: max dose is 1g
- eGFR <30: stop metformin completelyWhat medication is a good use when a patients A1C is above 9, and it needs to be dropped quickly for surgery? What happens if someone is given surgery while their A1C is above 9?- Sulfonylureas(works within a wk) and insulin
- A pt cannot get surgery because there will be an increase in infections and a decrease in healing.Sulfonylureas PharmacotherapyEfficacy: High
Hypoglycemia: Yes
Weight Change: gain
Effect on MACE: neutral
HF benefit: neutral
Progession of DKD(Diabetic kidney disease): neutral
Renal dose considerations: Glyburide generally not recommended in CKD; Glipizide and Glimepiride: initiate conservatively to avoid hypoglycemia
Route: Oral
Cost: low - used for no insurance, cheap. and they work fast - A1C will decrease really quickly
MOA: Stimulate the pancreas to release more insulinSulfonylurea- High glucose-lowering efficacy, inexpensive and accessible
- A heterogenous group - sulfonylureas with lower risk of hypoglycaemia to be selected when considered for therapy
- No difference in the incidence of MACE in patients at high CV risk treated with glimepiride or linagliptinSulfonylureas side notes
- 50 years of experience
- Non-obese patients
- Affect FBS, some help with PPG
- D/C when patient starts bolus insulin Or sooner...
-Start low, go slow (evaluate weekly)
+ Hypoglycemia 4-6 hours after taking - Especially if skip meals
- Max effective dose: ½ stated maximum dose
- People need to eat regularly during the day, or they will become hypoglycemic.
- helps the most with FBG and some PPG
Monitor:
- Hypoglycemia
- weight gain
- fasting glucose
- A1c q 3 to 6 mos
- BMP ( for eGFR - Scr and K+) at least annually, more often if eGFR <60)What are the renal adjustments for sulfonylureas?Know: If the eGFR<50 for any of the SU drugs, you might want to think about Is the dose right.Sulfonylureas pros and consPros:
- Oral
- A1c reduction 1.5% (High)
- FBG control > PPG
- Rapid onset to effect - Few days to weeks
- Cheap
Cons:
- Hypoglycemia
- Weight gain
- Caution in elderly
- Caution in renal impairment
- CI if hepatic failure
- Cardiovascular risk?
- Not sustainable effect
- Additional ConcernsThiazolidinediones (TZDs)- High glucose-lowering efficacy, durability of glycaemic effect
- Beneficial effects in MACE seen with pioglitazone
- Side effects (e.g. weight gain, fluid retention) can be mitigated by using lower doses) and combining therapy with other medications (SGLT2 inhibitors, GLP-1 RA) that promote weight loss and sodium excretionTZD PharmacotherapyEfficacy: High - takes. while to work
Hypoglycemia: no
Weight Change: gain
Effect on MACE: Potential benefit pioglitazone
HF benefit: increase
Progession of DKD(Diabetic kidney disease): neutral
Renal dose considerations: No dose adjustment required; generally not recommended in renal impairment due to potential for fluid retention
Route: Oral
Cost: low
Lipid levels:↓TG, ↑HDL
MOA: Direct insulin sensitizer; increase glucose disposal and decrease gluconeogenesisWhat is the dosing for pioglitazone?- 15mg-30 QD initially ↓A1C 1-1.5% (High)
- Titrate dose every 12 wks based on A1C response
- Takes ≥6 weeks for full impact
- Always use a lower dose no more than 30mg a dayTZD side notesAdverse Effects:
- Edema, dyspnea
- Weight gain (dose related)
- Redistribution of fat
- Hepatotoxicity
- Lipids
- Bone loss:
- Reduce osteoblast, increase calcium excretion
- Bladder cancer? ( > 2yrs)
Monitoring:
- Fasting blood glucose
- Weight
- Heart Failure (BBW) pulmonary edema - s/sx HF, increase BNP, weight
- Peripheral edema (dose related)
- A1C
- AST/ALT (measured of liver disease - especially reasonable if pt already has liver issues)
+ Baseline
+ Annually thereafter
+ Pts with liver disease: Every 3-6 mos x 1 yr; Annually thereafterTZD pros and consPros:
- Oral
- Insulin sensitizer
- Cheap
- A1c reduction 1.5% (High)
- FBG control>PPG
- Sustained glucose control (5 years)
- ↓ CV risk (pioglitazone)
- Low risk hypoglycemia
Cons:
- Edema, CHF
- Weight gain
- CI if hepatic failure
- Slow onset to action (4-6 weeks)
- Additional Concerns
+ Fracture risk in women
+ slight increase risk of bladder cancer if used for over 2 yrsDPP-4 inhibitors- Intermediate glucose-lowering efficacy, neutral effect on weight, generally well tolerated, minimal risk of hypoglycaemia
- Early combination treatment with metformin and a DPP-4i (vildagliptin) increased glycaemic durability compared to stepwise approach to therapy
- Cardiovascular safety demonstratedDPP-4 inhibitors pharmacotherapyEfficacy: intermediate
Hypoglycemia: no
Weight Change: neutral
Effect on MACE: neutral
HF benefit: neutral
Progession of DKD(Diabetic kidney disease): neutral
Renal dose considerations: Renal dose adjustment required (sitagliptin, saxagliptin, alogliptin); can be used in renal impairment; No dose adjustment required for linagliptin
Route: Oral
Cost: high
MOA: Dipeptidyl Peptidase 4 inhibitor-slows the inactivation of GLP-1 and GIP ;
↑ glucose-dependent insulin release; Decrease hepatic glucose production and releaseWhat DPP-4 inhibitors can increase risk of heart failure hospitalizations?Saxagliptin and alogliptinDPP-4 inhibitors side notes
Mono or comb tx with metformin, TZD, sulfonylurea, SGLT2, insulin
- Weight neutral
- PPG
- Usually 0.6-0.8% A1c reduction (Intermediate)
- May need to decrease secretagogue dose
- CHF (SAVOR TIMI-53)
- Hospitalization risk saxagliptin
- BNP, HF, CKD
- Not seen in sitagliptin (TECOS)
- Pt population
Monitoring:
- Post-prandial bg
- A1C q 3 to 6 mo
- Renal function (Scr, GFR )- Annually - More frequent if eGFR<60
- Sx of heart failure: Wt gain, dyspnea, etc.
- Sx of pancreatitis: Mod to severe abd pain; Abd pain after eating
Adverse events:
- URI: DPP-4 in lymphocytes
- Pancreatitis? (along with GLP-1)
- Severe arthralgia
- Great to use if you have an older person with renal dysfunction that we're worried about hypoglycemia and is also close to their target.
- Some people have joint pain with these that goes away in 3-4 wks once they stop using it.Linagliptin (Tradjenta)- 5mg
- No dose adjustment needed for renal impairment
- Only 5% renal excretionDPP-4 inhibitors Pros and ConsPro:
- Oral agents: QD dosing
- A1c reduction ~ 1%
- PPBG > FBG control
- Well tolerated
- Weight neutral
Clinical benefits:
- CKD/ESRD
- Elderly
- Additional benefits: Beta cell preservation?
Cons:
- FDA Warnings: Severe arthralgia, pancreatitis
- Upper respiratory infections
- Hypersensitivity reactions
- Cost
- Additional Concerns: Cardiovascular effects?Oral GLP-1 Receptor Agonist
- Semaglutide approved September 2019
- Rybelsus (3mg,7mg,14mg)
- take at least 30 min before first food, beverage, or other oral meds of the day with ≤4 oz of plain waterSGLT2 inhibitors- Glucose-lowering mechanism of action: Reduce renal tubular glucose reabsorption
- Clinical Efficacy Profile: Intermediate to high glucose-lowering efficacy, lower at lower eGFR; low inherent risk of hypoglycaemia; intermediate weight loss
- Cardiorenal Effects: Demonstrated protective effects in studied trial populations:
+ Reduction in major adverse cardiovascular events
+ Reduction in overall CV death (with heterogeneity across the class)
+ Reduction in risk of hospitalisation for heart failure
+ Reduction in risk of kidney outcomes
- Increased confidence surrounding safety issues of interestSGLT2 inhibitors pharmacotherapyEfficacy: intermediate to high
Hypoglycemia: no
Weight Change: loss (intermediate) - 2-3 kg (Plateau at 26 weeks); Initial fluid loss, then decrease fat mass
Effect on MACE: Benefit: Canagliflozin; empagliflozin (a protective effect for people at very high risk of having a heart attack or stroke)
HF benefit: Benefit: canagliflozin, dapagliflozin, empaglifozin, ertugliflozin
Progession of DKD(Diabetic kidney disease): Benefit: canagliflozin. dapagliflozin, empagliflozin
Renal dose considerations: see labels for renal dose considerations of individual agents; glucose-lowering effect is lower for SGLT2 inhibitors at lower eGFR
Route: Oral
Cost: high
MOA: Increase glucose excreted in urine-- ↓BG, ↓A1C
Other: May decrease systolic BP (5-7mmHg), TGWhen should SGLT2 be avoided?- Don't start if eGFR <20ml/min/1.73m2*
- For glucose lowering, avoid if eGFR,45ml/min - need eGFR of 50 to see glucose lowering.SGLT2 side notesAdverse effects:
- Genital mycotic infections ( 11-14% vs 2% glimepiride)
- Euglycemic ketoacidosis
+ Especially on exogenous insulin (most in Type1DM)
+ Surgery, AMI, prolonged fasting, other stressors
+ DKA rates of 0.1-0.6% compared with rates of <0.1-0.3% with placebo
- Fracture ?
- Amputations?
- Hyperkalemia ,hyponatremia
- Hypotension/dizziness
+ Caution elderly on diuretics, pts on loop diuretics
+ Caution other volume-depleted states
Monitoring:
- Dose titration
- BG, A1c q 3 to 6 mos: May require dose decrease of insulin or secretagogue
- BP
- Scr, eGFR, Na+ and K+ (BMP): Baseline, 4 weeks and At least annually; Q3-6 months as patients approach cutoffs or dehydration concerns
- PTH (bone loss)
- Urinary infections (yeast and UTIs)/ Fournier's gangrene(Females > males)
- Check feet
- Optimal glucose lowering is at max dose.
- This medication can cause a bump in eGFR (increase K+ and Scr). ACEs/ARBs do this as well. We accept that there will be a less than 30% increase in eGFR. If there is more, we need to check out other things as well such as acute kidney issues.What is euglycemic ketoacidosis?Ketoacidosis in the setting of normal or near-normal blood sugars. It develops at sugar even less than 200. This is why we don't use SGLT2 inhibitors in T1DM in the USA. Most of the time, this happens during periods of high stress on the body. This is also why we stop SGLT2 3 days before surgery.SGLT2 inhibitors pros and consPros:
- Oral QD dosing
- A1c reduction ~ 1%
- Weight loss
- Low risk of hypoglycemia
- CV mortality benefits (empaglifozin/ canagliflozin)
- CHF, CKD benefits
- Indirectly improve insulin sensitivity
Cons:
- FDA Warnings: Euglycemic ketoacidosis; Bone fractures (canagliflozin)
- UTIs & genital infections
- Do NOT use in ESRD/dialysis (CI GFR<20)
- Caution in elderly: Hypotension, esp with loop diuretic
- Amputations (canagliflozin)GLP-1 agonists adverse effectsAdverse effects:
- N/V "fullness"
+ Lessens over time (within 6 weeks)
+ Smaller meals, less fat
- Hypoglycemia
(with secretagogues or insulin)
- Reduce rate/extent of orally admin drugs
Monitoring:
- FPG, PPG periodically
- A1c every 3 to 6 months
- Scr, GFR (at least annually)
- Symptoms of pancreatitis
- Injection site reactions ( if applicable)GLP-1 receptor agonist- Glucose-lowering mechanism of action: Augment glucose-dependent insulin secretion & glucagon suppression, decelerate gastric emptying, curb post-meal glycemic increments, reduce appetite, calorie intake and body weight
- Clinical Efficacy Profile: High to Very High glucose-lowering efficacy, low inherent risk of hypoglycemia; intermediate to high weight loss
- Cardiorenal Effects: cardioprotective, with evidence of reduction in major adverse cardiovascular events, CV death, fatal or non-fatal MI, fatal or non-fatal stroke, all-cause mortality, composite kidney outcome driven by macroalbuminuria
- Increased confidence surrounding safety areas of interestGLP-1 RA Pros and COnsPros:
- Efficacy: A1c ~1-1.5%
PPG > FBG: Exenatide
FBG and PPG: Longer acting
- Weight Loss
- Low risk of hypoglycemia
- Insulin dose reduction
- Long Acting: Compliance,
- Use in CKD
- CV Benefits-liraglutide, ozempic, trulicity
- Delayed disease progression?
- Beta cell preservation?
Cons:
- FDA Warnings: Kidney failure, pancreatitis, thyroid c-cell cancer
- Prescriber unfamiliarity
- N/V/D , constipation
- Nodules
- Gastroparesis
- Injectable
- CostGLP-1 RA pharmacotherapyEfficacy: high to very high
Hypoglycemia: no
Weight Change: low (intermediate to very high)
Effect on MACE: Benefit: dulaglutide, liraglutide, semaglutide (SQ); Neutral: eventide once weekly, lixisenatide
HF benefit: neutral
Progession of DKD(Diabetic kidney disease): Benefit for renal endpoints in CVDTs, driven by albuminuria outcomes:dulaglutide,liraglutide,semaglutide (SQ)
Renal dose considerations: see labels for renal dose considerations of individual agents; no dose adjustment for dulaglutide, liraglutide, semaglutide; monitor renal function when initiating or escalating doses in patients with renal impairment reporting severe adverse GI reactions
Route: SQ: oral (semaglutide)
Cost: high
MOA: Increase glucose excreted in urine-- ↓BG, ↓A1C
Other: secondary option if pt cannot handle a SGLT-2How do you titrate Victoza (Liraglutide) dosing?0.6,1.2,1.8mg
Without regards to meals, titrate at 1 week
QDWhich GLP-1 agonist should not be used if eGFR <30?ExenatideGlucose-dependent insulinotropic polypeptide (GIP) receptor and GLP-1 receptor agonist (tirzepatide) pharmacotherapyMounjaro
Efficacy: very high
Hypoglycemia: no
Weight Change: loss (very high)
Effect on MACE: under investigation
HF benefit: under investigation
Progession of DKD(Diabetic kidney disease): under investigation
Renal dose considerations: see labels for renal dose considerations of individual agents; no dose adjustment; monitor renal function when initiating or escalating doses in patients with renal impairment reporting severe adverse GI reactions
Route: SQ
Cost: highGlucose-dependent insulinotropic polypeptide (GIP) receptor and GLP-1 receptor agonist (tirzepatide)- Glucose-lowering mechanism of action: GIP receptor and GLP-1 receptor agonist; enhances first and second-phase insulin secretion, and reduces glucagon levels, both in a glucose-dependent manner
- Clinical Efficacy profile: Very high glycemic efficacy; low inherent risk of hypoglycemia; weight loss (high); cardiorenal effects unknown (trials in progress)Glucose-dependent insulinotropic polypeptide (GIP) receptor and GLP-1 receptor agonist (tirzepatide) pros and consPros:
- Efficacy: A1c ~2%+
- FPG and PPG
- Superior weight Loss
- Low risk of hypoglycemia
- Insulin dose reduction
- Long Acting: Compliance
- DM remission?
Cons:
- FDA Warnings: Kidney failure, pancreatitis, thyroid c-cell cancer
Prescriber unfamiliarity
- N/V/D , constipation
- CV Benefits?
- Gastroparesis
- Injectable
- CostInsulin- Advantage of lowering glucose in dose-dependent manner, able to address any level of glycaemia
- Clinical Profile: High to very high glycemic efficacy, increased risk of hypoglycemia and weight gain; neutral cardiorenal profile
- Efficacy and safety are largely dependent on education and support to facilitate self-management
- Importance of matching insulin to physiologic needInsulin Use in T2DM- Consider as initial tx (with metformin) if BG > 300mg/dL or A1c 10-12% [Especially if symptoms of hyperglycemia/ wt loss]
- Basal:
+ Usually initial dose 0.1-0.2 units/kg body weight
+ Depends on degree of hyperglycemia
+ T2DM pts may need higher doses ( higher wt and insulin resistance)
+ Titrate!
* 2-4 units (10%) every 3-7 days
* If hypo, ↓ 4 units or 10-20% dose
- Basal + 1 injections (start with 4 units prandial)
- Basal + GLP-1
- Basal + ≥ 2 injections
- Avoid "sliding scale"Insulin in T2DM continuing non insulin drugs- Continue metformin unless CI
- Secretagogues (Sulfonylureas) are stopped after basal/bolus or split/mixed
- Caution with TZDs: Edema, CHF, weight gain, ↓insulin requirements
- GLP-1 agonists
- Addition of pioglitazone or GLP-1↓ insulin requirementsPatient education of insulin in T2DM- SMBG (check fasting for basal, before meals and bedtime for bolus) or CGM
- diet /exercise, Monitor weight
- Hypoglycemia & treatment
+ Rule of 15s
+ Increased risk with split/mixed , NPH, Regular insulin
- Converting between products ( 100u/mL, 200u/mL, 300 u/mL 500 u/mL)
- Sick daysAfrezza- Inhaled insulin
+ Available in 4u,8u, 12 u blister packs
+ Ultra rapid acting (peak 12-15 min, duration 180 min)
- CI in asthma/COPD/ smokers
- Storage/replacement requirements
- Monitoring (in addition to SMBG):
+ Hypo, cough, throat irritation, acute bronchospasm
+ Spirometry(FEV1) :baseline, 6 months, and 12 months and then yearly. If FEV1 drops ≥ 20% from baseline, consider discontinuationGLP-1 have multiple beneficial effects on defects in T2DM. GLP titration and patient counseling is key. But, GLP-1 agonist are the preferred injectable over insulin except when?Marked A1c elevation with symptoms (>10% with polyuria, polydypsia,wt loss, etc)What is the basal insulin starting dose for T2DM?- 0.1-0.2 u/kg/day
- Increase by 2 to 4 units every 3 to 7 days or 10% until fasting glucose at goal
- Start bolus or GLP-1 once basal dose is > 0.5- 0.7-1u/kg/day or a1c not at goal despite FBG goals metCombination Therapy in T2DM- Increased durability of glycemic effect, potential to address therapeutic inertia
- Simultaneous targeting of multiple pathophysiologic processes characterized by type 2 diabetes
- Potential impact on medication burden, adherence, and treatment persistence
- Complementary clinical benefits (glycaemia, weight, cardiovascular risk profile)What is the dosing of Meglitinides - Prandin(repaglinide); Starlix(nateglitinide)?- Taken up to 30 min before meal, up to TID
- If skip meal, skip dose
- Max effective dose: ½ dose repaglinide, max dose nateglinide
- if A1c < 8% take 0.5 or 60, if >8% take 1 or 120What are the DI in Prandin(repaglinide) and Starlix(nateglitinide)?- Repaglinide: CYP 3A4
- Nateglinide: CYP 3A4, 2C9, protein boundMeglitinides - Prandin(repaglinide); Starlix(nateglitinide) pros and consPros:
- Oral
- A1c reduction 0.5-1%
- PPG control>FPG
- Weight neutral/ loss
- Rapid on and off
Cons:
- Hypoglycemia (less than SU)
- Weight gain
- TID dosing adherence
- Cost
- Drug interactions
- Cardiovascular risk
- Additional Concerns?
+ Beta cell burnout
+ hyperinsulinemia
Other:
- Short onset and short half-life
- Affects post-prandial glucoseAlpha-Glucosidase Inhibitors CI, monitoring, and Adverse effectsContraindications
- SCr >2mg/dL
- Cirrhosis
- IBD
- Pregnancy
Monitoring
- PPG periodically
- A1C q 3 to 6 mo
- AST/ALT (Baseline, 3mo, 6mo)
Adverse Effects
- GI upset
- Improves with time
- ↑ LFTs ( 2-8 months)What are some patient counseling points for Acarbose?- Take with 1st bite of meal
- If skip meal, skip dose
- Flatulence, diarrhea and abdominal pain are primary side effects
- Decrease intake of complex sugars
- Keep lab appointments (AST/ALT, A1C, )
- If hypoglycemia occurs:Must use glucose tablets or gel, NOT juice, candy or other complex sugars
- SMBG? Post-prandialBromocriptine- Cycloset 0.8mg tabs
- MOA: sympatholytic D2-dopamine agonist - "re-sets" biological clock to improve metabolism
- Administration QAM within 2 h of awakening
- Monitoring: fasting bg, A1c, BP
- Low A1c loweringBromocriptine Pro and ConsPros:
- Oral
- PPG > FBG lowering
- BP lowering
- Weight neutral
- Adherence- QD
- Cardiovascular benefit?
Cons:
- Low Efficacy: A1c ~0.6%: Limited use
- Hypotension, dizziness
- Adverse effects: Nausea; Asthenia
- Interactions
- CostColesevelam (Welchol)- Use limited
- Constipation
- Nausea, bloating
- ↑ TG
- Drug interactions
- Monitoring FBG, PPG, A1c, lipid panelColesevelam (Welchol) Pros and consPros:
- Oral
- No hypoglycemia
- Weight neutral
- ↓LDL
Cons:
- Constipation
- Nausea, bloating
- ↑TG
- Modest Efficacy
- Several drug interactions
- Pill burden ( 6 tabs QD)
- Large tablet size
- ExpensiveCombination products in T2DM Pros and ConsPros:
- Decrease pill burden
- Decrease Inj burden
- May improve adherence
- May decrease patient copays (cost)
Cons:
- Difficult to titrate
- May increase cost in some situations (especially with generics or $4 plan drugs available)OverbasalizationClinicians should be aware of the potential for overbasalization with insulin therapy. Clinical signals that may prompt evaluation of overbasalization include basal dose more than ~0.5 IU/ kg, high bedtime-morning or post- preprandial glucose differential, hypoglycemia (aware or unaware), and high variability. Indication of overbasalization should prompt reevaluation to further individualize therapy. For example, adding a bolus insulin or if not already on GLP-1, add a GLP-1.If someone has hypoglycemia on acarbose (alpha glucoside inhibitor) would do you give them?Glucose or glucagonWhat is the brand name name of insulin glargine?LantusWhat is the brand name of sitagliptin?JanuviaWhat is the brand name of dapagliflozin?FarxigaWhat is the generic name of dulaglutide?TrulicityWhat is. the brand name of semaglutide?Ozempic, RybelsusWhat are some lifestyle changes in T1DM?- Carbohydrate counting education
- A consistent pattern of carbohydrate intake with respect to time and amount can result in improved glycemic control and a reduced risk of hypoglycemia
- Children: exercise at least 60 minutes per day
- Adults: exercise at least 150 minutes per week( Moderate intensity aerobic activity over at least 3 days/week with no more than 2 consecutive days without exercise)
- Reduce sedentary time
Break up extended amounts of time (>30 min) spent sitting
- Advise all patients not to use cigarettes or any tobacco products
- Offer smoking cessation counseling and treatment as a routine component of diabetes careWhat are the glycemic goals for most adult/pediatric T1DM pts?- A1C <7%
- FBG 80-130 mg/dL
- 2 hr PPG <180 mg/dL
- Pre exercise 90-250 mg/dLWhat are the glycemic goals for most pregnant diabetic pts?- A1c <6% (ideally)
- FBG <95 mg/dL AND
- 1hr PPG <140 mg/dL
- 2hr PPG <120 mg/dL
- may have to test between 7-16 times per day
- CGM is recommendedMedication management in T1DMGoals of treatment:
- Eliminate symptoms
- Prevent short-term complications
- Prevent long-term complications
- Attain glycemic goals
- Anticipated insulin requirements
- Insulin options and pharmacokinetic properties
- Correctional insulin doses
- Insulin delivery devicesInsulin is required for survival in T1DM. What are the 2 insulin administration methods?Multiple daily injections (MDI):
- 1-2 injections basal insulin per day
- Prandial insulin injections before each meal
Continuous subcutaneous insulin infusion (CSII):
- Insulin pump using rapid acting insulin analogWhat are the T1DM insulin requirements?- Most patients require a Total daily dose (TDD) of 0.5-1 unit/kg/day
- Starting dose: 0.5 unit/kg/day
- Honeymoon phase:
0.1 to 0.5 unit/kg/day
(Less frequent in young children; More common in late teenagers and adult)What is the anticipated insulin requirement for pubertal children?- may need up to 1.5 units/kg/day
+ Hormonal changes
+ Relative insulin resistance
+ Increased caloric intake during growth spurts
- Higher TDD needed for obese patients, those with sedentary lifestyles, and during pubertyTypical T1DM patients' insulin requirements: basal-bolus conceptTypically T1DM patients' insulin requirements:
50% basal
50% bolus
Pre-mixed insulin yields:
70% basal 30% Bolus (regular)
75% basal 25% bolus (fast acting)Basal insulin- Controls glucose production between meals and overnight
- Near-constant levels
- try to keep peak lessBolus insulin- Limits hyperglycemia after meals
- Immediate rise and sharp peak at 1 hour post-meal
- 10% to 20% of total daily insulin requirement at each mealBasal options for insulin- Insulin glargine (Lantus®, Toujeo®, Basaglar®) - Burning sensation due to acidic pH can be bothersome to children; Few patients require twice daily glargine dosing
- Insulin detemir (Levemir®) - 70% of pediatric patients required twice daily dosing
- Insulin degludec (Tresiba®) - logical for pts who work night shift
- Neutral protamine Hagedorn (NPH) (increased risk hypo - only on board for 12 hrs, bid)bolus options for insulinRapid acting preferred over Regular (bc regular takes longer to work)
- Aspart (Novolog)
- Lispro (Humalog)
- glulisine (Apidra)
- Technosphere insulin (Afrezza)
- Regular insulin: Increased risk of hypoglycemia due to longer durationPremixed insulinIntermediate acting PLUS rapid acting (aspart, lispro)
- Take within 15 minutes before meal
- 70/30% or 75/25%, intermediate (protamine)/rapid acting
Intermediate acting PLUS regular insulin
- Take 30 minutes prior to meal (longer onset)
- 70/30%, intermediate (NPH)/regular
- Premixed insulins are dosed twice daily
- Increased risk hypoPremixed insulin pros and consPros:
- Fewer injections per day
- Cost effective
Cons:
- Fixed dose ratios
- Only provides 2 bolus doses per day
- Higher risk of hypoglycemia
- Needs to be taken 30 min prior to mealsMealtime bolus doses- Can be a set amount if patient eats consistent meals
- If patient counts carbohydrates you can teach them how to dose their insulin before the meal -> 500 Rule
- Patients can use correction factors to correct pre-meal high blood glucose -> 1500 & 1800 RulesContinuous Subcutaneous Insulin Infusion (CSII)- Approximately 30 to 40% of T1DM use CSII
- Provide a continuous infusion of fast acting insulin driven by mechanical force
- Deliver insulin via a cannula under the skin
- Can still give bolus dose at meal time
- Can change basal rates throughout the day and nightContinuous Subcutaneous Insulin Infusion benefits over MDI1. Best way to imitate the physiological insulin profile
2. On-board calculators for meal insulin boluses
3. Alarms/reminders (eg, missed bolus)
4. Downloadable to show bolus calculations, bolus doses, missed doses, and control
5. Improved A1c control
6. Reduces risk of severe hypoglycemia
7. Improved quality of lifeCGM or intermittent glucose monitoringUse:
- Measures interstitial glucose at real time
- alarms for hypo- and hyperglycemia
- Wireless interfaces withdownloadable/printable data
Limitations:
- Invasive
- May require daily calibration with fingerstick SMBG
- Data download can be a challenge
- Requires highly motivated/informed patients and healthcare support team
- CostCandidates for CGMGood candidates:
- A1C levels >7% and able to use the device near-continuously
- T1D Preconception and pregnancy
- T2DM using multiple insulin doses per day
- Pregnant or trying to conceive
Other candidates:
- Anyone with DM who wants to look for glucose trends regardless of medication
- T2DM patients willing to use the information for dietary adjustmentSMBG monitoring- Review readings/ report at every visit with patient
- Frequency of patient testing depends on control
- More frequent SMBG in newly diagnosed T1DM, T1DM with erratic BS, and children with T1DM
Useful testing times:
- Fasting (FPG)
- Pre-prandial
- 2-hr post-prandial (PPG)
- Pre exerciseinsulin and their SMBG targetsLevel 1 hypoglycemiaBG level: 54-70
Symptoms: Neurogenic: palpitations, tremor, hunger, sweating, anxiety, paresthesiaLevel 2 hypoglycemia- BG level: <54 mg/dL
- symptoms: Severe confusion, unconsciousness, seizure, coma, death, Requires help from another individualWhat are the consequences of hypoglycemia?- Cognitive, psychological changes (eg, confusion, irritability)
- Accidents
- Falls
- Hypoglycemia unawareness
- Refractory diabetes
- Dementia (elderly)
- CV events: Cardiac autonomic neuropathy, Cardiac ischemia, Angina, and Fatal arrhythmiaHow do you treat hypoglycemia if pt is conscious and alert?- Consume 15 g of CHO-containing foods (fruit juice, soft drink, crackers, milk, glucose tablets); avoid foods also containing fat
- Repeat glucose intake if SMBG result remains low after 15 minutes
- Consume meal or snack after SMBG has returned to normal to avoid recurrenceHow do you treat hypoglycemia if pt is confused or unconscious (requires help)?- Glucagon injection or nasal, delivered by another person
- Patient should be taken to hospital for evaluation and treatment after any severe episodeHypoglycemia: treatment15-20 grams CHO (simple glucose preferred)
- ½ cup of regular pop
- 3 to 4 glucose tablets
- ½ cup of canned or frozen fruit
- 1 small piece of fresh fruit
- 1 slice of bread
- 4-6 crackers
- 1 Tbsp syrup, jam, jelly, sugar, honeyGlucagon emergency kit in hypoglycemia- Use if unconscious or cannot swallow
- Dosed by weight
- As outpatient, given IM or SQ
- Seek medical assistance and give another, if no response within 15 minutes
- All close contacts should be aware of how to use glucagon kit
- Every T1DM should have a glucagon kit
- check glucagon expiration datesNasal Glucagon-Baqsimi in hypoglycemia- 94% of caregivers correctly gave a full dose of glucagon intranasal vs 13% with glucagon inj
- 50% of caregivers failed to give any inj at all vs 6% with intranasla
- Less time to administer: 16 seconds for intranasal glucagon vs. 1 minute and 53 seconds for the injection kitWhat are the risk factors for hypoglycemia?- Alcohol
- Exercise
- Starvation
- Organ failureWhat is the impact of alcohol on BG?- Alcohol inhibits gluconeogenesis in the liver, acutely improves insulin sensitivity with the possibility of delayed severe onset hypoglycemia
- May occur 10-12 hours post ingestion
Prevention:
- Eat CHO while drinking
- Stay hydrated, avoid binge drinking
- SMBG prior to bedtime and have CHO before sleep to minimize riskWhat is the impact of exercise on BG?- Exercise can cause hypoglycemia immediately after, and 2-12 hours after
Prevention:
- Pre-exercise, during exercise and/or post-exercise snacks may be required
- Test SMBG and adjustment insulin dosing if needed
Variables effecting risk:
- Duration of exercise
- Type: anaerobic activity may ↑ BG due to the release of adrenaline glucagon
- Baseline BG prior to exercise
- Excessive insulin administration
- Familiarity with activity (greater energy expenditure if untrained)
Pre exercise goal 90-250mg/dLHow is diabetes managed on sick days?- Never STOP insulin
- The insulin dose may need to be increased or decreased
- Frequent monitoring of blood glucose
- Monitor at least every 3-4 hours including through the night
- If severe illness, sometimes up to 1-2 hours
- Monitoring blood or urine ketones (acidosis can sometimes occur without elevated glucose if oral intake is poor)
- Check ketones if BG consistently >250 or if you feel ill
- Blood ketone testing enables earlier identification and treatment of ketosis compared to urine ketone testing
- Food every other hour, fluid intake 8 fl oz of caffeine free liquid every hourDiabetic Ketoacidosis (DKA)- A low insulin, high glucagon state
- More common in T1DM than T2DM
- Ketones are produced by the liver from free fatty acids (FFA) that are mobilized when there is a lack of an alternative energy source
- Ketones are also produced when insulin is low and cannot transport glucose from the bloodstream into the cells
- Accumulate because ↑ lipolysis, ↑ ketogenesis and ↓ketone body utilization due to low insulin levelsDKA: Precipitating factors- Infection
- Discontinuation or inadequate insulin therapy
- Pancreatitis
- Myocardial infarction or cerebrovascular accident
- Drugs
- Dehydration
- Stress such as trauma or sepsis
- Mismanagement of sick days
- Pump malfunction
- In young patients with T1DM psychological problems complicated by eating disorders contribute to ~20% of recurrent ketoacidosisWhat are the symptoms of DKA?- Onset over 4-10 hours
- Some usual symptoms of hyperglycemia: Polyuria, Polydipsia, Weight loss
- Nausea/vomiting/diffuse, abdominal pain (>50%)
- Dehydration, thirsty
- Mental status changing
- Physical exam findings (poor skin turgor, deep labored breathing pattern/hyperventilation, tachycardia, hypotension)
- Hypothermia-very poor prognostic sign
- Sweet breathWhat is the diagnosis criteria of DKA?What is the diagnosis criteria of HHS?- BG>600 mg/dL
- Arterial pH: >7.30
- Serum bicarb: >18
- Urine ketone: small
- Serum ketone: small
- Effective serum osmolality: >320 mOsm/kg
- Anion gap: variable
- mental status: stupor/comaDKA: treatment approach1. Dehydration:
- Initial treatment 0.9% NaCl ("normal saline")
- Once BG is stable (~200 mg/dL), 5% dextrose should be added to fluids to allow continued insulin administration and avoid hypoglycemia
2. Hyperglycemia
- Regular insulin via continuous IV infusion (or SC if mild)
- Goal 50-75 mg/dL drop in BG in the first hour
3. Potassium ( if <3.3mEq/L or when K comes down to < 5.2 to maintain 4-5mEq/L)Electrolytes in DKA txt1. Potassium (K)
- Despite total body K depletion, mild to moderate hyperkalemia is common
- Insulin therapy (insulin drives K intracellularly) and fluids ↓K
- Once serum K falls below the upper limit of normal, K replacement is initiated
2. Bicarbonate
- Only used in severe DKA, not generally recommendedHyperglycemic hyperosmolar state (HHS)- Severe hyperglycemia (>600 mg/dL), dehydration
- More often seen with elderly or T2DM
- More life threatening than DKA
- Similar treatment to DKA but more insulin may be needed (fluids, insulin, K+ management)What if you have T1DM and want to become pregnant?You will have prenatal care ensuring your glucose is optimized before you get pregnant, ideally1st Prenatal visit: screen for pre-existing DM- If you don't have pre-existing DM at your first prenatal visit, you will be screened for your blood glucose if they think you have DM.
- Test for undiagnosed diabetes at the 1st prenatal visit in those with risk factors, using standard diagnostic criteria
- If diagnosed with DM, this is overt DM and not GDMRisk factors for DM- Overweight BMI ≥ 25 kg/m2
- Physical inactivity
- First degree relative with DM
- High-risk race/ethnicity (African American, Latino, Native American, Asian American, Pacific Islander)
- Women who were diagnosed with GDM
- HTN
- HDL <35 mg/dL and/or TGL >250 mg/dL
- Women with PCOS (polycystic ovarian syndrome)Gestational diabetes (GDM)- a form of diabetes that occurs during pregnancy
- In pregnant women not previously known to have DM, screen for GDM at 24-28 weeks' gestation
- GDM increases risk of birth defects, miscarriage, eclampsia, and maternal DM after pregnancy (also giant baby)What are the diagnostic criteria for GDM?- FPG: >92 mg/dL
- 1h PG:≥180 mg/dL
- 2h PG: ≥153 mg/dLPostpartum considerations- Screen for persistent DM at 6-12 weeks postpartum, using the OGTT (not A1c)
- Screen for development of diabetes or prediabetes at least every 3 years, lifelong
- If found to have prediabetes (A1c 5.7-6.4%) treat with lifestyle interventions or metformin to prevent diabetesTreatment of diabetes in pregnancy1. diet
2. insulin
All women with T1DM, T2DM, or previous GDM should first receive education on lifestyle management:
- preconception care to ensure adequate nutrition and glucose control before conception, during pregnancy, and in the postpartum period
- SMBG education
70-85% of women with GDM can control it with lifestyle aloneMedication therapy in pregnancy- Insulin is preferred medication treatment for diabetes in pregnancy
- Most effective agent
- Doesn't cross placenta
- Need to stop metformin by end of first trimester if used for ovulation in PCOS patients
- Metformin and sulfonylureas are NOT generally recommended
- Titration may need to occur at more frequent intervals during pregnancy due to the physiology of pregnancyWhat is the relationship between preeclampsia and ASA?Women with existing type 1 or type 2 diabetes should be prescribed low-dose aspirin 60-150 mg/day (usual dose 162mg/day) from the end of the first trimester until the baby is born in order to lower the risk of preeclampsia.What is the connection between DM and Coronary heart disease?Risk of CHD is 2 to 4x greater in diabetes than patients without
Address multiple CV risk factors:
- HTN
- Lipids
- Smoking cessation
- Antiplatelet therapyFor individuals with diabetes and HTN at higher CV risk, existing ASCVD or a 10 yr ASCVD score ≥ 15%, what is the blood pressure target?<130/80, if it can be safely obtainedFor individuals with diabetes and HTN at lower risk for CVD (10 yr ASCVD score <15%), what is the blood pressure target?<140/90If DM patient has BP of ≥ 140/90 mmHG, what are the treatments?in addition to lifestyle therapy, have prompt initiation and timely titration of pharmacologic therapy to achieve blood pressure goals.If DM patient has BP of ≥ 160/100 mmHG, what are the treatments?in addition to lifestyle therapy, have prompt initiation and timely titration of two drugs or a single-pill combination of drugs demonstrated to reduce cardiovascular events in patients with diabetes.What are the medications for HTN in DM pts?Drug classes demonstrated to reduce cardiovascular events in patients with diabetes (ACE inhibitors/angiotensin receptor blockers, thiazide-like diuretics, or dihydropyridine calcium channel blockers).
- Thiazide- like diuretic, long acting agents are shown to reduce CV events, such as chlorthalidone and indapamide.When is an maximum tolerated ACEi or ARB indicated for HTN in DM pts?An ACE inhibitor or ARB, at the maximum tolerated dose indicated for blood pressure treatment, is the recommended first-line treatment for hypertension in patients with diabetes and urinary albumin-to-creatinine ratio ≥300 mg/g creatinine A or 30-299 mg/g creatinine. B If one class is not tolerated, the other should be substituted.For patients treated with an ACE inhibitor, ARB, or diuretic, serum creatinine/estimated glomerular and serum potassium levels should be monitored how often?at least annuallywhat is UACR test?We use it to screen for nephropathy. If it is over 30, the pt has microalbumina, and that's an indication that there is progression of DKD. If it is over 300, that's really bad. There is significant protein in the urine.What is the txt of resistant HTN in DM pts?Patients with hypertension who are not meeting blood pressure targets on three classes of antihypertensive medications (including a diuretic) should be considered for mineralocorticoid receptor antagonist therapy.Statins and Primary Prevention in DMPatients with diabetes 40-75 YO w/out ASCVD: Moderate intensity statin
Patients with diabetes 20-39 YO with ASCVD risk factors: Reasonable to initiate statin
Patients with diabetes 50-70 at high ASCVD risk or have CVD: Reasonable to start high intensity
Patients with diabetes with 10-year ASCVD score risk ≥20%: Reasonable to add ezetimibe to maximum tolerated statin to reduce LDL by 50%Statins and Secondary Prevention in DMAll aged patients with diabetes and ASCVD: High intensity statin
All aged patients with diabetes and ASCVD at very high risk if LDL ≥70 on max tolerated statin: Consider adding ezetimibe or PCSK9 inhibitor
Patients >75 YO already on statin, it is reasonable to continue
Patients >75 YO not on a statin, it is reasonable to start after discussion of benefits and risksWhat are the high intensity statins?Atorvastatin 40-80 mg
Rosuvastatin 20-40 mgWhat are the moderate intensity statins?1. Atorvastatin 10-20 mg
2. Rosuvastatin 5-10 mg
3. Simvastatin 20-40 mg
4. Pravastatin 40-80 mg
5. Lovastatin 40-80 mg
6. Fluvastatin 80 mg
7. Pitavastatin 1-4 mgFor DM patients with fasting triglyceride levels ≥500 mg/dL...evaluate for secondary causes of hypertriglyceridemia and consider medical therapy to reduce the risk of pancreatitis.In adults with moderate hypertriglyceridemia (fasting or non-fasting triglycerides 175-499 mg/dL), clinicians should...address and treat lifestyle factors (obesity and metabolic syndrome), secondary factors (diabetes, chronic liver or kidney disease and/or nephrotic syndrome, hypothyroidism), and medications that raise triglyceridesIn patients with atherosclerotic cardiovascular disease or other cardiovascular risk factors on a statin with controlled LDL cholesterol but elevated triglycerides (135-499 mg/dL),...the addition of icosapent ethyl can be considered to reduce cardiovascular risk.Lipid Monitoring- Lipid profile at initiation
- 4-12 weeks after initiation or change in dose
- Annually thereafterUse ______________ as a secondary prevention strategy in those with diabetes and a history of atherosclerotic cardiovascular disease.aspirin therapy (75-162 mg/day)For patients with atherosclerotic cardiovascular disease and documented aspirin allergy, ____________ should be used.clopidogrel (75 mg/day)Dual antiplatelet therapy (with low-dose aspirin and a P2Y12 inhibitor) is reasonable for a year when?after an acute coronary syndrome (heart attack) and may have benefits beyond this period._____________ may be considered as a primary prevention strategy in those with diabetes who are at increased cardiovascular risk, after a comprehensive discussion with the patient on the benefits versus the comparable increased risk of bleeding.Aspirin therapy (75-162 mg/day)Aspirin therapy (75-162 mg/day) may be considered as a primary prevention strategy in those with diabetes who are at increased cardiovascular risk, after when?a comprehensive discussion with the patient on the benefits versus the comparable increased risk of bleeding.In DM patients with known ASCVD, consider _____________ to reduce the risk of cardiovascular events.ACE inhibitor or angiotensin receptor blocker therapyIn DM patients with prior myocardial infarction, __________ should be continued for at least 2 years after the event.b-blockersIn patients with type 2 diabetes with stable heart failure, ________ may be continued for glucose lowering if eGFR remains >30 mL/min but should be avoided in unstable or hospitalized patients with heart failure.metforminIn patients with type 2 diabetes and established ASCVD or multiple risk factors for ASCVD, ____________ with demonstrated cardiovascular benefit is recommended to reduce the risk of major adverse cardiovascular events.a glucagon-like peptide 1 receptor agonistSodium-glucose cotransporter 2 inhibitor in patients with chronic kidney disease progression- For patients with type 2 diabetes and diabetic kidney disease, use of a sodium-glucose cotransporter 2 inhibitor in patients with an estimated glomerular filtration rate ≥20 mL/min/1.73 m2 and urinary albumin ≥200 mg/g creatinine is recommended to reduce chronic kidney disease progression and cardiovascular events.
- For patients with type 2 diabetes and diabetic kidney disease, use of a sodium-glucose cotransporter 2 inhibitor is recommended to reduce chronic kidney disease progression and cardiovascular events in patients with an estimated glomerular filtration rate ≥20 mL/min/1.73 m2 and urine albumin ranging from normal to 200 mg/g creatinine.Diabetic Retinopathy Recommendations- Optimize glycemic control, blood pressure and lipids to reduce the risk or slow the progression of diabetic retinopathyDiabetic Retinopathy-Screening- At diagnosis: Dilated and comprehensive eye examination
- Eye exam
- If no evidence of retinopathy for one or more exams can extend to every 1-2 years
- If retinopathy dilated exams at least annually
- If retinopathy progressing more frequent exams
- More often in pregnancyNeuropathy Screening- Initial diagnosis of type 2 diabetes and 5 years after type 1
- Assessment for diabetic peripheral neuropathy
- At least annually thereafter
- All patients: Annual 10-g monofilament test to identify ulceration and amputation risk
- S/Sx of autonomic neuropathy assessed in patients with microvascular complications
- Inspect feet at every visitNeuropathy Treatment- Optimize glucose control
- Assess and treat patients to reduce pain related to
+ Diabetic peripheral neuropathy
+ Autonomic neuropathyWhat are the initial treatments of neuropathy?- Pregabalin 300-600mg/day
- Duloxetine 60-120mg/day
- Gabapentin 900-3600mg/day
Secondary options:
- Amitriptyline 25-100mg/day
- Venlafaxine 75mg-225mg/day
- Topical capsaicin 0.075% QIDThe risk of ulcers or amputations is increased in people who have what risk factors?- Poor glycemic control
- Peripheral neuropathy with LOPS
- Cigarette smoking
- Foot deformities
- Pre-ulcerative callus or corn
- PAD
- History of foot ulcer
- Amputation
- Visual impairment
- CKD (especially patients on dialysis)Lifestyle and glycemic control are essential to minimize or slow progression all complications!Dental Care
Depression
Separate Section for Older adults
Other endocrine disorders...The ideal candidate for CSII- Patients with T1DM or absolutely insulin deficient T2DM
- Currently performs 4 or more insulin injections per day
- Assesses blood glucose levels 4 or more times per day
- Highly motivated to achieve control
- Intellectually and physically able to undergo pump initiation and maintenance
- Must be able to count carbohydrates and calculate correction doses
- Emotionally mature, with a stable life situation
- Maintain frequent contact with their health care providers
- Generally not appropriate in newly diagnosed patientsWhat is the generic name of jardiance?empagliflozinWhat is diabetes mellitus?Diabetes mellitus (DM) is a group of chronic metabolic disorders
- characterized by hyperglycemia & abnormalities in carbohydrate, fat, and protein metabolism
- due to resistance to the action of insulin, insufficient insulin secretion, or both
- may result in chronic microvascular, macrovascular, & neuropathic complications.Gluconeogenesisformation of glucose from noncarbohydrate sourcesGlyconeogenesisProcess of producing glucose from fat and proteinUncontrolled DM is the leading cause in the US for?- Legal blindness
- Peripheral neuropathy: lack of sensation in the extremities leads to gangrenes
- Chronic renal failure
- Below-the-knee amputationEtiologic classification: Type 1 Diabetes mellitus (T1DM)∼ 5% to 10% of cases (diagnosed in younger children usually)
- β-cell destruction → absolute insulin deficiency
- Previously known as insulin-dependent DM
A. Immune mediated ∼ 90%
- Cellular-mediated autoimmune destruction of β- cells - There is some anti antigens. Body produce antibodies to destroy beta cells.
- Individual prone to ketoacidosis
- Little or no insulin secretion → Insulin dependent
- 75% of individuals develop < 30 y; can occur at any age
- Usually not obese
Idiopathic ∼ 10%
- No defined etiologies - may be sporadic
- Absolute requirement for insulin replacement therapy
No matter if it is immune mediated or idiopathic, it always is dependent on insulin.Etiologic classification: Type 2 diabetes mellitus (T2Dm)∼ 90% to 95% of DM cases
- previously known as non-insulin-dependent diabetes
- Generally occurs at >40 y (↑ frequency in children due to metabolic syndrome)
- Progressive loss of β-cell insulin secretion with insulin resistance
- not insulin dependent - but may require insulin
- not ketosis prone - but may form ketones under stress
- Obesity - abdominal region - visceral adipose tissue (VAT)→ insulin resistance - Truncal obesity - insulin resistance's ins produced due to the VAT. They are likely to be pre diabetic or diabetic.
- Often associated with htn & dyslipidemia
- Strong genetic predisposition
- Because they're is already circulating insulin in the individual, the individual does not need insulin. Although under certain circumstances, you may need insulin to control T2DM. Also because of the circulating insulin ketone bodies are not easily produced (under certain circumstances we CAN see them).Etiologic classification: Gestational diabetes mellitus (GDM)- Any degree of glucose intolerance with onset or 1st recognition during pregnancy
- Hormonal changes in pregnancy → insulin resistance with inadequate insulin secretion → hyperglycemia
- ↑ risk in women who are obese, >25 y, family history of DM or previous GDM, or are of certain ethnic groups (Hispanic, Native American, Asian, or black)
- The metabolic stress of pregnancy may uncover a genetic tendency for T2DM
- If this isn't take care of during/after pregnancy, the individual could live with diabetes.Etiologic Classification of DM: othersOther specific types - uncommon causes of DM < 5% of cases
- Genetic defects of β-cell function or insulin action
- Pancreatic exocrine dysfunction e.g. pancreatitis (inflammation of the pancreas that is not managed could destroy the beta cells)
- Endocrinopathies e.g. acromegaly, Cushing syndrome, hyperthyroidsm
- Infections
- Maturity onset diabetes of youth (MODY) - disorder where beta cells are impaired and insulin that is produced is abnormal; linked to certain genes in certain individuals
Drug/chemical - induced - glucocorticoids, thiazides, niacin, pentamidine,
- streptozotocin, thyroid hormone, diazoxide, β-adrenergic agonists, phenytoin, γ-interferonStreptozocindrug that is used in the treatment of pancreatic cancer - can destroy beta cells and induce diabetesDM affects ∼ 30.3 million (∼ 9.4%) of US population. ↑ prevalence of DM is influenced by:Lifestyle
- sedentary lifestyle + ↑intake of high-fat/carbohydrate foods→↑rates of obesity.
- ∼ 36.5% of US population is obese - BMI > 30 kg/m2
Race/Ethnicity
- Groups at high risk for -T2DM - American Indians/Alaska Natives (15.1%) > blacks (12.7%) > Hispanics (12.1%) > non-Hispanic whites (7.4%)
- Socioeconomic status - education level plays a role in the dev. of DM
Age
- Incidence of T2DM with aging population; cases in children are ↑The pancreas- Located behind the stomach, between the spleen & the duodenum
- exocrine gland →digestive enzymes. - have ducts where they secret their contents
- endocrine gland → hormones - ductless. They secrete their contents into near by blood stream where the content travels to other organs
- houses the islets of Langerhans - 4 types of hormone-secreting cells: α, β, δ, & F (or PP) cells
- the pancreas is one of the few organs that double up in function. It is both an endocrine as well as an exocrine organ.Regulation of secretion in the pancreas- Delta cell - Gastrin and somatostatin (inhibit glucagon and insulin)
- Alpha cell - Glucagon - induce the mobilization of energy during moments of starvation - under starving conditions we have increase glucagon secretion from alpha cells
- Beta cells - insulin (mobilizes glucose in fat state and stores them; utilization of glucose is enhanced in the presence of insulin) and amylin (inhibiting glucagon action and enhance the decrease absorption of glucose during fat state and it plays a role in slowing down gastric motility)
- F (or PP) cells - Pancreatic polypeptidePancreas pathophysiology- Insulin secretion is stimulated by blood glucose, & Incretins - gastric inhibitory peptide (GIP) [produced by K type cells] & glucagon-like peptide-1 (GLP-1) [produced by the L type cells] from the gut
- *actions of GIP & GLP-1 are terminated rapidly by dipeptidyl peptidase-4 (DPP-4)
- incretins - induce the release of insulin upon arrival of nutrients within the GI tract.
- PNS - rest and digest - can trigger release of insulinInsulin- is a fuel-storage hormone
- affects cell growth & differentiation &↓blood glucose by:
↑ glucose uptake into muscle & fat via Glut-4
↑ glycogen synthesis
↓ gluconeogenesis
↓ glycogen breakdown (glycogenolysis)
- the principal function of insulin is to increase the rate of uptake of peripheral tissue for its utilization.
- When insulin is absent and glucose cannot be utilized, then a whole lot of things can ensue. If glucose cannot get into tissues, tissues will attempt to use the course of ATP. It will try to convert it to glucose and will, but it isn't able to use it. The glucose will be dumped into the blood stream induce hyperglycemia.Glucagon- a fuel-mobilizing hormone - stimulate
↑ Gluconeogenesis
↑ Glycogenolysis
↑ Lipolysis
↑ Proteolysis
- net effect of increasing plasma glucose level
- mobilizes glucose form non-carbohydrate sources or carbohydrate sourcesNormal glucose homeostasis is tightly regulated by 3 interrelated processes:1. glucose production in the liver - happens in fasting state - is relevant to keep individual going
2. glucose uptake & utilization by peripheral tissues - skeletal muscle
3. actions of insulin & counterregulatory hormones - glucagon.
- Principal function of insulin is to ↑ the rate of glucose transport into certain cells in the body
- Insulin ↓ production of glucose from the liver.The brain is the only tissue that?can pick up glucose without the need of insulinAdipose tissue in the presence of insulin- takes up glucose and it also induces lipogenesis. It will decrease the breakdown of lipids which are meant to produce energy.Striated muscle in the presence of insulinMuscles will take up more glucose and use it for the production of ATP and glycogen synthesis. There is also increase protein synthesis.Liver in presence of insulin- There is decreased prod glucose from non- carb sources, like lipids and proteins (decrease gluconeogensis). Glycogen synthesis is increase, so we mobilize more glucose from storage to the form of glycogen. Lipogenesis is increase, so we are storing energy. We are producing lipids, but lipolysis is decrease. There is enhanced glucose uptake by the liver which is used to elaborate the glycogen.Pancreatic β-cell Pathway- This pathway induces insulin release.
1. Glucose is sensed by β-cell, enters via GLUT-2; metabolized to yield ATP.
2. ATP-sensitive K+ channel allow K+ efflux; a. Resting state - β cell is hyperpolarized & insulin secretion is low;
b. Glucose ↑ATP → When ATP is greater than ADP, the K+ channel will close. ↓K+ efflux
3. Resulting depolarization →open voltage-dependent Ca2+ channels → Ca2+ influx
4 ↑ Ca2+ → exocytosis of stored insulin into blood stream
5. GLP-1 binding to incretin receptor (GPCR) ↑ cAMP → insulin release
6. SUR: sulfonylurea receptor; sulfonylurea binds to ↓K+ efflux → depolarization2 phase release of insulin in response to glucose infusion- the injection of glucose will activate insulin release under normal circumstances
- Basal insulin level is usually low (20 µU/mL). The moment we inject bolus of glucose we have phase 1 spike within 15 minutes. Phase 1 spike last about 15 minutes. Then we have phase 2 phase of insulin in normal individual.
- iN pts withT2DM, the first phase is missing. However delayed release occurs, so phase 2 is still present. There is still some circulatory insulin.
- In pts with T1DM, beta cells are destroyed. You will not have phase 1 or phase 2.
- The response in normal individuals are even higher when you give glucose via oral route because of the incretin effect.T1DM- Autoimmune destruction of pancreatic β-cells → absolute deficiency of insulin; deficient amylin (which ↓glucagon secretion)
- Autoimmune process is mediated by macrophages & T lymphocytes with autoantibodies to β-cell antigens (eg, islet cell antibody, insulin antibodies)
- long preclinical period of positive autoimmune markers → immune-mediated β-cell destruction →hyperglycemia (80% - 90% β-cells is destroyed).
- "honeymoon" phase sometimes occur after the initial diagnosis before β-cell destruction
- ↓ glucose uptake by insulin-sensitive tissues
- Lipolysis &muscle proteolysis → weight loss & weakness.
- ↑ blood levels of free fatty acids & glycerol
- ↑ acetyl-CoA in the liver → acetoacetic acid → β-hydroxybutyric acid & acetone
- 'ketone bodies' accumulate in the blood → ketoacidosisstages in development of T1DM- You have genetic disposition, but until immunologic trigger occurs, you will produce normal level of insulin.
- The moment immunologic abnormalities start there is destruction of beta cells. There is decline in insulin release. The decline can go until you are left with only about 250,00 beta cells in the pancreas. That is where we will have overt diabetes.
- in certain individuals, there can be some rebound release of insulin with the refinance of beta cells left. Eventually that also declines. Now the pts is at full blow T1DM.Why does ketoacidosis occur?When glucose cannot get into the cells, the body will find another source of energy. One resullt is lipolysis. There will be increase levels of free FA and glycerol floating around. The body will not utilize this for energy, so there will be production of ketone bodies. Free FA and glycerol will be converted to acetoacetate then to beta hydroxybutrate and acetone. That results in ketone bodies that will build up in the body. This is known as metabolic acidosis. Because that acidosis is induce by ketone bodies we say it is ketoacidosis. Because it occurs in diabetics it is called diabetic ketoacidosis.What is the clinical presentation of T1DM?- Hyperglycemia
- Patients are often thin & prone to develop DKA under lack of insulin or severe stress
- 20% - 40% of patients → DKA after several days of polyuria (frequent urination due to an osmotic diuresis from glucosuria - due to hyperosmotic nature of glucose which is being excreted.), polydipsia (excessive thirst due to dehydration), polyphagia (increase appetite due to loss of macromolecules), weight loss (due to conversion of structural proteins to use for nutrients like glucose, & fatigue and lethargy.
- T1DM are mostly diagnosed < 20 y (75%)Truncal fatBeta cell mass and function begins to decline at some point in T2DM. When there is obesity, the truncal obesity or VAT begins to produce adipokines. They are very useful. However production of adipkines that are useful decline. Other inflammatory cytokines will be produced, There is increase FA released and lipotoxiity can cause insult the beta cells. Glucotoxicity can also cause insult to beta cells. Beta cell function is greatly reduced. Incretin activity also decreases.GhrelinIn T2DM, there is decrease in gherlin activity. It is a hormone that plays a role in enhanced metabolism. There is decreased glucose uptake by muscle The muscles are not utilizing glucose.Name the factors in the ominous octet T2DM.1. impaired insulin secretion
2. Insulin resistance
3. decreased gut incretin hormones
4. increase glucagon secretion
5. increased hepatic glucose production
6. increased sodium glucose cotransporter 2 (SGLT-2)
7. systemic inflammation
8. diminished satietyimpaired insulin secretion (ominous octet)- Hallmark finding - progressive↓ β-cell mass/function & β-cell failure
- characterized by multiple defects
- the etiology is unknown
- a strong genetic component is presentinsulin resistance (ominous octet)↓hepatic glucose production, ↓skeletal muscle uptake of glucose, & ↑lipolysis & free fatty acid production.
- Resistance to circulating insulin → protect the patient from ketosis
- ↓ in the number of insulin receptors → obesity
- Diet & exercise → ↓weight→ ↓insulin 'resistance' → controls 1/3 of T2DM.
- corresponding increase breakdown of lipids in adipose tissuedecreased gut incretin hormones (ominous octet)glucagon-like peptide-1 (GLP-1) & glucose-dependent insulinotropic peptide (GIP) due to ↓ conc or resistanceincreased glucagon secretion (ominous octet)due to GLP-1 resistance/deficiency & insulin resistance/deficiency, → ↑glucagon.↑ Sodium-glucose cotransporter-2 (SGLT-2)in the kidney → ↑ reabsorption of glucose by proximal renal tubular cells→ hyperglycemia
- this cotransporter is all over the body, We have type 1 especially in the intestines, kidney, and else where in the body (10%). They have very high affinity. However, they have less efficacy. The SGLT-2 is along the nephron. They try to capture the glucose. It has very low capacity but high efficiency. It is known that there is over expression of SGLT2 in T2DM. This means there is enhanced recapture of the glucose back int the bloodstream.Stages in development of T2DMInitially there is a decrease in insulin sensitivity. That is corresponded by gradual increase in the post prandial plasma glucose level. That occurs yrs before diagnosis. Eventually at the point of diagnosis, fasting blood glucose has started to increase because of dysfunction of production of insulin. Beta cell function decreases as well.
T2DM slowly progresses from development of insulin resistance to a state where the pancreas loses its ability to produce enough insulin to compensate for the insulin resistance of peripheral tissues.
Metabolic changes over time during the development of type 2 diabetes mellitus. T2DM - Metabolic syndrome Multiple metabolic abnormalities → higher risk for developing T2DM & subsequent CVD
Definition - central obesity + ↑waist circumference with ethnicity-specific values + any 2 of these 4 factors:
1. ↑triglycerides (≥ 150 mg/dL)
2. ↓HDL cholesterol - (< 40 mg/dL in males or < 50 mg/dL in females);
3. ↑ BP (systolic ≥ 130 mm Hg, diastolic ≥ 85 mm Hg, or previously-diagnosed htn)
4. ↑fasting plasma glucose (≥ 100 mg/dL or previous diagnosis of T2DM)Clinical signs of T2DM- Central (upper body) obesity with↑ waist circumference
- Acanthosis nigricans (hypertrophic, hyperpigmented skin changes)
- Patients are often asymptomatic
- May be diagnosed secondary to unrelated blood testing
Some patients →
Lethargy, polyphagia, polyuria, nocturia, & polydipsia
- Most patients are overweight or obese.
- Recurrent infections (e.g., boils, skin infections) & prolonged wound healing (due to abundance of glucose in the system)
- Genital pruritus - fungal infections, yeast infection
- Visual changes - Blurred vision - retinopathy
- Paresthesias (numbers in limbs) - neuropathies
Comorbid Illnesses - Htn; atherosclerosis; hyperandrogenism +polycystic ovary syndromeModifiable risk factors for DMnon - Modifiable risk factors for DMT1DM vs T2DMAdults: overweight or obese (BMI ≥25 or ≥23 kg/m2 Asian Americans) should be screened for T2DM or prediabetes if they have ≥ 1 risk factors:- 1st-degree relative with DM
- High-risk race/ethnicity (Black, Latino, Native American, Asian American)
- History of CVD
- Htn (≥140/90 mm Hg or on htn therapy)
- HDL <35 mg/dL &/or TG >250 mg/dL
- PCOS
- Physical inactivity
- Conditions associated with insulin resistance: acanthosis nigricans, severe obesityFrequency of testing in T2DM- Patients with prediabetes (A1c ≥ 5.7%), impaired glucose tolerance, or impaired fasting glucose should be tested yearly.
- Women with GD should be tested at least every 3 years for life.
- Testing for all other patients should begin at 45 years.
- If normal, repeated at a minimum of every 3 years unless initial results or risk status warrants more frequent testing.Screen for T2DM or Prediabetes if overweight with ≥ 1 additional risk factors:- Maternal history of DM or GD during the child's gestation.
- Family history of T2DM in 1st- or 2nd-degree relative.
- Race/ethnicity (Native American, black, Latino, Asian American, Pacific Islander).
- Signs or conditions associated with insulin resistance - acanthosis nigricans, htn, dyslipidemia, PCOS, or small-for-gestational-age birth weight).Physical Assessment of DM- Patients with hypoglycemia - tachycardia & diaphoresis on physical assessment
- Patients with hyperglycemia
- T2DM no physical symptoms
- T1DM → Kussmaul respirations & signs of ketoacidosis.Annual foot examination with 10-g monofilament + one of the ff:- pinprick, temp., vibration sensation using 128-Hz tuning fork, or ankle reflexes
- Absent monofilament sensation → loss of protective sense & ↑risk of complications
Faint or absent pedal pulses upon palpation → peripheral vascular disease & ↑risk for lower extremity complications (ulcerations & amputation)Diagnostic Criteria for Diabetes Mellitus- HbA1c (as measured in a DCCT-referenced assay) ≥6.5%
- FPG ≥126 mg/dL (≥7.0 mmol/L); fasting → no caloric intake for ≥ 8 h
- OGTT - 2-h plasma glucose ≥200 mg/dL (11.1 mmol/L) (75 g anhydrous glucose dissolved in water)
- Random plasma glucose ≥200 mg/dL (11.1 mmol/L) in a patient with classic symptoms of hyperglycemia or hyperglycemic crisisCategories of Increased Risk for Diabetes (Prediabetes)- FPG 100 - 125 mg/dL
- 2-h PG in the range of 140 to 199 mg/dL during an OGTT
- HbA1c 5.7% to 6.4%Basal vs Postprandial Hyperglycemia in T2DMIf we take plasma glucose level under normal circumstances, you have some basal plasma glucose level When you take in a meal, it shoots up and falls back to normal. In diabetes, the basal level is already high. Sometimes it can even be as high as 200 and beyond. When you take in a meal, it should stop beyond normal. So, in T2DM, the basal level is already high, So, when you take in food, that level shoots up.Hyperglycemia - Monitoring with glucometers Hemoglobin A1c (HbA1c)Formed slowly & nearly irreversibly during the 120-day lifespan of RBCs
HbA1c level reflects the mean plasma glucose conc. during the preceding 3 months3 major acute complications of DM:- Diabetic Ketoacidosis (DKA) - common in T1DM
- Hyperosmolar Hyperglycemic State (HHS) - common in T2DM
- Hypoglycemia - result of meds
- life-threatening conditions - demand immediate recognition & treatment.Chronic complications in DM - If glycemic state remain uncontrolled for long timeMicrovascular complications
Macrovascular complications
GI motility Disorder
Foot ulcersDiabetic Ketoacidosis - DKA- Common in T1DM
- lack of insulin → ↑ release of fatty acids from adipose tissue
- lipase breaks down TGs into fatty acids & glycerol.
- ↑ fatty acid levels → ketone production by the liver.
DKA - can occur at the disease onset, before diagnosis or as a complication of the disease.
- results in ketonuria and glycosuriaDKA - Clinical PresentationCauses - Physical, emotional stress, infection, pregnancy, extreme anxiety, 1st presentation prior to diagnosis
Signs & symptoms
- preceded with polyuria, polydipsia, NV, & fatigue, stupor, confusion - can progress to coma & death (up to 5%)
- abdominal pain & tenderness; dehydration & electrolyte loss
- volatile ketone bodies → fruity smell in breath
- Compensatory mechanisms
- Hypotension & tachycardia due to ↓ in blood volume
- ↑rate & depth of respiration (Kussmaul respiration) → prevent further ↓pH
Labs
- Hyperglycemia
- ↑H+, ↓HCO3-, blood pH < 7.3 (↑anion gap metabolic acidosis)
- ↑urine & blood ketone levels
- Osmotic diuresis →↑K+ loss in urine → total body K+ depletion (Remember K+ is required for insulin action. In the absence of insulin, there is hyperkalemia within the bloodstream. In the presence of insulin, potassium K+ is taken up by the cells. One way to decrease hyperkalemia is give insulin.Hyperosmolar Hyperglycemic State - HHS- State of profound hyperglycemia-induced dehydration & ↑ serum osmolality
classically seen in elderly T2DM with limited ability to drink
Pathogenesis
- ↓insulin deficiency →↓ glucose utilization, ↑glucagon release & hepatic glucose output
hyperglycemia → excessive osmotic diuresis → dehydration
- Plasma volume contracts → renal insufficiency → further ↑blood glucose levels → severe hyperosmolar state
HHS may ↑coagulability → thromboembolic eventsHyperosmolar Hyperglycemic State - HHS signs and symptoms- weakness, dehydration, dry skin, tachycardia, polyuria, orthostatic hypotension, & excessive thirst.
- Neurologic alterations - seizures, coma
- can progress to death if left untreated ~ 30% of patients
Labs:
- Hyperglycemia (often > 600 mg/dL)
- ↑serum osmolality (> 320 mOsm/kg)
- No acidosis (pH normal)
- No ketone production - inhibited by presence of insulinHypoglycemia- any blood glucose conc. <70 mg/dL ± symptoms
common with insulin injections or oral antidiabetic agents.
- Etiology - T1DM
error in insulin dose; failure to eat; ↑exercise
↓insulin need after removal of a stress situation
medication changes
a change in insulin injection site
- Alcohol ↓ liver gluconeogenesis; ingestion of large amts or on an empty stomach in DM → hypoglycemia
- Not complication in itself but with the treatment of the disease. It is an emergency situation.
Symptoms
- Hunger
- headache, anxiety, difficult problem solving, anxiety, irritable
- tachycardia, sweating, cool/clammy skin
- potential to advance to seizures or coma
- Autonomic related: sweating, shakiness, palpitations, tremor
- CNS: confusion, weakness, irritable, convulsions, coma
- Nocturnal hypoglycemia: night sweats, nightmares, morning headaches
- Beta blockers can mask symptoms of hypoglycemia. Sweating cannot be masked because the sweat receptors are muscarinic at the preganglionic site. Hunger cannot be masked either.How do you know whether a diabetic pt's coma is due to hyperglycemia causing ketoacidosis or insulin overdose that is causing hypoglycemia?Check blood pH, check blood glucose, most importantly smell of the pt's breath.What are examples of Chronic Complications of DM?Microvascular complications (neurons)
- Retinopathy
- Neuropathy
- Nephropathy
- GI motility disorder
Macrovascular complications (CV)
- Coronary heart disease
- Stroke
- Peripheral vascular disease.
- Foot ulcers
- Infections 4 main molecular mechanisms of chronic complications of DM1. ↑ polyol pathway flux
2. ↑ advanced glycation end-product (AGE) formation
3. activation of protein kinase C (PKC) isoforms
4. ↑ hexosamine pathway flux.
- account for microvascular and macrovascular pathologies
- all are related to the diabetic hyperglycemic state
- associated with the overproduction of superoxide radicalMicrovascular complications: Polyol pathwayPersistent hyperglycemia will result in the presence of reactive oxygen species which h will cause reduction of glucose and the alcohols to sorbitol. Sorbitol is a hyper osmotic agent. It can also be converted to fructose. It can really cause damage to neuronsMicrovascular complications: Hexosamine pathwayHexosamine will result in glucosamine-6-p production. That will result in a lot of UDP-GLcNAc. This product is used to glycoslate a lot of proteins like collagen and other molecules. When some of these AA are glycoslated, the product that is formed is not very functional.Microvascular complications: Protein kinase C pathway and AGE pathwayGlyceralderhyde-3-p, resulting from the metabolism of glucose, will yield AGEs. Glyceralderhyde-3-p can easily be converted to methylglyoxal. This results from diketone groups that results in AGEs. These products are what we see especially in HB. HB becomes gylcosylated over a period of time. Other proteins in the body can also be easily glycosylated because of persistent hyperglycemia.Microvascular complications of DM- DM is a leading cause of vision loss/blindness as well as chronic kidney disease.
- Related to production of advanced glycation end products (AGEs) - reflected in HbA1C measure
- AGEs stimulate ↑reactive oxygen species (ROS) production
- ROS damage endothelial cells by ↓NO (very important in vasodilation) → endothelial dysfunction
- - damage from AGEs + oxidative stress, chronic systemic inflammation, & dyslipidemia are all associated with microvascular complications
- We can measure glaciated Hb as a measure go glycemic level of the individual. IF A1C is high, every increase in the glycemic state by about 28 mg/dl results in the increase in the unit of A1C. That can give you an idea of glycemic control by a period of 1-3 months.Retinopathy- The osmotic damage can easily cause retinopathy when it comes to the retinol cells.
- Myelin sheath losing the osmotic balance can easily damage the neurons.
- Poor glycemic control causes osmotic damage → retinopathy
- aldose reductase converts glucose to sorbitol which draws water into tissue causing damage to pericytes and myelin sheath→ microaneurysms of retinal vessels → retinopathy
- Could cause formation of cataracts
- Non-proliferative: microaneurysm formation, flame hemorrhages, exudates
- Proliferative: formation of new vessels (neovascularization), ↑ risk for retinal detachment & blindnessPeripheral neuropathy - Diabetic Foot Ulcers- Especially with long neurons, there is damage to myelin sheath. There is also damage to Schwann cells (producers of myelin sheets that cover neurons). This can easily lead to neuropathy. Pain is also protective mechanism. because of pain, you can withdraw before damage is done. When there is neuropathy, the level of sensation is decreased. That can lead to damage of the tissues. Because of the decrease in microcirculation, healing is also impede Eventually you can have neuropathic ulcer. This can result in gangrene if not treated.
- Poor glycemic control → osmotic damage of Schwann cells → demyelination & sensorimotor peripheral neuropathy →neuropathic ulcers - on the bottom of the feet
- Peripheral neuropathy - risk factor for neuropathic ulcers (patient cannot feel pain)
- Sensory: paresthesia, patients complain of burning feet, ↓pinprick sensation, ↓proprioception (ataxia)
- Motor dysfunction: muscle weakness, ↓deep tendon reflexesGastroparesis- Autonomic neuropathy is one of the early detecting of underlying disease. Most of the time when there is neuropathy in diabetic individuals, there is impotence.
- Gastroparesis - decreased stomach motility → delayed emptying of stomach.
Autonomic neuropathy e.g., diabetes mellitus
Previous vagotomy
- Clinical findings include: early satiety; vomiting undigested food
*Autonomic neuropathy can also cause impotence, neurogenic bladder, orthostatic hypotensionMacrovascular Complications- Vascular damage owing to hyperglycemia & metabolic syndrome ↑ risk of macrovascular complications in DM.
- Microalbuminuria
+ strong risk factor for macrovascular disease
+ present at the time of diagnosis
+ require screening - urinary analysis for albumin
- Most of the macrovascular changes are due to non enzymatic glycoslyation (glucose + Amino acids). It can cause structure malfunctions like nonezymatic glycosylation of arteries/arterioles. When it occurs in the kidneys or vessels supplying the heart we can have consequent diseases.
- Nonenzymatic glycosylation - glucose combines with amino groups in proteins
- Nonenzymatic glycosylation of arteries/arterioles → hyaline arteriosclerosis
+ coronary artery disease
+ cerebrovascular disease & stroke
+ peripheral vascular diseasePeripheral Arterial Disease & Foot Ulcers - Claudication & non-healing foot ulcers are common in T2DM.
- Gangrene of the lower extremities - most common cause of non-traumatic amputation of the lower extremity
- Smoking cessation (smoking enhances this process), correction of dyslipidemia, good glycemic control, & antiplatelet therapy are important treatment strategies.
- Claudication and gangrene are associated with nonenzymatic glycosylationRenal disorders - nephropathy- Poor glycemic control cause nonenzymatic glycosylation of renal arterioles → glomerulosclerosis → small scarred kidneys with granular surface
+ Glomerulosclerosis of efferent arterioles → hyperfiltration injury + microalbuminuria(due to increase in secretion of albumin which are not supposed to be filter into glomerular filtrate.)
+ Diabetic microangiopathy - ↑ synthesis of type IV collagen in basement membranes → diabetic nephropathy
+ Glycemic & BP control prevent/slow progression of nephropathy.
- Nephropathy is associated with both micro and macrovascular symptomsInfections- DM→ ↑ susceptibility to certain types of infections - soft tissue infections, osteomyelitis, UTIs & pyelonephritis, candidiasis, dental caries, & periodontitis
Reasons for ↑risk for infection in DM:
1. The senses - impaired vision & sensory neuropathy → loss of protection with injury. - If vision is not well, you can easily injure yourself. You cannot feel pain associated with injuries.
2. Hypoxia - compromised skin integrity, vascular disease & hypoxia - glycosylated hemoglobin in the RBCs ↓release of O2 to tissues.-- Circulated RBCs are impaired. This means oxygen that is required to the circulating tissues for healing is not occurring.
1. Pathogens (thrive in hyperglycemia state) - ↑glucose in body fluids →↑proliferation of pathogens
2. Blood supply - vascular changes & autonomic dysfunction →↓ blood supply →↓ supply of WBCs to the affected area.
3. Suppressed immune response due to chronic hyperglycemia
4. Delayed wound healing - ↓collagen synthesis & angiogenesis →↑infection.Pharmacologic targets in the treatment of T2DMTherapeutic effects of diet, exercise, & drugs used in the treatment of patients with T2DM Treatment of T2DM - Key ADRsAgents that act primarily as insulin sensitizersThese agents promote glucose utilization in the presence of insulin
1. Biguanides (agonist) - AMP kinase activator - Metformin-Glucophage®
2. Thiazolidinediones (agonist) "TZD's" (glitazones) - Peroxisome proliferator activated receptor (PPAR) agonists - pioglitazone-Actos®, rosiglitazone-Avandia®
NB: glucagon like peptide -1 (GLP-1) agonists have insulin sensitizing effects as part of their MOA
i.e. liraglutide-Victoza®, dulaglutide-Trulicity®, etc (we don't have orally activating agents at this time)Metformin-GlucophageDose
- 500, 850, 1000mg IR BID dosage
- Glucophage-ER® 500; Riomet® oral soln
- Fortamet®; Glumeteza® ER 500, 750, 1000 mg QD
- Best benefit-risk profile for glycemic control, weight loss, safe of all orals
- Good for early in DM or pre-diabetes & obese T2DM - Weight loss is observed
- ↓ FBG mainly & some ↓ PPG
- Most common oral agent
- Pcol effect starts to ↓ after 5 y of use
- One of the most useful agnents and is one of the safest drugs on the market.
- Patient can be on it for a long time (5 yrs) before it hits the ceiling of its efficacy. You can also titrate it up. Unlike sulfonylureas that hit a ceiling within a short period of time.Metformin-Glucophage® - SAR- Guanide is not a safe chemical. If you take two and combine, you have biguanide. Biguanides are quite safe and decrease glucose levels because they sensitize insulin.
- If we modify the structure of biguanide, we have metformin. Phenformin was on the market for a while but withdrawn from the Markey due to the induction of lactic acidosis.
- Originally from Plant source of biguanides - French lilac (Galega officinalis)
- PO - easily absorbed from the small intestine - No significant plasma protein binding
- Metformin uptake into cells is via organic cation transporters (OCT)
- OCT 1 - hepatocytes & myocytes (therapeutic effect) - gets into cells
- OCT 2 - renal tubules for excretion - elimination - It uses OCT 2 when it is having excreted Anything that competes with metformin at OCT2 will increase metformin levels.Metformin - Pharmacological effects Insulin sensitizer - anti-hyperglycemic agent - very beneficial
- Primary antidiabetic effect: insulin sensitizer, ↓ insulin resistance
- ↑ insulin-stimulated glucose uptake in skeletal muscle, fat cells
- ↑ GLUT-4 transporters
- ↑ insulin-stimulated glycogen synthesis in liver & muscle
- ↓ hepatic glucose production & secretion - metformin does not ↓ glucagon secretion
- ↓ hepatic fatty acid synthesis
- Weight loss (modest)
- Enhance glucose uptake in the presence of insulin through. Glut - 4 transporter. It also enhance glycogen synthesis though insulin effect.
- decrease hepatic gluconeogenisis and glycolysis
- decrease hepatic FA synthesis
MOA:
- Activates AMP-dependent protein kinase (AMPK)
A. ↑ AMP stimulates AMPK
B. Act to ↓ lipidsMetformin-Glucophage® - Pharmacology1. Metformin enters cell thru transporter OCT1
2. inhibits mitochondrial breakdown of ATP inside liver cells → ↑ ADP & AMP in cytoplasm
3. ↑ AMP activates AMP-dependent protein kinase (AMPK) in cytoplasm
4. inhibits the effects of adenylate cylase ↓ cAMP & PKA in cytoplasm
5. ↓ gluconeogenesis
6. ↓ glucose secretion from GLUT2
When metformin is taken up by OCT 1 transporter, it binds to mitochondrial complex 1. It enhances generation of ADP and AMP in the cytoplasm. We have inhibition of breakdown of ATP. Increase in AMP activates AMPk in cytoplasm. When AMPK is activated, we have inhibition of cyclic AMP by inhibiting Adenylate cyclase. decrease in cAMP will affect DKA downstream, There will be decrease in gene expression that express various gluconeogenic affects within the liver. If we are inhibiting genes the express enzyme involved in gluconeogensis, there will be a decrease in gluconeogenesis. There will also be a decrease in generation of glucose in through GLUT2. Increase in AMP will inhibit FBPase. This will block a critical step of gluconeogenesis. Then we have decrease amount of glucose. Overall the effect is decreased dumping of glucose into the blood stream.What are the direct effect of increasing AMPK?It inhibits affect of adenylate cyclase to decrease cAMP and PKA in cytoplasm and inhibit expression of lipogeneic gene expression within the nucleus. It also inhibits FBpase.Metformin-Glucophage® - ADR- GI (>10%): NVD, anorexia
- DERM (1-10%): rash
Loss of vitamin B12 due to malabsorption:
+ peripheral neuropathy
+ Weakness
+ Numbness
+ Tingling
+ macrocytic anemia - 13%/y ↑ risk of B12 deficiencyLactic acidosis in metformin(rare)
- Electrolyte disturbances, ↓ blood pH, hypothermia, hypotension, arrhythmias, confusion, coma, death may occur in marked acidosis
- can occur in patients with severe kidney disease
- Metformin inhibits lactate uptake by the liver for gluconeogenesis - occurs mostly in:
+ renal failure → lactate clearance may be impaired
+ heart failure → ↑lactate productionMetformin-Glucophage® DI/CIDrug Interactions:
Cimetidine-Tagamet® ↓ renal elimination of metformin →↑ [metformin]pl
- metformin (90%) eliminated by tubular secretion (There is competition of OCT2 within the kidney. It is known that in the present of cimetidine, it decreases renal elimination of metformin)
Contraindications:
- Avoid metformin in hepatic disease (Metformin effect occurs in a key organ, the liver. If someone has liver disease, there is a likelihood that toxicity is high. Caution with liver disease)
- Kidney failure: FDA - metformin is contraindicated in severe kidney disease (eGFR < 30 mL/min/1.73 m2)Peroxisome Proliferator Activated Receptor (PPAR) agonists- PPARγ agonists for DM - pioglitazone-Actos®; rosiglitazone-Avandia®
Thiazolidinediones-TZDs "glitazones":
- Anti-hyperglycemic agents, insulin sensitizers
- takes weeks to months to ↓blood glucose
- No hypoglycemia
MOA: Bind to nuclear peroxisome proliferator activating receptor-gamma (PPAR-) which leads to increased sensitization of cells to insulin; decrease hepatic gluconeogenesis;
upregulate insulin receptors; Afteer TZD bind go PPAR, it heterodimerizes with the retinoid x receptor and binds to PPRE elements. This binding activation and heterodimerization processes recruitment of coactivators and kicking off corepressors.Peroxisome proliferator activated receptor physiology/pathophysiology- PPAR found in the nucleus of many cells throughout body
- Endogenous ligands (ie Fatty acids, PG's) binds to PPAR which binds to DNA & form activated complexes that initiate new protein synthesisPPAR agonists - Pharmacology1. Glycemic actions due to PPAR-γ stimulation
Muscle cells: ↓ insulin resistance -↑ glucose uptake
- ↑ GLUT 4 transporters translocation from cytoplasm to plasma membrane
- ↑ glycogen storage
Liver: ↓ glucose secretion; ↑ glycogen storage
CV effects
- Adipogenesis: formation of fat cells; movement of triglycerides out of the blood
- Lipids: ↓ TG, ↑ HDL, ↑ LDL #s
NB: TZDs do not ↑ insulin binding to receptors, bind to insulin receptor, nor stimulate insulin secretionPPAR agonists - SAR- Core pharmacore is 2,3 - thiazolidnedione
- Acidic head group: contains TZD ring - interact with PPARgamma by several H-bonding with AA groups on the receptor
- Lipophillic side chain: modifies pharmacokinetic & toxicity profiles
- Linker region with central aromatic ring:essential for activity - large grp substitution on aromatic ring →↓ activityPPAR agonists metabolism and ADRADR:
- Weight gain, edema, ↑ total fat (2-6 kg) - wt gain of > 10 Kg documented
- Bone: ↑ risk of fractures
- Boxed warning: elevated risk of CHF (both Rosiglitazone & Pioglitazone)
Rosiglitazone - cardiovascular events (MI, stroke)
NB: Pioglitazone may have effect protective effect on ASCVD
CI: Liver disease (monitor LFTs)Sulfonylureas - PharmacologyOral hypoglycemics (induce insulin which will mobilize glucose to the point where hypoglycemia can occur)
- Need some endogenous β cells in pancreas
- Lower FBG > PPG
- Work better in non-obese & earlier onset T2DM (when there are more beta cells) - agents lose efficacy with time
MOA:
Main effect: stimulate the release of endogenous insulin from β cells
Bind to sulfonylurea receptor (SUR) KATP channel complex → closes the channel → longer Ca2+ channel opening → [Ca2+]i ↑ → longer duration of insulin secretion
Elicits insulin release regardless of plasma glucose conc.
NB: Prolonged use → persistent depolarization of β cells & loss of efficacy
- cannot be used in T1DMSulfonylureas - SAR- Sulfa antibacterial agent origin with urea moiety
- Phenyl ring with large groups in para position ( R1 ) ↑binding →↑ potency to ATP-sensitive K+ channelsFirst generation sulfonylureas vs second generation sulfonylureasFirst gen: Most of the first gens are obsolete. They fell out of favor because the R1 (which determines potency) is very small. Potency of the products are very low. Although the N3 substitution (the linear and cyclic substitution) enhances DOA. You have to use higher concentration. Major ADR is hypoglycemia.
Second gen: N3 Substitution is almost all cyclic and R1 position are all bulky. Bulky groups create better lipophilicty. Bioavailability is enhanced. Potency is enhanced as well.Sulfonylureas - Second GenerationGlyburide - 1.25, 2.5, 5 mg non-micronized; QD ±food
Glyburide-Glynase® - 1.5, 3 & 6 mg micronized; QD ± food; <GI ADR
Glipizide-Glucotrol®; Glucotrol XL® - 2.5, 5, 10, 20 mg; best on empty stomach AM
Glimepiride-Amaryl®
- QD, w/o regard to meals
- insulin secretion may be influenced by plasma glucose levels
- best in class due to ↓ hypoglycemiaSulfonylureas pk and ADRs- 90-99% bound to plasma protein; plasma protein binding is greatest for glyburide.
- Hepatic metabolism - the metabolites are excreted in the urine
- Caution in renal or hepatic insufficiency.
ADR:
- CNS (>10%): headache
- GI (1-10%): Nausea, heartburn, weight gain (not as much as insulin)
- Endocrine (<1%): marked hypoglycemia w/ associated CNS & autonomic abnormalities
CI: - Treatment of Type 1 DM, Pregnancy
There has been research reports about CVD events associated with Sus. The research is that there are other isotherms of SUR on vessels and heart.Activation of the SUR on vessels causes constriction and reduction of blood flow. On the heart, it causes retention of K+ or closer e of K+ channel leading to problems with contractility and rhythm.Metabolism of Glyburide and Glipizide1. Oxidation of the ring
2. Oxidation of the R group
Oxidation is major metabolism
Metabolism to inactive metabolites via CYP2C9Metabolism - GlimeperideMethyl group is oxidized to an alcohol, but this is still an active metabolite. It is further oxidized to carboxylic acid to render it inactive.
- Metabolism via CYP2C9 to active metabolite M-1, & inactive metabolite M-2"Glinides" - Repaglinide-Prandin®; Nateglinide-Starlix- Carboxylic acid instead of sulfonylurea
- Dosing: 30 minutes immediately preceding each meal
- Quick onset and short duration of action
- Largely used to control post-prandial rises in BG (PPG)"Glinides" - Pharmacology- Short acting insulin secretagogues
- Main effect: stimulate the release of endogenous insulin from functional β cells
- Closes ATP-dependent K+ channel → longer Ca++ channel opening → ↑[Ca]i → ↑ duration of insulin secretion
- Acts at 2 binding sites in common with sulfonylureas & one unique binding site
- Better PPG-lowering effects than sulfonylureas; quicker onset
- Nateglinide: - glucose dependent action; very little stimulation of insulin secretion in absence of glucose
- They bind to SU site and their own site causing closure of the K+ channels and opens VGCC.
- Quicker onset of action than SU, but shorter DOA
- Even though SUR induce release of insulin without glucose, Nateglinidine is different. IT works better in the presence of glucose.GlinidesADR:
Endocrine (<1%): hypoglycemia with associated CNS and autonomic abnormalities
DI:
- Agents that cause hypoglycemia (alcohol, salicylates)
- Agents that cause hyperglycemia (glucocorticoids, β-adrenergic blockers - becomes less effective with agents that cause hyperglycemia)
CI:
Treatment of T1DM & pregnancyDipeptidyl peptidase IV (DPP-IV) inhibitorsAlogliptin-Nesina® - PO QD - ↓ doses in patients with ↓ renal function
Linagliptin-Tradjenta® - PO QD ± food
Advantages:
more potent / more selective for DPP-IV than other agents in class
Eliminated via the liver → dosage adj. not necessary due to renal problems e.g. nephropathy
Saxagliptin-Onglyza® - PO QD; Active metabolite is 2 fold less active than parent
Sitagliptin-Januvia® - PO QD, ↓ nausea
None of the agents in the class should be used in T1DMDPP-IV inhibitors - PharmacologyThe moment your meals gets into the GI tract there is a spike of insulin. The K and L cells secrete GIP and GLP-1. This activates G coupled receptors on beta cells. This cause the release of insulin. The GIP and GLP-1 activities are short lived. The moment they are released DPP-4 hydrolyzes them to inactive them. The inhibitor inhibit DPP-4 causing prolongation of GLP-1 and GIP.
MOA: Inhibits DPP-IV which ↓ GLP-1 inactivation
- Slow reversible competitive binding to DPP-IV
- Saxagliptin, vildagliptin, alogliptin contain cyano group
- forms a reversible covalent amidate with Ser630 → deactivation of DPP-IV
Pcol actions not exactly same as with GLP-1 receptor agonist
- Suppressed endogenous GLP-1 levels in certain disease states (i.e. IBD, bariatric surgeries) → ↓ effect DPP-IV inhibitors
- Low to no hypoglycemia observed when these agents used alone
- DPP-IV inhibitors less efficacious than GLP-1 receptor agonists - A1c ↓: 0.85 vs 1.7DPP-IV inhibitors ADRs and PKPharmacokinetics:
Dosage adjustment in moderate to severe renal disease required - not Linagliptin-Tradjenta®
ADR:
- Headache 5%
- Pancreatitis reported with class: Sitagliptin (88 cases)
- patient at greater risk - e.g. excessive alcohol use or very high TG levels
NB: Both GLP-1 RA and DPP-IV inhibitors have had some association with pancreatitis
Warnings/Cautions/CI
- May cause joint pain (reversible with discontinuation)
- Saxagliptin-Onglyza® and Alogliptin-Nesina® may ↑ risk for developing heart failureGLP-1 receptor agonists vs DPP-IV inhibitorsSodium-glucose linked transporter (SGLT-2) inhibitorsCanagliflozin-Invokana® 2013 - PO QD
Dapagliflozin-Farxiga® 2014 - PO QD
Empagliflozin-Jardiance® 2014 - PO QD
Ertugliflozin-Steglatro® 2017 - PO
-gliflozin or florin
- ↑ urination; take in morning vs at bedtime
- used in T2DM, not approved in T1DM
- ↓ FBG, ↓ A1c 0.7-1.0%, - ↓ SBP
- modest weight loss
Empagliflozin has demonstrated CV benefit in T2DM
- ↓ non-fatal MI & ↓ non-fatal stroke, ↓ CV death
- FDA expanded indication (↓ risk of CVD)SGLT-2 inhibitors - Pharmacology- Renal threshold for absorption from plasma 180-200 mg/dL
- Diabetics have ↑ SGLT2 transporters, yet get overwhelmed
- SGLT transport both glucose and sodium in the same direction. They are expressed in a lot of tissues especially the type 1. The type 1 is expressed in GIT and CNS in addition to the kidney, nephron. These have very high affinity to glucose. They transport glucose back into the bloodstream. We also have SGLT2. It is about 80-90% expressed along the plasma tubule. These have low affinity for glucose but high affinity at high capacity. Renal threshold for absorption is usually around 180-200mg/dL. When glucose is at 200 for a normal person it overwhelms the level of recapture. Glucose is a good nutrient. It is very important for energy. The body tries to recapture as much as it can within the proximal tubule. If the threshold is exceed, the glucose spills over into the urine. If more of it is being spilled the body decides to increase expression of SGLT-2. The threshold for will increase to 220-240in T2DM. This means recapture will increase as well.SGLT-2 inhibitors pcol- Blockade of the Na-glucose linked cotransporter-2 in the proximal tubule of the nephron
- Allows for glucose excretion independent of insulin secretion
- When we have high glucose, we want to excrete it, so we would block SGLT-2. If you are able to bloc this, glucose cannot be recaptured. It will stay within the lumen and be excreted. When glucose is being excreted, it draws water with it. There will be increased urination. We will also be blocking NA+ transport, so there will be a decrease in BP.SGLT-2 inhibitors - Beneficial effectsFDA granted a new indication to dapagliflozin (Farxiga)
- ↓ risk for sustained eGFR decline
- end-stage kidney dx
- CV death & hospitalization for HF in adults with CKD at risk for progression.SGLT-2 inhibitors ADRsADR:
- Urinary bacterial tract infections; female yeast infections (7.0%) candidiasis
Caution/CI:
- Moderate renal disease, GFR <30mL/min, end stage renal disease, or patients on dialysis
- Risk of ketoacidosis, typically w/in 2 wks of initiation of therapy - Check ketone levelsalpha -glucosidase inhibitors - PharmacologyThese are complex carbs. Acarbose and Miglitol inhibit the breakdown of carbs to the point where the available ones do not become available. IT delays absorption. You can then eliminate those carbs and decrease glucose level.
MOA: Competitive and reversible inhibition of pancreatic α-amylase, sucrase & α-glucosidase
- Monosaccharide & polysaccharide analogs
- membrane bound intestinal ɑ-glucosidase includes maltase, sucrase, isomaltase, glucoamylase
- Delays digestion of carbohydrates in the small intestine →↓ PPG
- Do not stimulate insulin release→ no hypoglycemia, preserve beta-cell function
- Minimal systemic absorptionɑ-glucosidase inhibitors - Pharmacology
- Dosing: initial therapy - start low and work up
25mg QDw/ meals → 100 mg TID 4-6 weeks
- Each dose should be taken at the start of each meal - indicated to control PPG rises
ADR: -
Initial GI:
- acarbose - flatulence(77%), diarrhea(33%), abdominal pain (21%)
- miglitol - flatulence(42%), diarrhea(29%), abdominal pain (12%)
chronic GI:
- acarbose - flatulence(20%), diarrhea(13%), abdominal pain (5%)
DI: Pancreatic enzymes - Pancrease®, Cotazyme® etc.
CI: Inflammatory bowel disease, obstructive bowel disorders
Flatulence - you have a lot of complex carbs present within the GIT. The bacteria will work on it producing tons of gas.Semaglutide -Rybelsus®Oral GLP-1 receptor agonist (RA)
- Semaglutide - Rybelsus® -3 mg, 7 mg or 14 mg tablets PO QD
- not recommended as 1st choice treatment
used in T2DM, not approved in T1DM & DKA
Indication - adjunct to diet & exercise to improve glycemic control in adults with T2DM
- Co-formulated with sodium N-[8(2-hydroxybenzoyl) amino] caprylate (SNAC)
- lipophilic - acts as a transcellular carrier across GI enterocytes by ↑ solubility
- ↑ resistant to proteolysis
- oral bioavailability is only 0.4% to 1%
- Only orally available GLP-1 agonist
- GLP-1 receptor agonist are polypeptides. How did we formulate a polypeptide that is able to stay within theGI tract and still be effective? Visa structural changes made in the AA sequenc (SNAC technology). The SNAC technology makes it resistance to enzyme hydrolysis. It also enhances absorption across the enterocytes.MOA of semaglutide (rybelsus)MOA:
- GLP-1 receptor agonists ↑ insulin secretion & ↓ suppress high PPG secretion → ↓ hepatic glucose production, ↑ satiety, ↓ gastric emptying, & weight loss
- normalizes FBG & postprandial insulin secretion.
Adverse Reactions: - GI (≥5%): NVD, abdominal pain, ↓appetite, & constipation
Warnings & Precautions- Risk of thyroid c-cell tumors, pancreatitis, diabetic retinopathy complications, hypoglycemia, acute kidney injury, hypersensitivityBromocriptine quick release (QR)-CyclosetPharmacology
- Centrally acting D2 dopamine agonist that affects patterns of food intake & nutrient storage
- ↑ Dopamine activity in the brain - exact MOA unclear
Indications
- ↓ PPG in T2DM; ↓ A1c 0.4-0.7%
- 0.8 mg daily much lower dose than used in Parkinsons Disease
- PO QD AM; No hypoglycemia; Not used in T1DMColesevelam - Welchol® Pharmacology- Added to oral therapy in T2DM when A1c are not too elevated - (6-7 tabs/day)
- Control basal glucose levels: FBG: ↓ 15 mg/dL HbA1c: ↓ 0.8%
- Lipid lowering - ↓ total cholesterol & LDL
MOA:
- Large non-absorbable anion-exchange resin that binds bile acids in exchange for Cl- in the intestine which later gets excreted
- ↓ metabolism & absorption of dietary cholesterol and fats
It is theorized to work on Farnesoid receptors. They are intracellular receptors. Binding to these receptors turns on certain transcription factors that brings about a change. IT is also thought that being a resin, it traps glucose from being absorbed.
- Binding to bile acid means the bile acids cannot undergo inter hepatic circulation. They will have to be excreted.
- Bile is made from cholesterol. The body will have to use cholesterol form the body.Combination products/therapies for DM- BG or A1C lowering is not always additive and no reports of synergistic lowering
- Undesirable combinations i.e. : same class; 2 agents that work on post-prandial; 2 insulin secretagogues
- Important because they increase pt compliance and clinical outcomesMetformin in combination therapyWhen you have agents used alone, the A1C doesn't go down that fast. When we have combinations, A1C goes down quicker and certain agents when used with metformin work better than when used alone.GLP-1 agonists + insulinChromium- Alpha Betic® : multivitamin with chromium & alpha lipoic acid
- Diachrome® : chromium + biotin
- Chromium Improves insulin sensitivity & enhances biological efficacy of insulinSoluble fibers ie pectin, mucilages found in Nopal, fenugreek, psyllium, gymnema-Beta fast GXR®- "Maintain normal blood glucose, curb sweetness cravings"
- ↓ postprandial glucose rises and ↓ fat absorptionKarela - bitter melon- Insulin secretagogue & ↓ glucose absorption
- CI - pregnancy: abortifacientHerbals- Beta Fast GXR Glucose Tolerance - Gymnema sylvestre extract plus Chromax® (Chromium Picolinate) & Vitamin C, formulated in extended release tablets.
- Blood Sugar Balance: + Gymnema, bitter melon, alpha lipoic acid, vanadium, quercetin, chromium, Mg2+, Zn2+
+ On Label: "helps support healthy blood sugar levels already in the normal range"
5- Aloe vera - Omatrix® oral 1200mg daily
+ preponderance of evidence suggests a trend towards benefit from oral aloe vera in ↓ FBG & ↓ HbA1c (AJHP 2010)What are the Ultra-rapid insulin?Inhaled insulin-Afrezza®
Insulin aspart-FIAsp®What are the Rapid acting insulin?Insulin lispro-Humalog®
Insulin aspart- Novolog®
Insulin glulisine-Apidra®What are the short acting insulins?- Regular- Humulin R U100, Novolin R U100
- Regular-Humulin R U500What are immediate acting insulin?- NPH (neutral protamine hagadorn)
- Humulin N®, Novolin N®What are the Long acting insulin?- Insulin glargine-Lantus® U100
- glargine-Basaglar® U100
- insulin detemir-Levemir®What are the ultra long acting insulins?- Insulin degludec-Tresiba®
- Insulin glargine-Tougeo® U300What are the premixes of insulin?- Humulin 70/30 (70 NPH/30 reg)
- Novolin 70/30
- Humulin 50/50
- Humalog 75/25
- Humalog 50/50
- degludec + Insulin aspart -Ryzodeg® 70/30Insulin - Synthesis & processingInsulin is a polypeptide hormone.
- We first have preproinsulin which consists of the signaling peptide of 24 AA, Beta chain of 30 AA, C peptide of 31 AA, and A chain of 21 AA. Within the ER, the SP will take the peptide to the right location for processing. Within the Er, there is cleavage of SP. There is folding into intra disulfide bonds between cysteine moiety with polypeptide A. We have inter disulfide binds between polypeptide A and B. When this is done, we have prohormone convertase type 1 and 2. They are going to further cleave polypeptide at specific sites. PC1 is going to cleave Arg units 31 and 32. PC2 will cleave Lys 64 and Arg 75. This takes place in the Golgi apparatus. When it is at the point of release we have insulin with polypeptide A+B and Polypeptide C released together in equal molar amts. They will be packaged secretory granules.How do you measure insulin in a person?Insulin half life is only 5-10 minutes so we measure polypeptide C.Insulin - Regulation of secretion- Insulin is produce by pancreatic islet beta cells. The beta cells will produce insulin under the influence of several factors. The most potent factor for insulin release is glucose. Apart from that AA, fatty acids can induce beta cells to release insulin.
- The moment food enters the digestive tract, incretins (GIP from K cells and GLP-1 from L cells) of intestine can stimulate beta cells by binding to G protein coupled receptor beta cells to release insulin. We also have incretin mimetic. These endogenous incretins work by activating insulin release.
- PNS enhance insulin rlease
- SNS, somatostatin, and glucagon inhibit insulin release.Insulin - Downstream effects of receptor activation- Insulin binds to tyr kinase linked receptor. This causes dimerization of the receptor leading to autophosphorylation. then subsequent signaling involved phosphorylation of GRB2 and SOS will lead to mitogenic pathway (leading to cell proliferation) This is why if you keep ins insulin in the same site there will be hypertrophy.
- Signaling through PI3-kinase leads to protein and glycogen synthesis and more importantly the insertion of GLUT 4 into the cell membrane. When we have glucose transporter inserted into the membrane, it can enhance uptake of glucose,. Glucose can then be metabolized and stored within the target cell.Insulin Physiologic actions↑ Glucose uptake
↑ Glycogen synthesis
↓ Glycogenolysis
↓ GluconeogenesisInsulin - Sources- Previously in order to treat T1Dm, insulin was readily made accessible through using porcine and bovine sources. These are close to human insulin and are easy to produce. However it comes with allergic rxns.
- Now we have advanced technologies.
- Produced by recombinant DNA tech.
- Soluble in aqueous solution
- Most preps are supplied at neutral pH
- Insulin in solution: Monomer, Dimer, Hexamer
- Conc-dependent effect
- Monomer - more soluble; binds to the receptor
- t1/2 of 5-6 min - extensive hepatic clearance
- 1 IU of insulin = bioequivalent of 34.7 μg of crystalline insulinRecombinant DNA origin-Humulins, Novolins- Huge improvement over porcine (pig) and bovine (beef)
- Biosynthetic/semi-synthetic preps
- Least antigenic
- More solubleInsulin analog - Humalog, Novalog- They are produced through recombinant tech, but you have side directed mutagenesis. We have modifications on insulin.Engineering insulin analogues- Modifications like Glulisine - Apidira enhances monoermic and helps wit rapid absorption and action.
- Insulin can associate into hexamers by means of zinc within the binding site. When it is absorbed, it needs to be diluted to dissassociate into monomers before it can act.
- Insulin can aggregate to dihexamers or multihexamers. This delays the process of absorption.Insulins - StabilityPhysical instability
- Insulin fibrils: Hydrophobic interactions → aggregates- insoluble & inactive.
- common in pumps - can be fixed with additives or modifying to a phosphate buffer
- Adsorption to PVC tubing
Chemical Incompatibilities:
1. Instability associated with peptidic drugs (terminal AA can associate at the terminals. This can form a residue that can impact the stability.)
2. At acid pH:
- Deamidation/dehydration of AsnA21
- Covalent linkage between terminal amino acid residuesInsulinsRoute of Admin:
- IV, IM, or SC - Long-term treatment - subcutaneous injection.
- Regular can be IV- absorbed directly into the blood stream
Factors influencing absorption
- absorption at site: abdomen > arm > thigh > buttocks
- exercise and heat: ↑absorption
injection: IM > SC; but SC is recommend due to ↓ pain
- inject into same body area: maintains constant absorption
- rotate site not injection area
- do not rub injection site (you dont want to move it to other areas of the body or to impact PK)
Brand substitution
A. should not interchange types or manufacturers
B. notify patient & physician of switches
Storage
- avoid freezing or heating; keep in refrigerator until used
- unopened vials/pens - store refrigerated until exp date on vial
- opened vial/pens can be kept at room temp. - based on manufacturer recommendationIndividual agent - Advantage/Disadvantage of insulinsimmediate onset with rapid acting :
- inject prior to meals
- ↓ potential for hypoglycemia
Continuous SC insulin infusion (CSII):
A. Rapid acting insulin throughout day & night
B. Dial in extra units for meals & snacks
C. Best for young, health care knowledgeableInsulins - ADR/complicationsHypoglycemia
- Risk factors: intensive insulin therapy, error in admin, unusual exercise, infection
- Other drugs associated with hypoglycemia - hypoglycemic agents (sulfonylureas) - alcohol acute ingestion, salicylates
Weight gain (2-4 kg) - insulin cause excess glucose to move into adipose cells
Hypokalemia - insulin facilitates K+ entry into cells
Hypersensitivity reactions (rare) - local injection site reactionsLipodystrophy- local atrophy or hypertrophy of subcutaneous fatty tissue at the site of injections
- Lipohypertrophy - growth of adipocytes
- Lipoatrophy - dimpling at site
- prevent by rotating injection site
- Insulin is a metabolic hormone. It enhances metabolism.Treatment of hypoglycemia:- Glucose (10-15 g) PO for conscious patients is preferred
- Dextrose IV may be required for unconscious patients.
- Glucagon, 1 g IM - preferred in unconscious patients when IV access cannot be establishedDrugs that may cause ↑ blood glucose (hyperglycemia) with insulin- changing meds may require dose adjustments
- β-blockers, glucocorticoids, niacin, pseudoephedrine
- thiazides, statins, cough syrups, quinolones
- protease inhibitors, immunosuppressants e.g. cyclosporin, antipsychotics e.g. clozapine
- alcohol (chronic use)Insulins - dosing regimens- Fixed dose - for a typical patient
- Sliding scale insulin dosing - based on blood glucose levels, carbohydrates counting
- more ambitious situation - continuous pump used in T1DM, young, athletesinsulin regimens1 long-acting & 3 rapid-acting injectionsRapid Acting Insulins - structural variationPost prandial glucose (PPG) control - injected immediately (15 min) before or after starting a meal
- Onset: 5-15 min, peak: 0.5-2.5 h, duration: 5 h
Modified to retain either a monomeric or dimeric configuration
- analogs dissociate into monomers almost immediately after injection
- β-chain substitutions prevent the formation of hexamers → shorter actingInsulin Lispro (Humalog)rapid acting insulinInsulin Aspart (Novolog)rapid acting insulinInsulin glulisine (Apidra)rapid acting insulinRegular Insulin - AfrezzaUltra-rapid acting - peaks within 12 to 15 min - eliminated within ∼ 1 h
- Regular insulin absorbed into technosphere micoparticles for pulmonary absorption
- excipient - fumaryl diketopiperazine (∼ 2.0 -2.5 µm) is used to adhere/microencapsulate insulin
Insertable cartridge - discard device after 15 days
- Bring to room temp 10 min prior to inhalation
- 1 inhalation at beginning of meal
CI/caution
asthma and COPD
not to be used in smokers
Side effects - Cough & throat irritationUltra-Fast actng Insulin Aspart - FIAspFIAsp - formulation of insulin aspart with 2 excipients added
1. Niacinamide (vitamin B3): ↑ speed of absorption
2. Arginine: formulation stabilizing amino acid
"ultra-fast-acting"Short Acting Regular InsulinsInsulin regular-Humulin R® Novolin R® U100 U-500
- should be injected 30-45 min before a meal
1. regular has same sequence as human insulin
2. PPG control
3. Onset:
- U100 30-60 min, peak: 2.5-5 h duration: 4-12 (8) h
- U500 30-60 min, peak: 4-8 h duration: 13-24 h
- U-500 used in insulin resistant patients
+ High alert labeling recommended
+ Dosing errors have occurred when from vial
+ Pre-filled pen is a better option.
+ associated into hexers, a form that is absorbed at a slower rateIntermediate Acting InsulinsInsulin NPH (neutral protamine hagedorn)-Humulin N, Novolin N®
- Fasting/basal blood glucose (FBG) control
- Onset: 1.5-2 h, peak: 4-12 h, duration: 14-24 h
Pharmacological properties
- Protamine + Zinc (low conc)
- protamine complexes with insulin to keep hexameric form longer
- suspending agent results in a cloudy opaque appearance of the preparation
- shaking can disrupt hexamer structure & alter rate of absorption
ADR
- Allergic reactions to additives such as protamine, a fish protein derivative can occurLong acting - Insulin detemir-Levemir- Basal (FBG) control - Onset: 90 min no peak duration: up to 24 h
Pharmacological properties:
- Long acting
- Removal of threonine (B30 position) & binding of a 14-carbon fatty acid (myristic acid) to the B29 lysine → prolonged DOA (N-acetylation)
- Myristic acid enhance formation of hexamers & dihexamers - very stable; take longer to dissociateLong acting and ultra long acting InsulinsLong-acting Insulins - 24 h
1. insulin glargine
A. Lantus® U100
B. Basaglar® U100
Ultra long-acting Insulins
1. insulin glargine-Toujeo® U300 30 h
2. insulin degludec-Tresiba® U100, U200 36 h
General Information
1. FBG control (basal)
SN: If you take 1 unit of Lantus, it contents 100 IU/mL. Toupee is 1 unit = 300 IU/mLLong acting - Insulin glargine-Lantus- FBG control - Onset: 2 h no peak duration: 24 h
- Basal insulin - Once daily dosing; No peaks observed, more consistent blood levels
- Acidic pH → pain at injection site with larger vols (> 60units)
- Do not mix with other insulins in same vial
- Good in fridge for 42 days after opening, warm prior to injection
- Gly replaces Asn21(A chain); Arg-Arg dipeptide replaces Thr30 (B chain)
- Formulated at pH 4 →↓ solubility when injected at physiological pH
- Glargine precipitates in SC tissue → aggregation & delayed absorption after SC injection
- When you inj it under the tissue, it precipates. It is already in multi hexametric form. It precipates and dissociates slowly to hexamers then dimers then monomers.Ultra-long acting - Insulin glargine-Toujeo- FBG control - Onset: 2 h no peak duration: 30 h
- 300 units/mL (high concentration makes it last long)
- Solorstar Pen- max 80 units/dose 450 units/penUltra-long acting - Insulin degludec-Tresiba- Ultra long-acting insulin formulation for FBG control
Onset: 90 min no peak duration: 36 h
- Typically dosed QD at dinner - Lower risk of hypoglycemia (bc it is basal insulin)
SAR
- Deletion of threonine at B30
- Addition of 16-carbon fatty diacid (C16 FA- hexadecandioic acid) coupled to lysine at B29 via glutamic acid 'spacer'
- Forms large soluble multihexamer with hexadecandioic acid side chain binding to plasma albumin (PPB >99%) after SC injection.
- Results in protracted DOA due to delayed absorption from SC tissue to systemic circulation
- First there is hexametric form of tresiba. Once injected, it will aggregate. When it aggregates are in depot formation, it takes a long time to dissociate. Even after it dissociates into bloodstream and is absorbed, it lingers because it binds to plasma protein albumin, which prolongs DOA.Amylin receptor agonistAmylin
- endogenous neuroendocrine hormone
- co-secreted with insulin by pancreatic β cells in response to glucose & amino acids
- has most of its actions in the brain
↑ satiety
↓ gastric emptying
↓ glucose secretion from liver
- Plasma amylin levels ↓ up to 50% in T2DM in addition to ↓insulinAmylin effectInsulin is usually cosecreted with amylin. Amylin also in some ways changes the actions of glucagon. More importantly, it has its own effect. Even though it is a hormone, it has some effects on neuro pathways. How does it do that Most of its effects are in the CNS with the Area Postrema. The receptors are located there. When amylin acts on its receptors, it normally also acts on alpha cells to decrease glucagon secretion. Gluconegensis will be inhibited. Release of glucose by the liver into the blood stream will decrease.Pramlintide (Symlin)a synthetic analog of human amylin
Pharmacological effects
- Delays gastric emptying
- Regulates caloric intake by modulating amylin receptors in the CNS
Anorectic effect - promotes satiety: ↓ total caloric intake; ↓ glucose uptake
- Inhibits glucagon secretion from α cells;
Liver: Glycogen → glucose production & secretion
- ↓ postprandial glucose, ↓ weight
ADR:
hypoglycemia (normally happens when given with other hypoglycemic agents)
- inhibits the breakdown of glycogen or mobilization of glucose from non-carb sources. It allows liver to synthesis/store glycogen instead of breaking it down to form glucose and dumping it into the blood.Pramlintide acetate solution- (pH 4) - Pens only
- SC dosing just prior to meals, snack
- Adjunctive mealtime therapy in patients using insulin (Type 1 & Type 2)
- Able to ↓ insulin doses by as much as 50%
- Potential benefit in overweight diabetics using insulin
Refrigerate pens, 28-day expiration dating after opening
Boxed warning- associated with severe hypoglycemia when administered with insulin productsGLP-1 receptor agonists (incretin mimetics)- Normal individuals:
+ Insulin secretion is greater in response to oral vs IV glucose
+ incretin hormones are released from the gut to promote insulin release
T2DM
+ Insulin deficiency & glucagon hypersecretion
+ Loss of "incretin effect" on insulin release & lose suppression of glucagon secretion
Indication
- FBG (-20 mg/dL) < PPG (-6 to -70) control (affect on PPG is higher than FBG)
- Type 2 DM patients without GI disease
- Obesity - liraglutide-Saxenda® - require higher doses for efficacy (3.0 mg/dL vs 1.8 mg/dL)glycogen vs glucagonGlucagon and glycogen are not the same. Glycogen is a stored form of glucose (sugar). Your body primarily stores glycogen in your liver and muscles. Glucagon is a hormone that triggers liver glycogen to convert back into glucose and to enter your bloodstream so that your body can use it for energy.GLP-1 receptor agonists Effects on blood glucosePancreas:
- Stimulates insulin release from β cells; ↑ production of new β cells - ↑ insulin release is plasma glucose dependent
- ↓ glucagon secretion from pancreatic α cells → ↓ glucose secretion from liver - plasma glucose dependent
GI tract:
- ↓ gastric emptying; ↓ postprandial glucose spikes
CNS:
↑ satiety and ↓ urge to eat (unknown CNS mechanism)
Muscle, adipose:
acts to ↑ GLUT-4 transporters
Overall - ↓ FBG, ↓ PPG, ↓ A1c, ↓ weight (1-8 lbs)GLP-1 receptor agonists Non-glycemic effects/mostly CV benefit- ↓ blood pressure - Promote vasodilation;
- ↑ Na+ excretion
Improves the lipid profile (independent of weight loss) - just minor benefit - ↓TC, ↓LDL, ↑HDL, ↓TG
- Mild weight loss noted 0-4 kgGLP-1 receptor agonists - Incretin effectWhat is the incretin effect?It was realized that if you take individuals and give them glucose that higher insulin response was achieved when glucose was given orally.
- Orally delivered glucose produces much higher insulin plasma levels because β cells are stimulated by gut hormones to release additional insulinGLP-1 receptor agonists - ADR, Warnings, Precautions/CI1. NV during the initial weeks of therapy
- avoid in patients with pre-existing GI disorders
- Early GI incidence : NVD (≥ 28%,11%,17%)
- tachyphylaxsis to ADR with time
- can be reduced with dose titration and time
2. FDA 2011: monitor for severe unexplained abdominal pain
10/2006 - 36 cases of acute pancreatitis; 6 deaths with exenatide
3. CI with history of medullary thyroid cancerHow are incretins released?Upon the arrival of glucose. Glucose gets metabolized by K or L cells. App to ADP ratio increase. ATP dependent K+ channels are closed leading to depolarization of the K cells or L cell membrane. VGCC open and CA2+ influx happens. This leads to the release of GIP or GLP-1. GIP and GLP-1 bind to receptors on beta cells to induce release of insulin.GLP-136 residue peptide hormone released from L-cells in the intestines following food consumptionExenatide (Byetta)- Exenatide is a potent agonist of GLP-1 receptor and is resistant to degradation by DPP-4 because of the lack of alanine or proline at position 2.
- incretin (GLP-1) analog- stimulates glucose-dependent insulin secretion
- derivative of Exendin-4 - peptide isolated from Gila monster lizard's saliva (Heloderma suspectum)
- Ala replaced by Gly - resistant to metabolism by DPP-IV
- Admin. SC - BID (1/2 - 1 h before meals) in 60 dose autopen
- Keep refridgerated; discard after 30 days.Liraglutide (Victoza)GLP-1 receptor agonists
- Represents amino acid residues 7-37 of GLP-1
Modifications from GLP-1 include:
- Substitution of Lys34 with Arg34 = Resistant to hydrolysis by DPP-IV
C16 fatty acyl side chain (linked through glutamine to Lys at position number 26. This prolongs half life):
- permits plasma ptns/albumin binding
- ↓ renal elimination
extended t1/2 - once daily admin.
Black box warning
Risk of thyroid C-cell tumors -used only when the potential benefits outweigh the potential risk.Lixisenatide (Adlyxin)GLP-1 receptor agonists
Modified amino acid sequence of exenatide
- deleted Pro38 (replaced with GLY) & a string of 6 Lys residues added to the Ser at the carboxyl terminus
- allows for 1 - 2 x daily SC admin
= Available as a combination product with insulin glargineDulaglutide (Trulicity)GLP-1 receptor agonists
- Long acting GLP-1 analog -once a week admin.
- It is a recombinant fusion protein
two analogs of GLP-1 covalently linked by a synthetic 16 amino acid linker to a Fc fragment of human IgG4.
- Two molecules: Ala at position 8 has been replaced with Gly. Apart from that, we have a fragment of immunoglobulin 4 linking peptides by means of a linker.Semaglutide (Ozempic)- Long acting GLP-1 analog -once weekly SC admin.
- Substitution of Ala8 for AiB8 (α-aminoisobutyric acid)- allows for resistance to DPP IV degradation.
L- ys26 is derivatized with a C18 fatty acid using an ADO-linker
- permits binding to albumin & other plasma ptns
- ↓renal elimination
- extremely ↑ t1/2 ∼165 hWhat are the SABAs?albuterol (accuneb, proair, ventoline, Proventil)
levalbuterol (Xopenex HFA and Neb)What are the ICS?Beclomethasone (Qvar)
Budesonide (pulmicort)
Fluticasone propionate (FP) (Flovent)
Fluticasone furoate (FF) (Arnuity)
Mometasone (Asmanex)
Ciclesone (Alvesco)What are the LABAs?Salmeterol (Serevent)
Formoterol (Perforomist)
Arformoterol (Brovana)What are the ICS/LABAs?FP/Salmeterol (Advair, Wixela,AirDuo)
FF/Vilanterol (Breo)
Budesonide/Formoterol (Symbicort)
Mometasone/Formoterol (dulera)What are the LaLa inhalers (lAMA/LABA)?Umeclidinium/vilanterol (Anoro)
Tiotropium/Olodaterol (Stiolto)
Glycopyrrolate/formoterol (Bevespi)What is the SAMA?Ipratropium (atrovent)What is the SAMA/SABA?Ipratropium/albuterol (duoneb, Combivent)What are the LAMAs?Tiotropium (Spiriva)
Revefenacin (Yupelri)
Umeclidinium (Incruse)
Glycopyrrolate (Lonhala)What are the LAMA/LABA/ICS?Umeclidinium/vilanterol/FF (Trelegy)
Budesonide/Glycopyrrolate/Formoterol (Breztri)Asthma- "2019 GINA strategy report represents the most important change in asthma management in 30 years."*
- For safety, GINA no longer recommends treatment with short-acting ß2-agonists alone.
- Adults (≥12yr) - rec symptom-driven or daily low-dose ICS to reduce risk of exacerbations
- US - 1 in 8 children; 300 million worldwide; 1-18% (country dependent)
Definition: Heterogeneous, characterized by chronic airway inflammation...
- ...history of respiratory symptoms such as wheeze, shortness of breath, chest tightness and cough that vary over time and in intensity, together with variable expiratory airflow limitation.
- Pts have periods of almost normalacy
- Not everyone has severe asthma attacks that lead to the hospital
- Even thought pts may be fine in a short period of time things can go left.Pathophysiology of asthma- Airway hyperresponsiveness/inflammation
- Phenotypes:
+ Allergic - most common; eczema, food allergies, eosinophilic (people who have very uncontrolled asthma usually have a high level of eos), T2-type
+ Non-allergic (more difficult to treat) - adults, less responsive to ICS controller meds
+ Late-onset - women; non-allergic
+ Fixed airflow limitation - long-standing; airway remodeling (uncontrolled asthma can go for so long that it can cause fixed airflow)
+ Asthma with obesity - little eosinophilic inflammation (complicating factor so drugs will not work as well)
- Triggers - allergens, smoke, viral infections, exercise, weather
- Symptoms resolve - spontaneous or with meds (return of normal)
+ Sometimes absent for weeks or months at a time
+ Episodic flare-ups (exacerbations); can be life-threateningDiagnosis of asthma- With most other disease states, we diagnose first THEN medication. With asthma, we do medication then diagnosis.
- History of variable symptoms
- Spirometry confirms
+ Variable airflow
- <6yo Spirometry not possible
+ Eczema
+ Atopy (allergies)/food allergy
+ Family history
+Symptom questions
~Nighttime cough
~Exercise tolerance
~Triggers
- If someone doesn't have muscle skills or the mental compact to perform a PFT maneuver, we may have to use drug therapy to see if they will respond. IF clinical urgency and other diagnosis unlikely, we bypass the PFT and reversibility test.
- 12% FEV1 change = positive test
- Other things can bypass asthma testing such as family history, allergies, eczema (ped pt), and symptom questions. We can treat for 1-3 months with empiric ICS and SABA and review response.Probability of asthma diagnosis in 5 yo: Most have asthma- Symtpoms for >10 days during RTIs
- >3 episodes/year or severe episodes and nighttime worse
- between episodes has symptoms during play or when laughing
- Allergic sensitization, atopic disease, food allergic or family history of asthmaProbability of asthma diagnosis in 5 yo: Some have asthma- Symptoms for >10 days during RTIs
- >3 episodes/yr or severe episodes and nighttime worse
- Between episodes occasional symptomsProbability of asthma diagnosis in 5 yo: Few have asthma- Symptoms (cough, wheeze, difficulty breathing) for <10 days during RTIs
- 2-3 episodes per year
- No symptoms between episodesIntermittent Asthma- Symptoms less than once a wk
- Brief exacerbation
- Nocturnal symptoms not more than 2x/month
- FEV1 or PEF ≥ 80% predicted
- Every patient thinks they are intermittent, so this is not helpful indicationmild persistent asthma- Symptoms more than once a week but less than once a day
- Exacerbations may affect activity and sleep
- Nocturnal symptoms may affect activity and sleep
- FEV1 or PEF ≥ 80% predicted
- Mild implies you don't need to treat the disease. 30% or pts who died from asthma have not had symptoms in the past 90 days. That's mild. It is suggested that you nor the pt use the word mild to describe asthma. It gives the impression of low risk. Instead describe the situation in terms of their symptoms, control and risk factors.Moderate Persistent asthma- Symtoms daily
- Exacerbations may affect activity and sleep
- Nocturnal symptoms more than once a wk
- daily use of inhaled SABA
- FEv1 or PEF 60-80% predictedsevere persistent asthma- Symptoms daily
- Frequent exacerbation
- Frequent nocturnal asthma symptoms
- Limitation of physical activities
- FEV1 or PEF ≤ 60% predictedGINA severity levels- Mild - Controlled with Step 1 or 2 of treatment
- Moderate - Controlled with step 3 or 4
- Severe asthma - remains uncontrolled despite step 4+
+ Need to consider "difficult to treat"
- We decide on severity after given medication
- If you are controlled at step 3, you are moderate.
- Step 4 red alert: Ask: Are you using your inhaler correctly?
- IF you are step 4+, something needs to be done. Everything is rechecked.If you are at four and remain uncontrolled, you are severe. 4+ is difficult to treat first. If we find out everything is used correctly (right inhaler, correct usage, pt is adherent),it's severe.Goals for asthma control2 Domains of asthma control
Reduce symptoms
- Prevent chronic and troublesome symptoms (tight chest, poor sleep)
- Require infrequent use of SABA for quick relief of symptoms
- Maintain (near‐) normal pulmonary function
- Maintain activity levels (e.g. exertion, sports)
- Meet patient and family expectations of and satisfaction with care
Reduce risk
- Prevent recurrent flare-ups & minimize ER/MD visits, hospitalizations
- Prevent loss of lung function; for children, prevent reduced lung growth
- Minimal or no adverse effects of therapyNonpharmacologic TreatmentEnvironmental control (indoor trigger avoidance) - now deemphasized
- Single measures do not seem to be of benefit (other than smoking)
- No evidence of clinical benefit even with commonly recommended measures
Education - reinforce at each visit
- Asthma pathophysiology & role of medications
- Trigger identification/smoking cessation
- Inhalation technique (regular refresher @ refills)
- How to use a written action plan
- Self monitoring (symptoms vs. peak flow meter)Starting and stepping up treatment - adults and adolescents 12+ (we start here because of likely poor adherence with daily iCS even if infrequent symptoms;lower risk of severe flare and need for OCS) - Controller and Preferred reliever - Step 1 - 2 -Symptoms less than 4-5 days a week:
- Preferred Controller: Add as needed low dose ICS-formoterol - one puff of 160 PRN?? (86% of pts can be controlled here)
- Reliever: as needed low dose ICS-formoterolStarting and stepping up treatment - adults and adolescents 12+ - Controller and Preferred reliever - Step 3Symptoms most days or waking with asthma once a week or more:
- Preferred Controller: Low dose maintenance ICS-formoterol
- Reliever: as needed low dose ICS-formoterolStarting and stepping up treatment - adults and adolescents 12+ - Controller and Preferred reliever - Step 4Daily symptoms or waking with asthma once a week or more and low lung function:
- Preferred Controller: Medium dose maintenance ICS-formoterol
- Reliever: as needed low dose ICS-formoterolStarting and stepping up treatment - adults and adolescents 12+ - Controller and Preferred reliever - Step 5Add on LAMA
- Preferred Controller: Refer for phenotypic assessment ± anti - IgE, Anti-IL/5R, anti-IL4R
Consider high dose ICS-formoterol
- Reliever: as needed low dose ICS-formoterolStarting and stepping up treatment - adults and adolescents 12+ - Controller and alternative reliever - Step 1Symptoms less than twice a month:
- Controller: Take ICS whenever SABA taken
- Reliever: PRN SABAStarting and stepping up treatment - adults and adolescents 12+ - Controller and alternative reliever - Step 2Symptoms twice a month or more but less than 4-5 days a week:
- Controller: Low dose maintenance ICS
Reliever: PRN SABAStarting and stepping up treatment - adults and adolescents 12+ - Controller and alternative reliever - Step 3Symptoms most days or waking with asthma once a week or more:
- Controller: Low dose maintenance ICS-LABA
- Reliever: PRN SABAStarting and stepping up treatment - adults and adolescents 12+ - Controller and alternative reliever - Step 4Daily symptoms or waking with asthma once a week or more, and low lung function: -
- Controller: Medium/high dose maintenance ICS-LABA
- Reliever: PRN SABAStarting and stepping up treatment - adults and adolescents 12+ - Controller and alternative reliever - Step 5- Controller: Add on LAMA
Refer for phenotypic assessment ± anti - IgE, Anti-IL/5R, anti-IL4R
- Reliever: As needed short acting beta 2 agonistStarting treatment of 6-11 years with diagnosis of asthma - Step 1Symptoms less than twice a month:
- Preferred controller (to prevent exacerbations and control symptoms): Low dose ICS taken whenever SABA taken
- Other controller options: consider daily low dose ICS
- Reliever:As needed SABA (or ICS formoterol reliever for MART)Starting treatment of 6-11 years with diagnosis of asthma - Step 2Symptoms twice a month or more, but less than daily
- Preferred controller (to prevent exacerbations and control symptoms: Daily low dose inhaled corticosteroid
- Other controller options: Daily Leukotriene receptor antagonist (LTRA) or low dose ICS taken whenever SABA taken
- Reliever:As needed SABA (or ICS formoterol reliever for MART)Starting treatment of 6-11 years with diagnosis of asthma - Step 3Symptoms most days, or waking with asthma once a week or more
- Preferred controller (to prevent exacerbations and control symptoms: Low dose ICS-LABA OR medium dose ICS OR ICS-formoterol manttenance and reliever (MART)
- Other controller options: Low dose ICS + LTRA
- Reliever:As needed SABA (or ICS formoterol reliever for MART)Starting treatment of 6-11 years with diagnosis of asthma - Step 4Symptoms most days, or waking with asthma once a week or more, and low lung function
- Preferred controller (to prevent exacerbations and control symptoms: Medium dose ICS-LABA OR low dose ICS-formoterol maintenance and reliever therapy; refer for expert advice
- Other controller options: Add triotropiom or add LTRA
- Reliever:As needed SABA (or ICS formoterol reliever for MART)Starting treatment of 6-11 years with diagnosis of asthma - Step 5- Preferred controller (to prevent exacerbations and control symptoms: Refer for phenotypic assessment ± higher dose ICS-LABA or add-on therapy e.g. anti-IgE
- Other controller options: Add on Anti IL5 or add-on low dose OCS but consider side effects
- Reliever:As needed SABA (or ICS formoterol reliever for MART)Children 5 years and younger personalized asthma management - step 1- Preferred controller choice:: *crickets chirping*
- Other controller options: consider intermittent short course ICS at onset of viral illness
- Reliever: PRN SABA
- Consider this step for children with: infrequent viral wheezing and no or few interval symptoms
Most children at this age get 5-6 viral infections a year with wheezing episodes. It doesn't mean they have asthma. We could give the pulmicort or budesonide nebuilizations Everytime your kid gets a viral infection start pulmicort or budesonide nebulization at start of illnessChildren 5 years and younger personalized asthma management - step 2- Preferred controller: Daily low dose inhaled corticosteroid (ICS)
- Other controller options: Daily leukotriene receptor antagonist (LTRA) or intermittent short course of ICS at onset of respiratory illness (Singular doesn't prevent excerbations nearly at the trate of low dose ICS. It does reduce symptoms.)
- Reliever: PRN SABA
- Consider this step for children with: Symptoms pattern not consistence with asthma but wheezing episodes requiring SABA occur frequently, e.g. ≥ 3 per year. Give diagnostic trial for 3 months. Consider specialist referral.; Symptoms pattern consistent with asthma, and asthma symptoms not well controlled or ≥3 exacerbations per year.Children 5 years and younger personalized asthma management - step 3- Preferred controller: double 'low dose' ICS
- Other controller options: Low dose ICS + LTRA consider specialist referral
- Reliever: PRN SABA
- Consider this step for children with: Asthma diagnosis, and asthma not well-controlled on low dose ICS; Before stepping up, check for alternative diagnosis, check inhaler skills, review adherence and exposuresChildren 5 years and younger personalized asthma management - step 4- Preferred controller: Continue controller and refer for specialist assessment (Pt has higher eos, allergies, eczema, family history and food allergies)
- Other controller options: Add LTRA or increase ICS frequency or add intermittent iCS
Reliever: PRN SABA
- Consider this step for children with: Asthma not well-controlled on double ICS; Before stepping up, check for alternative diagnosis, check inhaler skills, review adherence and exposuresDevice selection in asthma- Device determinants of delivery
+ Particle size (single most important factor); reach the lower airways when 1-5 microns
+ Lung deposition (need asthma meds through mouth)
+ Pharmacokinetics (meds impact on you esophagus, oropharynx, may impact all the way down into airways and cilia will bring it back up)
- Patient determinants of delivery
+ Appropriate inhalation technique vital for optimal drug delivery and therapeutic effect
+ Many patients cannot master inhaler technique for a given device
+ Regular teaching helps
+ Spacer devices, mouth rinsing after ICS may reduce oral deposits
+ <4 yo usually need to use a face maskChoosing inhaler for 0-3yr- Preferred device: pMDI plus spacer with face maks
- alternative device ("less desirable device"): Nebulizer with face maskChoosing inhaler for 4-5yr- Preferred device: pMDI plus spacer with mouthpiece
- Alternative device ("less desirable device"): MDI plus face mask spacer, or nebulizer with mouthpiece or face mask (we actually don't want o use a nebulizer with a fat mask. We want to use it with mouth piece)Stepped care approach summary with asthma- NIH asthma guidelines out of date and are getting minor tweaks right now
+ Classifications do not agree with the GINA guidelines
+ Major difference is step 1 in GINA is "never albuterol monotherapy"
- Goal of stepped therapy is to reduce symptoms and risk
- Stepping up and down intensity requires repeated assessment
- As needed low dose budesonide-formoterol is preferred step 1-2 in 12yo-adult
- Vast majority of patients are controlled on step 1 or 2 therapy
- Step 4 therapy requires consideration of referral to asthma specialistGINA assessment of asthma control in 6 yo - adult: Symptom control- Symptoms and risk are independent variables. (not completely though because people who have a lot of symptoms tend to have more and worse attacks)GINA assessment of asthma control in 6 yo - adult: Risk of poor asthma outcomes- All of these will show that you have an increase risk of flare ups; even if you have few symptoms. E.g. Mild pts usually don't show symptoms, but some have the worse possible risk, and they die.GINA assessment of asthma control in children ≤ 5 yrsBefore stepping up to a higher level of asthma drug therapy...- conform the diagnosis of asthma: if we are still having symptoms, it could be something else.
- Here we have started pt on meds. We bring them back into the clinic and do a check box of their symptoms and risk. Now, do we step them up?Summary - Assessing Asthma Control- Assessing symptoms and risk as 2 separate domains
- Symptoms - 4 questions - get to know them, be able to ask a patient
- Risk - longer list; all related to risk of asthma flare-up
- Before changing (increasing) a medication regimen, need to evaluate:
+ Adherence
+ Technique
+ Trigger control/avoidanceDifficult to treat vs severe asthmaThe only difference between difficult to treat vs severe asthma is how well the patient is taking their medsSevere asthma- Look for factors: contributing to symptoms, exacerbations and poor quality of life:
+ incorrect inhaler
+ suboptimal adherence
+ comorbidities including obesity, GERD, chronic rhino sinusitis, OSA
+ Modifiable risk factors and triggers at home or work, include smoking, environmental exposures, allergen exposure (if sensitized on skin prick testing or specific IgE).medications such as beta-blockers and NSAIDs
+ Overuse of SABA relievers
+ Medication side effects
+ anxiety, depression and social difficultiesSevere asthma type 2 inflammationSummary - Difficult-to-treat asthma- Severe asthma is a subset of difficult-to-treat asthma
- GINA defines this as step 4-5 therapy with poor symptom control
- Need to evaluate adherence, technique and trigger control/avoidance
Severe asthma: uncontrolled on step 4-5 with good adherence & technique
- After diagnosed as severe, determine if Type 2 inflammation
- May be a candidate for biologic therapy
- Biologic therapy usually decided in asthma specialist setting
+ Lowering IgE - Omalizumab
+ Lowering eosinophils - Anti-IL-5 agents: Mepolizumab (Nucala), benralizumab (Fasenra), reslizumab (Cinqair)
+ Anti-IL4&13 - dupilumab (Dupixent)
+ Anti-TSLP - Tezepelumab (Tezspire) - (pending FDA approval)Flare up management- Home - self management
+ GINA: "All pts need a written Asthma Action Plan"
+ Not just verbal
+ Adjusting meds up and down
+ When to go to ER/Call 911
- Primary care/clinic setting
- ER/Hospital setting
- Pts need to know when flare ups are happening, so they all need an asthma action plan. Pts need to know when to go to the ERFlare up management asthmaasthma action plangreen zone: doing well
yellow zone: adding albuterol/SABA
red zone: asthma emergency - Saba not working, can't do activities, been in yellow for 24 hrsAssessing flare - up in primary care (home)- When to seek help (transfer to acute care faculty - i.e. ER/911)
+ Speechless - phrases vs. words
+ Restless - agitation (Consciousness - emergent) (CNS changes)
+ Breathless - increased respiratory rate vs. >30 bpm
+ Accessory muscles - suprasternal, intercostal use vs. not present
+ O2 saturation (RA) - 90-95% vs. <90%
+ Peak flows - >50% vs. ≤50%
- Always give inhaled albuterol, O2 first; even during assessment
+ Reassess for response within 1st hour; may re-administer q20min
+ Omit full course of systemic corticosteroid only if immediate & sustained response to SABA
+ Discharge with reliever, controller & oral corticosteroid (1-2 mg/kg/day max 40mg x5d)
+ Follow-up: check controller technique & adherenceManaging flare-up in acute care- Albuterol/ipratropium q20min x3
- Systemic corticosteroids - the next immediate intervention
+ Must be given for any moderate-severe flare-up
+ Mild with immediate improvement to SABA may not require systemic CS
- Continuous albuterol nebulization (guidelines don't recommend)
- Magnesium sulfate IVPB x1 if severe & unresponsive to above (smooth muscle relaxer)
- Patient education & written asthma action plan - for all patients
- Initiation of ICS prior to discharge
- Ipratropium is most useful in acute care setting because it can educe hospitalizations. It can reduce the need to admit patient.Summary - asthma flare up- Know the 4 "S" symptoms to teach patients/caregivers when to escalate
- What are patients supposed to do?
- Asthma action plan should be their guide
- Education and prescriptions after a moderate or severe asthma flareCOPD Definition - GOLD Guidelines- Chronic Obstructive Pulmonary Disease (COPD) - a common, preventable and treatable disease that is characterized by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases.What is the difference between asthma and COPD?Asthma has 12% reversibility. COPD is not reversible. IF you see some reversibility, the pt may have COPD and asthma.Management of COPDCOPD - Key indicators to consider diagnosis- Dyspnea, chronic cough OR sputum prod &/OR risk-factor exposure
+ Progressive over time, persistent, worse with exercise
- Chronic cough - may be intermittent and unproductive; wheezing
- Chronic sputum production - any pattern
- Recurrent LOWER respiratory tract infections
- Risk factors: tobacco, occupational, smoke, gases, genetic
- Childhood history or family history COPD - prematurity
- If ANY of above indicators present, consider COPD & perform spirometryDyspneadifficulty breathingSpirometry - required for COPD Diagnosis- We really don't consider COPD until someone has a 10 year pack history or more. Probably less than 10 years, you're going to have some COPD with your first cig, but ti doesn't become significant until you lost some lung function
- FEV1/FVC is a measure of obstruction; <0.7 confirms COPD
- Used for diagnosis, prognosis, ID of rapid decline
- Poor at predicting symptoms, exacerbation risk, drug responseCOPD Differential Diagnosis- Asthma
- CHF
- Bronchiectasis, Bronchiolitis Obliterans, Panbronchiolitis (sinusitis), TB
- Alpha-1 antitrypsin deficiency
+ One-time genetic screening
+ IV infusion of exogenous AAT if very low (<20% normal)
- 40% COPD pts still smokeStages of Chronic COPD- Typically defined by FEV1
+ Lower FEV1 indicating more impairment
+ Research: FEV1 doesn't correlate with QOL & function
- GOLD December 2011 - changed to a hybrid ABCD staging
+ FEV1 + risk + symptom score
+ Risk = # of exacerbations/year
+ Symptom score
= CAT or mMRC
+ Low risk, low symptoms to high risk, more symptoms
- GOLD 2014 further modified
- GOLD 2017 gives specific medication recommendations
- GOLD 2019 - follow-up recs based upon eosinophil countCategory C COPD-low symptoms
-high risk
- mMRC 0-1; CAT <10
- exacerbation history: 2 or more exacerbations or ≥1 leading to hospital admission
- Treatment: LAMA- Once we cross into exacerbations, LAMAs work better.Category D COPD- higher symptom burden AND high risk of exacerbation
- ≥mMRC 2; CAT ≥ 10
- exacerbation history: 2 or more exacerbations or ≥ 1 leading to hospital a admission
- Treatment:
+ LAMA
or
+ LAMA + LABA ( if highly symptomatic (e.g. CAT >20)
+ ICS + LABA (if EOS ≥ 300)
This is where we have a lot of symptoms and exacerbations. We should start on LAMA. If we have high CAT score (greater than 20), we start on dual therapy. Excerabations are prominent, and we have eos greater than 300.category A COPD-low symptoms
-low risk
- mMRC 0-1; CAT <10
- exacerbations: 0 or 1 that didn't to lead to hospital admission
- Treatment: a bronchodilator - not a lot of preference here. Usually it'd be a long acting bronchodilator. We could also start on albuterol or ipatropium, but they wouldn't be as effecting and would need to be given up to 4+ times a day.Category B COPD-High symptoms
-Low risk
- mMRC ≥ 2; CAT ≥ 10
- exacerbations: 0 or 1 that didn't to lead to hospital admission
- Treatment: A long. acting bronchodilator (LABA or LAMA) - Once symptoms are greater we use either of the LA bronchodilatorsmanagement goals COPDAfter dx - Prevention & non-drug therapy- Smoking cessation - Most effective (and cost effective)
- Pulmonary rehabilitation (physical tx, respiratory tx)
- Influenza & pneumococcal vaccine
- Knowledge of current therapies; inhaler techniqueOverall concepts of pharmacotherapy COPD- Treatment cumulative: increases as disease progresses
- Inhaled bronchodilators - mainstay of tx - decrease airflow obstruction
+ Reduce frequency & severity of exacerbations
+ Improve health status (QOL) and exercise tolerance
+ Education & training cannot be overemphasized - reassess each "visit"
+ Choice of inhaler device is multifactorial - needs to be tailored to individual
+ Availability, coverage, cost, prescriber
+ Patient ability to use and preference
+ After LA bronchodilators comes decision to add ICS
+ Possibly treatment with PDE4 inhibitor (roflumilast)Pharmacologic - Bronchodilators COPD- Short-acting (SABA, SAMA) - (PRN) pts occasional dyspnea; symptomatic
- LAMAs and LABAs preferred over short-acting agents
- LAMAs are more effective at preventing exacerbation tha n LABAs
- Start on single LA bronchodilator
+ Dual LA bronchodilator - LABA/LAMA
+ if severe symptoms at dx (CAT>20)
- If persistent symptoms, add the second bronchodilator Inhaled are recommended over oral bronchodilators - Theophylline is not recommendedPharmacologic - inhaled corticosteroids COPD- ICS more effective at ↓ exacerbation than reducing symptoms
- Major side effect is ↑ pneumonia risk
- Combined with LABA (LABA/ICS)
- History of exacerbations despite LA bronchodilator therapy
- GOLD 2019 - serum eosinophil-directed therapy
- Long-term therapy with OCS corticosteroids is not recommendedOther Pharmacologic Therapies in COPD- PDE4 inhibitor (roflumilast) - modest exacerb ↓ effect; s/e
- Antibiotics: (Azithromycin) - s/e limit use (QTc, possible ototoxicity)
- Methylxanthine (theophylline): "small bronchodilator effect"
+ Modest symptomatic benefit at near-toxic serum levels
+ Narrow therapeutic index, wide-ranging toxicity (CV, neuro, GI)
- Mucolytics/Antioxidants:
+ Not clear who benefits; inadequate/conflicting evidence
+ 2 agents in GOLD not available in US (carobcysteine, erdostine)
+ N-acetylcysteine = nebulized rotten eggs
- Antitussives: Not recommended despite cough symptomsWhat are some key points to know about the ABCD box?- ABCD box is used for selection of initial therapy ONLY
- Long acting bronchodilators play a significant role
- ICS role has become reduced for initial therapy compared to previous years
- Preferences for different agents should be reviewed and studied for application to patient casesFollow up pcol txt in COPD: exacerbations* consider if eos ≥ 300 or eos ≥ 100 and ≥ 2 moderate exacerbations/1 hospitalization
** consider de-escalation of ICS or switch if pneumonia, inappropriate original indication or lack response to ICSFollow up pcol txt in COPD: Dyspnea* consider if eos ≥ 300 or eos ≥ 100 and ≥ 2 moderate exacerbations/1 hospitalization
** consider de-escalation of ICS or switch if pneumonia, inappropriate original indication or lack response to ICS
- in dyspnea we try to get off ICS because it increase risk of pneumoniaWhen to initiate ICS in COPDTreating Exacerbation of COPD- About 80% are outpatient events; home, clinic, ER
- Non-pharmacologic - oxygen 25-35%, slowly increase
- Pharmacologic options and selection:
+ Inhaled bronchodilators (SABA+/-SAMA) - first line
+ Nebulizer or MDI with spacer
+ Dose: frequent at first; q20min then taper q1-4 hr
+ Nebs not more effective than MDI, but independent of pt effort
+ Systemic corticosteroids (↑SpO2 , ↑FEV1, shorten recovery)
+ Optimal regimen unknown; Prednisone 40 mg oral daily for 5-7 days
+ Oral route is not inferior to IV route; IV used when oral not possible
+ High doses, longer courses increase side effects but not efficacy
+ Tapering is not necessary if given for less than 2 weeks
+ Improves FEV1, oxygenation, shortens recovery, reduces failure of txExacerbation tx - Antibiotics- When indicated, ↓ recovery time, ↓ early relapse, ↓ treatment failure, duration of hospitalization.
- Indications: (Anthonisen criteria)
+ If 2 of 3 (↑dyspnea, ↑ sputum purulence, ↑ sputum volume) present
OR
+ ↑ purulence and one other sign OR mechanical ventilation or NIV
- H. influenza, S. pneumo, Moraxella; Pseudomonas if previously colonized
- Empiric choices: (depends upon severity & pseudo risk/colonization)
+ Non-pseudomonas: macrolide, amox/clav, cefuroxime, cefpodoxime, cedinir
+ Pseudomonas: Cipro (outpatient); IV antipseudomonal (inpatient)
+ If pt not responding or having severe/freq exacerb, then sputum culture
- Duration of treatment of 5-7 daysExacerbation tx - supportive care- Fluid balance, nutrition, DVT prophylaxis, comorbidities
- Monitor: SaO2 (>90%), O2 requirement, RR, signs of infxn
- Hospitalization discharge criteria:
+ Inhaled beta-agonist required no more frequently than q4h
+ Patient can walk across room (if previously ambulatory)
+ Able to eat and sleep without frequent awakening by dyspnea
+ Clinically stable for 12-24 hrs
+ Started preventative if not on & educated/verified appropriate use
+ Follow-up appointments made (MD, PFT)
- Discharge Meds: Prednisone 40 mg po 5-7 days, SABA prn, LAMA &/or LABA-ICS, +/- antibioticsPatient Follow-up COPD- 4-6 weeks post discharge (ambulatory RPh):
+ Ability to cope in usual environment
+ Understanding of medications
+ Observe inhaler technique
+ Reassess for long-term oxygen need and home nebulizer
+ Assess physical activity and ADLs (CAT)
+ ComorbiditiesCOPD - Summary- Fixed airflow limitation - non-reversible
+ Need a PFT for diagnosis
+ Tends to be progressive and smoking cessation is best way to reduce future risk
- Pharmacotherapy
+ Initial - based upon ABCD box; F/U - based upon dispnea vs. exacerb algorithm
+ ICS is most contentious; pneumonia risk/benefit with eos, current tx help decide
+ Some rarely used modalities at the severe end of disease progression
- Exacerbation - loosely-defined
+ Treated with SABD, OCS, +/- abx
+ Need to maximize prevention as part of exacerbation planHistamine storage- Mostly in mast cells and basophils.
- Mast cells (in respiratory tract, skin, GI tract, & blood vessels) store histamine in a granule complex with heparin, ATP & acidic protein.Histamine release1. Immunologic - Energy/Ca2+-dependent degranulation reaction
- Induced by IgE fixation to mast cells (sensitization) & subsequent exposure to a specific antigen
- Complement activation (mediated by IgG or IgM)
2. Energy/Ca2+-independent release (displacement)
- Drug- induced e.g. morphine, tubocurarine, guanethidine, & amine antibiotics
- mast cell damage by noxious agents
- Histamine is trying to help our immune response cells to the area. We will have increase blood volume and increase endothelial permeability. This will cause edema.
-Histamine isn't Tre only thing that activates this. In asthma, leukotrienes cause this reaction as well.Histamine receptors: Histamine (h1) receptors- Location - Smooth muscle, endothelial cells, CNS
- Coupled to Gq/11, - 2nd messenger - ↑ Ca2+; ↑ NO and ↑ cGMP
+ CNS functions - neurotransmission, wakefulness
+ Contraction of most smooth muscle, except blood vessels - bronchoconstriction and GI contraction (vomitting and cramping)
+ Relaxation of vascular smooth muscle - vasodilatation, ↓BP, ↑vascular permeability
1. promotes wakefulness
2. appetite suppressive
- Histamine binds to receptors in heart. (increase HR decrease BP)Key pathophysiological roles of histamine:- stimulation of gastric secretion (H2) - GI ulcers, GERD
- mediator of type I hypersensitivity reactions (urticaria, hay fever) (H1)Pathophysiology histamineAllergic rhinitis (inflammation of the nose)
- runny nose, itchy eyes, & sneezing;
- blood vessel dilation & ↑ vascular permeability → edema/swelling in the nasal mucosa → nasal congestion
Urticaria (hives or rash)
- wheal (↑ permeability of postcapillary venules)
- flare (sensory nerves release peptide mediator) (reduces redness)
- erythematous - reddening (local vasodilatation)
- pruritic & edematous plaques on the skinAnaphylaxis Pathophysiology- Life-threatening condition caused by systemic mast cell degranulation.
- hypersensitivity reaction by sensitized individual to insect bite, drugs - penicillin, ingestion of certain allergenic foods e.g. peanuts
- Systemic distribution of allergen can stimulate mast cells & basophils to release massive amounts of histamine throughout the body.
+ systemic vasodilation & vascular permeability → severe hypotension
+ bronchoconstriction & epiglottal swelling → can be lethal within min.; require rapid admin. of epinephrine (Epi) [faster and hits important things first: constricts blood vessels, relaxes bronchioles, and increase BP].
- Systemic- takes longer to happen; a lot of IgE - you have already been exposed and now you are hyper sensitized.
-Release of histamine can occur by two processes:- Energy/Ca2+-dependent degranulation reaction - induced by immunoglobulin E (IgE) fixation to mast cells (sensitization) and subsequent exposure to a specific antigen; complement activation (mediated by IgG or IgM) may also induce degranulation.
- Energy/Ca2+-independent release (displacement) - induced by drugs such as morphine, tubocurarine, guanethidine, and amine antibiotics, mast cell damage by noxious agentsEpinephrinehas actions on smooth muscle that are opposite to those of histamine. It acts via β2 receptors on smooth muscle, causing cAMP-mediated relaxationAntihistamines- drugs that act as inverse agonist at the histamine receptor (H1)
- not just antagonist → they are inverse agonist - it decrease activity of receptor below baseline and block agonist from bindingH1 receptor antagonists MOA- Cholingeric: conspitation, pupil dilation, tirednessss
- The first gen antihistamines aren't very specific (e.g. Benadryl)
+ block H1 receptor (target)
+ block muscineric cholinergic rceptors
+ Block ɑ - adrenergic receptor
+ Block 5 - HT receptors
+ no documented effects of H2, H3, H4H1 receptors coexist in two conformational states (an inactive and active state)The states are in conformational equilibrium with one another.
- Histamine acts as an agonist for the active conformation of the H1 receptor and histamine binding shifts the equilibrium toward the active conformation.
- Antihistamines act as inverse agonists that bind and stabilize the inactive conformation of the H1 receptor, thereby shifting the equilibrium toward the inactive receptor state.Histamine antagonist1. Physiologic antagonists - vasoconstrictors - ɑ1 agonists; constrict capillary beds
- Nasal decongestant sprays - oxymetazoline, phenylephrine
- Epinephrine - anaphylaxis
2. Release inhibitors - ↓degranulation of mast cells that results from immunologic triggering by antigen-IgE interaction.
-Cromolyn & nedocromil - mostly ophthalmic and otic preparations
- Beta2-adrenoceptor agonists
3. Histamine receptor antagonists - competitive antagonist at HA receptor siteHistamine Antagonists - 1st Generation - Have low specificity, interact with muscarinic cholinergic, α-adrenergic, & 5-HT receptors.
+ Ethanolamines - Diphenhydramine (Benadryl), doxylamine (Unisom)
+ Piperazine - Cyclizine (Marezine), hydroxyzine (Atarax, Vistaril)
+ Alkylamines - Chlorpheniramine (Chlor-Trimeton), brompheniramine (Dimetane)
+ Piperidine: Cyproheptadine (Periactin)
+ Phenothiazine - Promethazine (Phenergan)Histamine antagonist 1st generation structureDiphenhydramine (Benadryl) structure- hydrophobic: ring structures, no charges, small, symmertrical, will be good crossing barriers and acting peripherally - adding to its sedating and appetite affectHistamine Antagonists - 2nd Generation - Have low lipid solubility (generally less fat soluble) & poor CNS penetration, little/no anticholinergic activity & less sedation
+ Piperidine - Fexofenadine (Allegra)
+ Miscellaneous - Loratadine (Claritin), desloratadine (Clarinex), Cetirizine (Zyrtec)
- Rapidly effluxed by the P-gp transporter if they cross the blood-brain barrier.
- More likely to allow patients to remain alert during therapy than 1st-gen str.
- Have higher affinity for the H1 receptor - Slow receptor dissociation results in prolonged durations (can't get into CNS and less sedative due to decrease anticholingeric effect)Therapeutic uses for antihistamines- Treatment of chronic allergic and chronic inflammatory conditions
+ Oral antihistamines - useful in allergic rhinitis, urticaria & atopic dermatitis
+ Ophthalmic antihistamines - allergic conjunctivitis
+ Diphenhydramine also has some antitussive effect
- Insomnia - doxylamine, diphenhydramine are marketed as OTC sleep aids
- Prevention of motion sickness & nausea
- Appetite stimulants - cyproheptadine
- Acute anxiety - hydroxyzineHistamine Antagonists - ADR from on and off-target binding- CNS Effects (primarily 1st gen: diphenhydramine, hydroxyzine, promethazine block histaminergic transmission in the CNS):
+ sedation
+ dizziness
+ lack of coordination
+ tremors
- GI effects:
+ nausea
+ constipation or diarrhea
- Anticholinergic effects:
+ dry mouth
+ blurred vision
+ urine retentionDrug interactions of antihistamines- Potentiate the effects of other CNS depressants, including alcohol.
- Avoid with MAOIs e.g. phenelzine - can exacerbate sedative & anticholinergic effects
- 1st-gen. antihistamines with antimuscarinic actions may decrease the effectiveness of cholinesterase inhibitors in the treatment of Alzheimer disease (donepezil, rivastigmine, & galantamine)CI and Warnings of antihistaminesAvoid use in
- the elderly (due to strong anticholinergic effects; Beer's criteria)
- children < 2 yrs
Lactating women - prefer specific 2nd gen agents (cetirizine, loratadine, fexofenadine)
- CNS depression/sedation - avoid while driving, operating machinery, or essential to be alert
- Use with caution in patients with cardiovascular disease, prostate enlargement, glaucoma, pyloro-duodenal obstruction & thyroid disease
- Avoid use with MAO inhibitorsAntihistamines structure Summarized- Most contain a substituted ethylamine moiety
- Tertiary amino group (vs 2' for histamine)first gen antihistamines- e.g. diphenhydramine; lipophilic, crosses BBB
- Sedation at therapeutic dose, agitation at overdoseSecond gen antihistamines- Mast cell stabilizing effects
- Reduced cytokine secretion
- Eosinophil infiltration reduced
- More hydrophilic & p-glycoprotein pumps out of CNS1st gen antihistamines warnings2nd gen antihistamines warningExpectorants, antitussives & decongestants- Discuss the mechanism of action, pharmacologic effects, indications and ADRs of expectorants, antitussives & decongestants
+ Guaifenesin
+ Dextromethorphan, Codeine, hydrocodone, Benzonatate, Gefapixant
+ Pseudoephedrine
+ Phenylephrine
(know these drugs)Guaifenesin (Mucinex)Pharmacological properties:
- Emetic drug given at lower dose than induces vomiting
- Irritate the gastric mucosa & stimulate secretions of the respiratory tract
- Little to no evidence for efficacy
- FDA has pulled indication for all agents except guaifenesin
Side effects: nausea, vomiting, dizziness, headache, rash, or diarrhea.Antitussives SummarizedDecongestants- Decongestants are sympathomimetics - primary treatment for sinus and nasal congestion.
Mechanism of action:
+ Cause vasoconstriction by stimulating α-adrenergic receptors
+ ↓ sinus vascular engorgement →↓ mucosal edema
Contraindications: Do not use within 14 days of MAO inhibitors
Warnings:
Avoid in children < 2 years (FDA)
Use with caution in patients with CV disease & uncontrolled htn (can ↑ BP)
Drug interactions: TCA or MAOIs - can ↑BP.Pseudoephedrine- Diastereomer of ephedrine - has fewer CNS ADR
- α1-selective agonist; causes arterial vasoconstriction
- Restricted - can be used in the illicit manufacture methamphetamine
- Sold "behind the counter" to control its availability in all states
Adverse effects: restlessness, nausea, vomiting, weakness, & headache.
Caution in htn; might antagonize anti-htn drugs - methyldopa, carvedilol, labetalol.
Avoid combination with MAOIs → life threatening htn.Phenylephrine- α1-selective agonist; causes arterial vasoconstriction
- Also used as a mydriatic
- Nasal decongestant; relieve symptoms of obstruction, sneezing, lacrimation, & itchy eyes
- Oral bioavailability < 10% - hydrophilic; GI metabolism by MAO & 3′-O-glucuronidation/sulfate conjugation.
ADR - tachycardia, hypertension, CNS effects - tremors, anxiety, & insomniaTopical DecongestantsTopical nasal & ocular decongestants contain α1-adrenergic agonists
DOA
Phenylephrine - short <4 h
Naphazoline & tetrahydrozoline - intermediate ∼ 4-6 h
Oxymetazoline & xylometazoline - long ∼ 12 h
Prolonged use → rebound congestion
Usually recommend to < 3-5 days; can rarely go longer per guidelines
Caution - elderly or patients with CVD, glaucoma, & diabetes
Nasal Sprays
Phenylephrine (Neo-Synephrine): 0.25% - 1%, every 4 - 6 h
Oxymetazoline (Afrin): 0.05%, every 10 - 12 hAnaphylaxis- Epi - critical, emergent
- H1, corticosteroids are NOT life-saving
- H2RA - not indicated
- IV fluid requirement can be massive
- Biphasic recurrence can occur (~5% of cases)Anaphylaxis background- Lifetime prevalence in U.S. is 1.6-5.1%; incidence 42/100,000 person-years
- Mortality: 0.5/million persons (case fatality rate 0.3%); associated with delay in admin of epinephrine
Pathophysiology
- Acute, potentially lethal immunologic reaction
- Typically to foods, drugs, insect stings
- Typically IgE-mediated; sensitized cells (mast cells, basophils)
- Antigen introduction leads to cross-linking antibodies
- Sudden degranulation of mast cells & basophils
- Release inflammatory mediators:
+ HA, tryptase, TNF-r1, IL-6 & 10, cyseinyl LTs, PAF, anaphlatoxins
+ Chain reaction of inflammation: distributive shock (↓BP), bronchospasm, skin/mucosal edemaRisk factors in anaphylaxisSevere anaphylaxis
- Cardiovascular disease (beta-blocker or ACEI use)
- Asthma
- Older age
- Additional coexisting, comorbid conditions
Leading causes - adults
- Medications - antibiotics, NSAIDs, immunomodulators, biologic agents
- Stinging insects
Leading causes - children
- Foods
- Stinging insects
- Food allergy present in 8-11% of US children & adultsCardiac disease and anaphylaxisCVD is worrisome because when a person with CVD takes a Beta blocker, we can't treat anaphylaxis well with that. IF you have terrible anaphylaxis, you should never be on a beta blocker.Criterion 1: anaphylaxisSudden onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both (eg, generalized hives, itching or flushing, swollen lips-tongue-uvula) - 90%
Respiratory compromise (eg, dyspnea, wheeze/bronchospasm, stridor, reduced peak flow, hypoxemia)
↓BP or associated symptoms & signs of end-organ malperfusion (eg, hypotonia, syncope, incontinence)Criterion 2: anaphylaxisTwo or more of the following that occur rapidly after exposure to likely allergen for that patient
Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen lips-tongue-uvula)
Respiratory compromise (eg, dyspnea, wheeze/bronchospasm, stridor, reduced peak flow, hypoxemia)
↓BP or associated symptoms & signs of end-organ malperfusion (eg, hypotonia, syncope, incontinence)
Persistent gastrointestinal symptoms and signs (eg, crampy abdominal pain, vomiting).Criterion 3: anaphylaxisReduced BP after exposure to a known allergen for that patient (minutes to several hours):
Adults - SBP of <90 mmHg or 30% drop from baseline
Infants & children, BP* or greater than 30 percent decrease in SBPHow is bp significant in anaphylaxis?Bp is a significant criteria in each of the 3 criterion. Low BP can be the only criteria that we may use for diagnosis of anaphylaxis.
Low BP:
<90 - adults
<70 - kidsRapid recognition and epinephrine administration is critical in anaphylaxis- Alpha-1 - tissue/mucosal vasoconstriction; ↓ edema
- Beta-1 - increased cardiac output
- Beta-2 - Bronchodilation; mast cell/basophil membrane stabilization
- Most responsive in earlier phases before shock
- No absolute contraindications to epinephrine administration
- Should be given to patients with mild (rash, wheezing), moderate and severe symptomsMethod of administration of epi- IM injection into the mid-outer thigh is recommended; SQ and IV not as desirable...
- Autoinjector - 0.15 for <30 kg and 0.3 mg for >30 kg; under 7.5 kg benefits likely outweigh risks
- if drawing up from a vial, typical dose is 0.01 mg/kg max of 0.5 mg
- Need to be instructed on how to use the device; anaphylaxis action plan; referral to allergist
IV fluids, albuterol, oxygen, supine position are appropriate, but steroids, H1 & H2 all optionalAAAAI good practice statements- Administer epinephrine as the first-line pharmacotherapy for uniphasic and biphasic anaphylaxis.
- Do not delay administration of epi; associated with higher morbidity & mortality.
- After diagnosis & treatment, all patients should be kept under observation in a setting capable of managing anaphylaxis until symptoms fully resolved.
- All patients with anaphylaxis should receive education on anaphylaxis, including
+ avoidance of identified triggers
+ presenting signs and symptoms
+ biphasic anaphylaxis
+ treatment with epinephrine and use of epinephrine auto-injectors
+ should be referred to an allergistAllergic Rhinitis - BackgroundEpidemiology:
- Affects 1 in 6 Americans - 60M (14% of adults; 13% of children); AR present in 75% of asthma pts
- Complications - headache, sinusitis, eye symptoms, sleep disordered breathing, earaches, cough
- $2-5 B in direct costs; $2-4 B in lost productivity
- Pathophysiology & Symptoms - "The diagnosis of rhinitis is suggested by the presence of 1 or more of the following symptoms: nasal congestion, rhinorrhea (anterior and posterior), sneezing, and itching. Rhinitis can be classified by pathogenic mechanisms, as allergic or nonallergic, and differentiated from other conditions." AAAAI Rhinitis Guideline '20
- Diagnosis - Physical exam consistent with an allergic cause and 1 of the following symptoms: nasal congestion, runny nose, itchy nose, or sneezing. AAO-HNSGeneral treatment strategy of AREnvironmental Control - balance between allergen exposure and QOL/social isolation
- Pollens, insects (dust mites/cockroach), animals (dander/saliva/fur/feathers), molds
- Greatest benefit from indoor allergen control when directed at pt sensitivities and ALL options used
Pharmacologic Therapy
- Corticosteroids - intranasal, oral
- Antihistamines - oral, intranasal, ocular
- Decongestants - oral, intranasal, ocular
- Cromolyn - intranasal
- Anticholinergics - intranasal
- LTRAs - oral
Allergen Immunotherapy - Subcutaneous immunotherapy; Sublingual immunotherapyAllergic Rhinitis treatment- INCS are the drugs of choice
- INCS monotherapy preferred
- LTRA not recommended as primary tx
- INAH recommended over oral H1RA when combo w/ INCS requiredNonallergic rhinitis (NAR)is generally described as chronic nasal symptoms, such as obstruction and rhinorrhea that occur in relation to nonallergic, noninfectious triggers such as change in the weather, exposure to caustic odors or cigarette smoke, barometric pressure differences, etc.allergic rhinitisinflammation of the inside of the nose caused by an allergen, such as pollen, dust, mould, or flakes of skin from certain animalNonallergic Rhinitis vs Allergic Rhinitis- features that differentiate NAR (vasomotor rhinitis is another term) from allergic rhinitis include
NAR (Vasomotor rhinitis)
I. predominant nasal congestion or stuffinesss
ii. post nasal drip (dry cough)
iii. no specific identifiable triggers
Allergic Rhinitis
I. Predominant eye sx, itching, and sneezingWhat should pts with rhinitis be assessed for?Assess for drug-induced (α1-blockers, ACEIs, ß-blockers, PDE5 inhib, CCB, gabapentin, psychotropics)Are 1st gen antihistamines or 2 gen recommended for rhinitis?Recommend against 1st gen H1RA in favor of non-sedating 2nd gen for ARWhen is montelukast used in AR?Recommend against montelukast unless alt AR agents ineffective/not tolerated; don't combineWhat are the intranasal antihistamines recommended for? Intranasal corticosteroids?Recommend INAH as 1st line for SAR, NAR or intermittent AR, but INCS for perennial/persistent ARWhat is the first line therapy for NAR? what about rhinorrhea?For NAR, can offer INCS or INAH as first-line therapy; if just rhinorrhea may offer IN ipratropiumIf moderate to severe nasal symptoms what may be recommended?If moderate to severe nasal symptoms, may recommend combo INCS + INAH over either agent aloneWhen should u suggest intranasal decongestants?We usually state that intranasal decongestants should not be used for more than 5 days. We shouldn't recommend their use routinely. This statement is suggesting that it might be helpful to use them for a short period of time to open up the nasal passages in order to start INAH or INCS therapy. In rare situations, could use for up to 4 wks in refractory patients starting INAH+INCS combo therapy.Who should oral decongestants be used with caution with?Use oral decongestants w/ caution <4yo & arrhythmia, angina, HTN, CVD, bladder obstr, glaucoma, etcHow should ≥12yo SAR or any pt with PAR be treated?treat initially with INCS alone rather than an INCS+oral H1 combo What is the time limit for systemic steroids?Avoid systemic steroids for >5-7 daysWhat is the guideline on adjunctive agents in AR?Nasal saline irrigation - ok, low-risk, low-cost, boil water 1-5minWhat do the guidelines suggest for alternative and complementary therapies?can't recommendWhat are the guidelines on treating pregnant women with AR?no oral/nasal decong; no triamcinolone INCS; nasal saline - 1st line; other prob okayEye symptoms (allergic conjunctivitis)- Often treatment of AR improves conjunctivitis symptoms
- Ocular agents preferred over systemic (e.g. oral antihistamines = drying)
- OTC topical antihistamine/vasoconstrictor - naphazoline/pheniramine
- Cromolyn - Rx only, 4-6 x/day; 1-2 wks for efficacy, 1 product available, not recommended unless pregnant/worried about side effects
- Corticosteroids "soft" - loteprednol, rimexolone, prednisolone; avoid (↑IOP)
- Ocular antihistamines (mast cell-stabilizing) - olopatadine, alcaftadine, ketotifen, bepotastine, azelastine, cetirizine, epinastine
- Contact lenses - ketotifenCold and cough- Supportive care
- Avoid remedies with side effects
- Risk-benefit leans toward not recommending pharmacotherapy
- Nothing works
- Don't use anything
- Don't make stuff upCough and cold - Background- Common cold - most frequent illness in developed countries
Usually caused by a virus
- Symptoms typically last 3-10 days; usually mild, inflammation-related
- Pharyngitis, nasal congestion, rhinorrhea, malaise
- Lower respiratory tract symptoms not typically severe; otitis, sinusitis, asthma/COPD trigger
Antivirals not available for typical pathogens
- Rhinovirus, enterovirus, coronaviruses, adenovirus, RSV, parainfluenza
- Influenza agent available, so for early, more severe infection, may consider neuraminidase inhib
Interventions should be low toxicity due to limited efficacy
- In children <6yo only antipyretics/analgesics (FDA pulled labeling ALL other OTCs <2yo)
- Significant adverse effects and almost no published dataBiofire Respiratory Paneldetects 22 respiratory pathogens, including SARS-CoV-2, to help clinicians quickly rule in and rule out common causes of respiratory illness in about 45 minutes.Moderate-severe symptoms of cold: Therapies that offer modest symptomatic benefit- Analgesics - muscle/joint pain, sore throat, fever
- Saline nasal spray/irrigation
- Intranasal cromolyn - modest benefit for rhinorrhea, sore throat, cough (q2hr taper to q6h)
- Intranasal ipratropium bromide - targeting rhinorrhea
- Cough - Honey (>1yo) - 2.5-5 ml diluted or undiluted; hard candy if not aspiration riskModerate-severe symptoms of cold: Therapies with minimal or uncertain benefits- Dextromethorphan/codeine as cough suppressant - no; (honey as alternative - not <1 yo)
- Antihistamine/decong combos - More drowsiness, dry mouth, dizziness, insomnia
- OTC Decongestants - minimal to no benefit; suggest only if bothersome nasal sympt & >12yo
- Expectorants, mucolytics - ineffective
- Vitamin C, zinc, Echinacea purpurea, or homeopathy - unproven (risk: anosmia with zinc)Summary of Cough & Cold- Supportive care: hydration, warm liquids, cold humidification
- Handwashing to prevent the spread
- If symptoms are more than mild, treat individually
- Exception would be monotherapy decongestant for adolescents ≥12yo
- Many products typically considered effective actually are not:
+ Antitussives
+Antivirals, antibacterials
+ Monotherapy, combo decongestants, antihistamines
+ CAM therapies
+ ZincMild to moderate asthma flare up- Talks in phrases, prefers sitting to lying, not agitated
- Respiratory rate increased
- Accessory muscles not used
- Pulse rate 100-120 bpm
- O, saturation (on air) 90-95%
- PEF >50% predicted or best
Treatment: SABA 4-10 puffs by pMDI + spacer, repeat every 20 minutes for 1 hour Prednisolone: adults 40-50 mg. children 1-2 mg/kg, max. 40 mg
Controlled oxygen (if available): target saturation 93-95% (children: 94-98%)
CONTINUE TREATMENT with SABA as needed
ASSESS RESPONSE AT 1 HOUR (or earlier)After assessing mild to moderate asthma flare up (after treatment) patient improves, what do you do?ASSESS FOR DISCHARGE
- Symptoms improved, not needing SABA PEF improving, and >60-80% of personal best or predicted
- Oxygen saturation >94% room air
- Resources at home adequate
ARRANGE at DISCHARGE
- Reliever: continue as needed
- Controller: start, or step up.
- Check inhaler technique, adherence
- Prednisolone: continue, usually for 5-7 days
(3-5 days for children)
- Follow up: within 2-7 days (1-2 days for children)
FOLLOW UP
- Review symptoms and signs: Is the exacerbation resolving? Should prednisone be continued?
- Reliever: reduce to as-needed. Controller: continue higher dose for short term (1-2 weeks) or long term (3 months), depending on background to exacerbation
- Risk factors: check and correct modifiable risk factors that may have contributed to exacerbation, including inhaler technique and adherence. Refer if › 1-2 exacerbations in a year.
- Action plan: Is it understood? Was it used appropriately? Does it need modification?After assessing mild to moderate asthma flare up (after treatment) patient worsens, what do you do?TRANSFER TO ACUTE CARE FACILITY
While waiting: give SABA/ipratropium bromide,
O., systemic corticosteroidsevere asthma flare up- Talks in words, sits hunched forwards, agitated
- Respiratory rate >30/min
- Accessory muscles in use
- Pulse rate >120 bpm
- O, saturation (on air) <90%
- PEF ≤50% predicted or bestWhat do you do during severe asthma flare up or life threatening asthma flare upTRANSFER TO ACUTE CARE FACILITY
While waiting: give SABA pratropium bromide,
O., systemic corticosteroidLife threatening asthma flare upDrowsy, confused or silent chest
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