Pharm II: Chelating Agents, Anemia, Growth Factors, Tocolytic Agents, Glaucoma, NSAIDs, Gout, RA, Opioid Analgesics, Migraines, Anesthetics, Muscle Relaxants, GIT, Toxicology

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Chelating Agents
-Dimercaprol (BAL)
-Dimercaptosuccinic acid (Succimer)
-Calcium Di Sodium Edetate (EDTA)
-Penicillamine
-Deferoxamine/Deferasirox

...

Dimercaprol (Anti-Lewisite)

For: acute mercury and arsenic poisoning
-Also for: severe lead poisoning + Calcium disodium EDTA
Analogs which are highly water soluble: succimer is commonly used

Succimer (Dimercaptosuccinic acid)

For: treatment of lead poisoning in children and also in adults if >45ug/dL
-Also: for arsenic and mercury poisoning

-Analog of dimercaprol but less toxic and orally available

Calcium Di sodium Edetate (Ca di sodium EDTA)

-Ethylene Diamine Tetra Acetic Acid
For: acute lead poisoning in combo. w/ dimercaprol
Also: in lead encephalopathy

SE: kidney damage and rapid admin. can cause hypocalcemic tetany

Penicillamine

For: copper poisoning and to prevent accumulation of copper in Wilson\'s Disease
Also: cystinuria and RA

SE: nephrotoxicity, aplastic anemia

Trientine Dihydrochloride

For: copper chelating agent for Wilson\'s Disease in pts who are intolerant to D-Penicillamine

Deferoxamine

For: transfusion siderosis and acute iron poisoning in children

-Has a high affinity for iron and removes iron from ferritin and hemosiderin*

Deferasirox

For: oral treatment for chronic iron overload in patients receiving therapeutic blood transfusions

Arsenic Poisoning

Use: Dimercaprol, Succimer

How: wood preservatives, pesticides, ant poison

S/S: gastroenteritis, cardiac, arrhythmia, skin pigmentation, neuropathy

Lead Poisoning

Use: Ca Na EDTA + Dimercaprol (BAL) succimer

How: tap water, herbal remedies, gas sniffing, paint chips, glazed ktichenware

S/S: N/V, encephalopathy, black feces, anemia, neuropathy, nephropathy, mental retardation

Mercury Poisoning

Use: Succimer, Dimercaprol (BAL), Penicillamine

How: batteries, dyes, fireworks

S/S: tremors, gingivitis, pneumonitis, peripheral neuropathy, nephrotic syndrome

Iron

Use: Deferoxamine

S/S: acute gastroenteritis, bloody diarrhea, coma

Iron Deficiency Anemia

Use: oral Ferrous Sulfate
-Use iron dextran either IV or IM only after test dose!

Megaloblastic Anemia

Use: Folic acid +/- Vit. B12

SE: A large dose of Folic Acid can result in apparent improvement by circumventing the methyl-folate trap, however does not alleviate neurological defects

Growth Factors:
-Erythropoietin (Epoetin Alfa) (Darbepoetin Alfa)
-Recomb. Human G-CSF (Filgrastim)
-Recomb. Human GM-CSF (Sargramostim)
-Recombinant Human IL-11 (Oprelvekin)

...

Epoetin Alfa, Darbepoetin Alfa

For: Chemo-induced anemia, prematurity, chronic renal disease, zidovudine induced anemia

SE: HTN, thrombosis, edema
-Abused by athletes, cause polycythemia in non-anemic patients
-Darbepoetin is longer-acting

Filgrastim

Recomb. Human G-CSF
For: neutropenia due to chemotherapy

SE: bone pain
-better tolerated
-enhances the phagocytic and cytotoxic functions of neutrophils

Sargramostim

Recomb. Human GM-CSF
For: neutropenia due to chemotherapy

SE: bone pain, more allergic rxns
-Dose dependent increase in eosinophils and monocytes at larger dose.

Oprelvekin

Recomb. Human IL-11
For: prevention of severe chemo-induced thrombocytopenia

SE: edema, arrythmia
-Dose-dependent increase in platelets and megakaryocytes

Prostaglandins

Functions:
-activate the inflammatory response
-inhibit gastric acid secretion and increase secretion of protective mucus
-involved in induction and maintenance of labor
-help in maintenance of blood flow to kidney
-TXA2 causes vasoconstriction and aggregation of platelets
-PGI2 causes vasodilation and anti-platelet action

NSAIDs

A large family of weakly acidic drugs which act through the inhibition of cyclo-oxygenase pathway involved in the synthesis of prostaglandins from arachidonic acid

-Have anti-pyretic, analgesic, and anti-inflammatory activities
-Also have GIT toxicity and renal toxicity

-Cox-1 in Platelets (which leads to TXA2- promotes platelet aggregation and vasoconstriction)
-Cox-2 in endothelial cells (which leads to PGI2- which inhibits platelet aggregation and causes vasodilation)

-Non-selective NSAIDs block COX-1 and 2
-Selective NSAIDs only block COX-2!

Celecoxib

Cox-2 Selective Inhibitor NSAID
For: OA and RA
-Have analgesic, antipyretic, and anti-inflammatory effects similar to traditional NSAIDs, but less GI side effects
-No effect on platelet aggregation
Less effective than naproxen and ibuprofen

SE: renal toxicity, HTN, and cardiovascular thrombotic events

Aspirin

Acetyl Salicyclic Acid- prototype of NSAIDs
ZERO-ORDER KINETICS- does not have fixed 1/2 life
-Irreversibly acetylates and inactivates cyclo-oxygenase
(all other NSAIDs are reversible)
-Has anti-inflammatory, analgesic, anti-pyretic, and anti-platelet* actions
-Low-dose (60mg/day) can irreversibly inhibit thromboxane production in platelets= anti-platelet effect. Used in 2ndary prophylaxis of myocardial infarction and TIA

SE: epigastric distress, ulceration, hemorrhage because aspirin inhibits the synthesis of protective mucous in the stomach and stimulates gastric acid secretion
-Use PPI like omeprazole in pts on chronic NSAIDs to reduce risk of ulcers
-ASA and Uric acid: at low doses: decreases secretion of uric acid
Int. doses: may not alter
High: blocks uric acid reabsorption= increased uric acid excretion, but such a high dose can\'t be tolerated!
Not good for use in GOUT= at low= uric acid increases and at high dose= decreases but pts can\'t tolerate such high doses
-Nephrotoxicity can inhibit synthesis of PGE-2 and PGI-2 in kidney resp. for maintaining blood flow
-Hyperventilation and resp. alkalosis- high doses causes mild uncoupling of oxidative phosphorylation= elevated CO2
-Central resp. paralysis and acidosis w/ very high toxic levels of aspirin
-Hypersensitivity in people with bronchial asthma and nasal polyps
-Prolonged bleeding time
-Reye\'s Syndrome: fatal hepatitis during viral infection in children, encephalopathy- so: use acetominophen to reduce fever in kids!
-Toxicity mild salicylism: N/V, hyperventilation, and tinnitus
severe: hallucinations, restlessness, convulsions, and acidosis
Treat aspirin OD w/ sodium bicarbonate and dialysis

Ibuprofen, Naproxen

For: RA and OA
Ibuprofen: equally effective as indomethacin in closing patent ductus arteriosus in pre-term infants

Ibuprofen: used in children and has an opioid-sparing effect
-also: IV injection is approved for analgesic effct

Naproxen: Juvenile RA, gout, dysmenorrhea
-has a long 1/2 life and can be co-packed w/ sumatriptan and lanzoprazole

Piroxicam, Meloxicam

For: RA, OA, ankylosing spondylitis
-oral

-Have long 1/2 life= 1/day dose
-Meloxicam is relatively COX-2 selective

Indomethacin, Etodolac, Sulindac

For: acute gouty arthritis and ankylosing spondylitis
Also: Indomethacin for closing patent ductus arteriosis in pre-term infants
-Indomethacin is 20x more potent than aspirin*

SE: Etodulac and Sulindac associated w/ SJS
Serious hematological toxicity

Acetaminophen

Para-Acetyl-Aminophenol
For: analgesic, anti-inflammatory
1st choice in OA
Safe anti-pyretic in children and in pregnancy
no antiplatelet effect and is not a gastric irritant like NSAIDs
Does not interfere w/ uric acid secretion and reabs.in kidneys

(weak anti-inflammatory because it is inactivated by peroxides in inflamed tissues*
-Inhibits prostaglandin synthesis via inhibition of COX in the CNS (not in periphery)= anti-pyretic effect
-Analgesic effect: peripherally blocks generation of pain impulses

Pathway:major: met. to produce non-toxic metabolite and undergoes glucuronide/sulfate conjugation in the liver and excreted in the urine
minor: produces a highly reactive intermediate NAPQI- N-acetylbenzoiminoquinone-(hepatotoxic) that normally conjugates with glutathione and is excreted in urine (as nontoxic cysteine and mercaptate) but w/ toxic doses, sulfate and glucuronide pathways become saturated which results in increased fraction of acetaminophen being met. by cyt. P450 enzymes and once glutathione is depleted, free NAPQI begins to accumulate and causes hepatic injury. Acetybenzoiminoquinone reacts w/ sulfhydryl groups of hepatic proteins to cause hepatic and renal tubular necrosis

Acetaminophen OD, use Acetylcysteine

SE: serious or fatal hepatic injury

Toxicity:
Phase 1: 0-24 hrs. asymptomatic: anorexia, N/V, malaise, increased serum transaminases after 12 hrs.
2: 18-72 hrs. RUQ pain, anorexia, N/V, transaminases continue to rise
3: 72-96 hrs.: centrilobular hepatic necrosis w/ continued abdominal pain, jaundice, coagulopathy, hepatic encephalopathy, renal failure, fatality
4: 3d-3wk: resolution of symptoms

Diclofenac

Longer duration vs. aspirin
-also as topical patch
-also w/ misoprostol to decrease GI toxicity

Mefenamic acid

For: more effective in cases of dysmennorhea but should not be taken >1 week

SE: rare hemolytic anemia

Ketorolac

As potent as morphine for analgesia 1st injection NSAID
-Can only use for 5 days

Acute Gout Treatment

Acute:
-NSAIDs
-Glucocorticoids
-Colchicine

Prophylaxis
-Probenecid
-Allopurinol
-Colchicine

Also: Indomethacin, Naproxen, Sulindac, Celecoxib

Aspirin is NOT used because it can inhibit urate excretion at low dose and can increase the risk of renal calculi at high doses

Glucocorticoids for Acute Gout

Prednisone and Betamethasone: provide rapid relief within hrs. of therapy. IV methylprednisolone and intra-articular triamcinolone equally effective, may also use ACTH injections

Colchicine for Acute Gout

TRADITIONAL TX and is especially effective if used early in the attack
-acts as a selective inhibitor of microtubule assembly and inhibits cell division also reduces leukocyte migration and phagocytosis and decreases free radical formation.
Can be used in low doses as a prophylactic TX to inhibit recurrent attacks during initial uricosuric TX

SE: diarrhea most common, severe kidney and liver damage OD can be fatal.

Prevention of Recurrent Gout Attacks

If uric acid kept <5mg/dL, prevents recurrent gouty arthritis and eliminates tophaceous deposits

Have to use:
Uricosuric drugs: Probenacid and Sulfinpyrazone to accelerate renal excretion of uric acid
AND
Allopurinol and Febuxostat reduce the conversion of purine to uric acid by xanthine oxidase

Probenecid

Prevention of recurrent attacks
Uricosuric drug which competes with uric acid for reabsorption in PCT of kidney
-Good for under-excretors of uric acid and when tophi are present

SE: inhibits secretion of penicillin and methotrexate
-Increases urate stones but can be prevented by making urine alkaline w/ sodium bicarbonate
-Can precipitate acute gout in early phase but can be avoided w/ use of colchicine or NSAIDs

Allopurinol

Prevention of recurrent attacks
Preferred and standard TX for chronic gout
Also as an adjunct for cancer chemo to slow formation of uric acid by purines- inhibits met. of mercaptopurine and azathioprine that depend on XO

-Act as irreversible inhibitors of xanthine oxidase and increases the concentration of more soluble hypoxanthine and xanthine and decreases the concentration of uric acid
(XO converts hypoxanthine to xanthine and then to uric acid)

SE: hypersens. rxns: skin rashes and toxic epidermal necrosis, bone marrow suppression

Febuxostat

1st non-=urine inhibitor of XO and approved for prevention of chronic gout

Pegloticase

For severe refractory chronic gout
-It is a recombinant uricase and metabolizes uric acid to allantoin. This reduces risk of precipitates since allantoin is 5-10x more soluble than uric acid*

Rheumatoid Arthritis Treatment

-See: bone erosion, pain + swelling, joint space narrowing from IL-1 and TNF-a

NSAIDs alleviate pain and inflammation but do not halt the loss of bone associated with RA

DMARD: Disease modifying anti-rheumatic drugs

SAARD: Slow acting anti-rheumatic drugs are used to reduce and prevent the joint damage in RA

DMARD- Disease modifying anti-rheumatic drugs

-Methotrexate
-Leflunomide
-Sulfasalazine
-Hydroxychloroquine
-Gold Salts
-Cyclosporine
-Corticosteroids
-Anti-cytokine therapy
-Etanerept
-Infliximab
-Adalimumab
-Anakinra

Methotrexate

1st choice DMARD in RA
-Also used in psoriasis and SLE
-Inhibits dihydrofolate reductase (DHFR) but mostly acts through aminoimidazole carboxamide ribonucleotide transformylase (AICAR) which leads to accumulation of adenosine. Also through the inhibition of thymidylate synthetase w/ 2ndary effects on chemotaxis.

SE: frequent, dose-related hepatotoxicity

Sulfasalazine

DMARD: RA and inflammatory bowel diseases: UC/Crohn\'s
-prodrug which is converted into sulfapyridine and 5-aminosalicyclic acid (5-ASA)
-Inhibits effects of IL-1 and TNF-a
-more effective than hydroxychloroquine

SE: SJS and aplastic anemia

Hydroxychloroquine

DMARD: relatively safe
-interferes w/ activity of T-lymphocytes, decreases leukocyte chemotaxis, stabilizes lysosomal membranes, interferes w/ DNA and RNA synthesis, traps free radicals

SE: Less toxic than chloroquine but long-term use can cause retinopathy and corneal deposits

Leflunomide

DMARD:
For: RA and Psoritic arthritis
-Can be used by itself of in combo. w/ methotrexate
immunomodulatory agent that causes inhibition of dihydroorotate dehydrogenase (key enzyme in pyrimidine synthesis)
-*deprives cell of UMP (necessary component of RNA and DNA) thus, inhibits T-lymphocyte proliferation

SE: liver damage and bone marrow suppression

Anti-cytokine Therapy in RA

Use if fail to respond to 2 DMARDs
-Must screen for TB because this therapy can cause activation of latent TB

Infliximab

Chimeric IgG, 25% mouse, 75% human
For: RA, psoriasis, Crohn\'s
MOA: Blocks TNF-a

Etanercept

Recombinant fusion protein
For: RA, psoriasis
MOA: Blocks TNF-a and b

Adalimumab

Fully human IgG
For: RA, psoriasis, Crohn\'s
MOA: Blocks TNF-a

Anakinra

Recombinant IL-1 receptor antagonist
For: RA (when not responding to other drugs)
MOA: IL-1 receptor antagonist

Abatacept

Recombinant fusion protein
For: RA (when not responding to other drugs)
MOA: Blocks co-stimulation- prevents CD28 from binding CD80/86)

Endogenous Opioid Peptides

Enkephalins, Endorphins, Dynorphins
Sensory role: pain
Modulatory role: GIT
Emotional role: reward and dependence

Opioid Receptors

G-protein coupled
Mu (u)= most important, related to most effects
Kappa (k)= spinal analgesic effect
Delta (s)= no single drug which effects, overlaps with other 2

Activation of receptors causes: inhibition of adenylylcyclase, activation of K current (outward), suppression of Ca current

Opioid Analgesics

Main Uses:
-analgesia
-dyspnea due to LVF
-diarrhea (Loperamide)
-Cough (dextromethorphan/codeine)

Agonists:
-Morphine and cogeners
-Meperidine and cogeners
-Fentanyl and cogeners
-Methadone and cogeners

Partial agonists/Mixed agonist-antagonist
-Pentazocine
-Nalbuphine
-Butorphanol
-Buprenorphine

Antagonists
-Naloxone, Naltrexone, Nalmefene

Acute Opioid Toxicity:
respiratory depression, pinpoint pupils, stupor, coma, urinary retention, hypothermia

Physical Dependence:
Withdrawal syndrome: rhinorrhea, sweating, yawning, and diarrhea

Psych. Dependence: persists months despite loss of physical dependence

See tolerance to opioids except in eye and GIT

Acute Action Withdrawal Sign
analgesia pain+ irritability
resp. depression hyperventilation
euphoria dysphoria +depression
relaxation+sleep restlessness+insomnia
tranquilization fearfulness+hostility
decreased BP increased BP
constipation diarrhea
pupillary constriction dilation
hypothermia hyperthermia
drying of secretions lacrimation, runny nose
reduced sex drive spontaneous ejaculation
flushed+warm skin chilly+goose flesh

Morphine

Analgesic effect from U and K receptors
Inhibit ascending pain transmission from the periphery and activates descending inhibitory pain pathway from the brainstem

Oral: only 25% so best given IV
-converted to morphine-6-glucuronide= active metabolite
-Morphine+naltrexone for 24/7 analgesia

Causes: Vasodilation, increased histamine, used for angina= decreased preload, negative chronotropic effect
Used for dyspnea in LVF
GIT: constipation decreased gastric emptying, spasm/increased contraction of anal and ileocecal sphincters
Biliary colic- sphincter of Oddi constricts
respiration, cough reflex (esp. dextromethorphan and codeine), temperature regulating center, and vasomotor centre are all depressed
CTZ stimulated- vomiting
Stim of EW nucleus- miosis/pinpoint pupils
Truncle muscle rigidity esp. w/ high dose fentanyl
Urinary retention
Prolongation of labor

Contra: not good for neonates and elderly due to unexpected profound resp. depression
Also contra in: bronchial asthma, head injuries, undiagnosed abdominal pain, pregnancy

Alvimopam

Used to ameliorate the GIT effects of chronic opioid use

Methylnaltrexone

Can reverse opioid-induced constipation

Codeine

Good oral avail., low abuse, less potent than morphine
More selective cough suppressant, used w/ acetaminophen/aspirin

Analgesic effect due to its conversion to morphine by CYP2D6. 10% of caucasians have genetic polymorphism which leads to inability to convert codeine to morphine, others can lead to ultra-rapid metabolism.

Hydrocodone (Vicodin)

-analgesic effect is highly dependent on metabolism to hydromorphone through CYP2D6
-typically comes together w/ acetaminophen
10% Caucasians= less responsive, 7% caucasians and 30% AA\'s and Asians are ultra metabolizers and may have increased toxicity.

Tramadaol and Tapentadol

Inhibits reuptake of NE and 5HT

SE: seizures
-Should not be used within 14d of MAOI b/c of risk of serotonin syndrome

Oxycodone (Oxy Contin)

Long-acting, 1.5x more potent than morphine
Oxycodone + acetaminophen= percocet
Abuse liability present

Meperidine (Demerol)

Anti-shivering drug

-analgesia similar to morphine
-less constipation than morphine
-does not prolong labor
-Should not be used with MAOI\'s= convulsions, encephalopathy and coma, Serotonin Syndrome
-Abuse potential
-Can only be used up to 48hrs.

SE: IM injection can cause muscle fibrosis Repeated doses leads to accumulation of normeperidine and can lead to tremors and seizures

Cogeners:
Diphenoxylate- avail. only in combo. w/ atropine, some abuse potential

Loperamide- TX diarrheaOTC does not cross BBB, safe, and NO abuse potential

Fentanyl (Duragesic)

Epidural fentanyl and sufentanil for post-op pain and labor analgesia
100x more potent as morphine as an analgesic
-short duration and rapid onset
-patches, lozenges

SE: muscle rigidity Transdermal causes fatal resp. depression Increased heat or fever will cause increased release of drug.

Contra: Don\'t use w/ CYP3A4 inhibitors like clarithromycin (increases level of drug) Not for use in opioid-naive pts.

Cogeners: Sufentanil, remifentanil

Methadone (Dolophine)

For: TX opioid dependence, chronic pain, neuropathic pain

u agonist, NMDA antagonist, and monoamine reuptake inhibitor
-high oral avail. and 24 hr. 1/2 life, tolerance and dependence develops very slowly

SE: unlike other opioids- QT interval prolongation and arrhythmia Must have pre-tx EKG and follow-up at 30d, then annually
like other opioids- resp. depression

Propoxyphene (Darvon)

For: acts as analgesic as a weak u agonist
Propoxyphene+acetaminophen= Darvocet

SE: cardiotoxic at high dose- WITHDRAWN

Dextromethorphan

Anti-tussive
-Free of analgesic action, addictive potential, and less constipation

Mixes Agonist-Antagonist Opioid Analgesics
-Pentazocine
-Nalbuphine
-Butorphanol
-Buprenorphine

Effects depend on previous exposure to opioids
-Relieve pain in naive individuals
-In opioid dependence can precipitate withdrawal syndrome
-Cause less respiratory depression than morphine
-Less dependence and abuse liability

Pentazocine

For mod. to severe pain
u partial agonist and k agonist
-used orally in combo. with naloxone

SE: hallucinations and sympathetic stim.

Butorphanol

For migraine and balanced anesthesia
u antagonist and k agonist
-nasal formulation, more effective in women

SE: increase load on heart

Nalbuphine

For mod. to severe pain, including angina
u antagonist and k agonist
-good analgesic

Buprenorphine

As an analgesic and in combo. w/ naloxone orally to Tx opioid dependence
u partial agonist and k antagonist
-sublingual pill, patches, long-acting
-creates limited opioid effect that is enough to prevent withdrawal and blocks receptors to keep other opioids from attaching to the opioid receptors.

Antagonist Opioid Analgesics
-Naloxone
-Naltrexone
-Nalmefene

...

Naloxone (Narcan)

For: Tx opioid OD

Competitive antagonist of all opioid receptors
Also blocks endogenous opioids

IV only (inactive orally- high 1st pass metabolism), short 1/2 life

Does NOT fully reverse buprenorphine and tramadol

Naltrexone (ReVia)

For: Tx Opioid and alcohol dependence
Pure antagonist
orally active, more potent than naloxone
long duration of action (1-2d)

Nalmefene (Revex)

For: Tx alcohol dependence
Universal opioid antagonist

General Anesthetics

-Most associated w/ decrease in systemic BP, myocardial depression and direct vasodilation
-Also reduce ventilatory drive and eliminates reflexes which maintain airway patency

Main goals: amnesia, analgesia, attenuation of autonomic reflexes, immobility, and unconsciousness

2 Types:
Inhalational for maintenance. Can control the depth of anesthesia, metabolism is minimal, and excreted by exhalation
IV for induction and short procedures

Mechanisms:
Halothane, Propofol, and Etomidate through GABA-A
Ketamine inhibits NMDA receptors

Stage I: Analgesia
II: Excitement, combative behavior, dangerous state
III: surgical anesthesia
IV: Medullary paralysis- respiratory and vasomotor control ceases.

Preanesthetic Medications

Benzodiazepines- to relieve anxiety
Anti-emetics- to prevent vomiting
Opioids- to supplement analgesia
Atropine- to prevent vagal stimulation and secretion

Inhalational Anesthetics
-Nitrous Oxide (very safe)
-Halothane Hepatotoxic
-Enflurane (rarely used)
-Isoflurane Most commonly used
-Desflurane- no psychomotor impairment
-Sevoflurane- no psychomotor impairment
-Methoxyflurane- possible nephrotoxicity, not available in U.S.

Characteristics:
Solubility in blood- blood:gas partition co-efficient the smaller it is, means it will not dissolve
-measure of solubility in blood
-determines rate of induction and recovery of inhalational anesthetics
The lower the blood:gas coefficient, the faster the induction and recovery: nitrous oxide
-would be at top of chart
The higher the blood: gas co-efficient, the slower the induction and recovery- halothane
-would be at bottom of chart

Solubility in fat- oil: gas partition co-efficient
-measure of lipid solubility and correlates strongly with the potency of the anesthetic
-The higher the lipid solubility, the more potent it is- halothane

MAC Value is a measure of inhalational anesthetic potency
The minimum alveolar anesthetic concentration, % of the inspired air, at which 50% of patients do not respond to a surgical stimulus.
MAC values are additive and lower in the presence of opioids

Halothane has a high oil:gas, but a low MAC
Nitrous oxide has a low oil:gas but a high MAC
Desflurane, Sevoflurane, and Isoflurane fall between them

All halogenated anesthetics reduce minute volume of ventilation in a dose-dependent manner which results in an increased arterial CO2 tension.

Nitrous Oxide

For: dental procedures
-quick induction and recovery
Admin. w/ other potent anesthetics to hasten uptake of other agents

Very low blood: gas coefficient quickly diffuses into blood and goes into CNS
Safest inhalational anesthetic
Weak anesthetic, but good analgesic

SE:NO toxic effects on heart, liver, or kidney
diffusional hypoxia megaloblastic anemia, presents w/ peripheral neuropathy and other CNS symptoms

Halothane

Last resort in status asthmaticus

-a potent and pleasant anesthetic
-Sensitizes the heart to catecholamines
-dilates bronchus
-Inhibits uterine contractions= severe bleeding

SE: met\'s to TFA and is responsible for hepatotoxicity, abortions, and congenital defects
-Not used in labor (severe bleeding)
Halothane hepatitis
Arrhythmias

Malignant hyperthermia Tx w/ dantrolene
See: fever >110F, life threatening

Dantrolene

Tx of Malignant hypothermia caused by halothane

-A muscle relaxant that acts by abolishing excitation-contraction coupling in muscle cells, probably by action on the ryanodine receptor.

Isoflurane

-commonly used with oxygen or nitrous oxide
-Pungent and can irritate the resp. system

SE: hepto-safe

Desflurane

Popular for day surgeries
-delivered through special vaporizer
Troublesome induction- can irritate air passages and produce cough and laryngospasm.
-Fast recovery: motor and cognitive impairment are short-lived

Sevoflurane

Good for pts. w/ myocardial ischemia
Effective bronchodilator due to lack of pungency
-fast induction and recovery
SE: nephrotoxicity

Enflurane

Widely Used
Pungent

IV Anesthetics
-Thiopental
-Midazolam
-Propofol
-Etomidate
-Ketamine

Used for induction of anesthesia
Rapid onset of action
-Recovery is by redistribution

Thiopental (Pentothal)

For: rapid control of seizures

-ultra short-acting barbiturate
-A typical dose produces anesthesia for only 5-8 mins. Restributes from brain to other tissues like skeletal muscle.
-single dose can produce psychomotor impairment for 8 hrs

SE: fatal attacks of porphyria in pts. w/ intermittent or variegate porphyria
-Resp. depression

Methohexital

barbiturate which is a preferred anesthetic in patients undergoing ECT because it has a short duration of action.

Propofol (Diprivan)

BEST for day surgery
Most commonly used IV anesthetic for induction and maintenance
-recovery rapid and clearer than thiopenthal

Anti-emetic

SE: pain on injection
PRIS propofol infusion syndrome w/ prolonged and high doses
See: acidosis and rhabdomyolosis
Resp. depression

Etomidate

For: induction in pts. at risk of hypotension
-CVS stability is the main advantage over anesthetics

-suppresses the production of steroids from the adrenal gland
-not for long-term use

SE: seizures, N/V

Ketamine

For: burn dressing and trauma surgery
Best for children and pts. w/ asthma because resp. NOT depressed

Dissociative anesthesia
-produces: profound analgesia, involuntary movements, amnesia, and spontaneous breathing

Acts by blocking NMDA receptors

SE: increased HR and BP due to sympathetic stimulation
Emergence delirium= hallucinations and vivid dreams during recovery

Contra: dangerous for HTN and MI pts.

Analgesic Opioids
-Sufentanil (1000x more potent than morphine)
-Remifentanil (300x)
-Fentanyl (100x)
-Meperidine (0.1x)

-Opioids primarily used analgesics during perioperative period

SE: Respiratory depression

Benzodiazepines in Anesthesia
-Midazolam (Versed)
-Flumazenil (Romazicon)

For Short procedures and in controlling seizures

Midazolam fast acting, potent, and short 1/2 life produces amnesia and muscle relaxation

Flumazenil can reverse OD/actions of benzodiazepines

Alpha-2 Adrenergic Agonists
-Dexmedetomidine

For short-term sedation in non-intubated patients
Sedation and analgesia from activation of a-2 receptors
-Sedative-hypnotic w/ little respiratory depression and only a mild BP drop

Local Anesthetics

Ester type: Has 1 i in name
-Benzocaine
-Cocaine
-Procaine

Amide type: Has 2 i\'s in name
-Bupivacaine
-Lidocaine
-Prilocaine

-Block the generation and conduction of impulse.
-Most are vasodilators (except cocaine)

Act by blocking the entry of Na ions through voltage sensitive Na+ channels during an AP
Ionized part is responsible for binding to specific part of Na channel and non-ionized part responsible for crossing the lipid membrane.

Hydrophilic group: amine
Hydrophobic group: aromatic residue
*Both linked by ester or amide

Ester linked short duration, less intense analgesia, allergies
-Cocaine, procaine, chloroprocaine, benzocaine
*PABA ester linkage may cause allergy in some, must then use an amide drug

Amide-linked met. in liver, longer duration, intense analgesia, less hypersens. risk
-Lidocaine, bupivacaine (cardiotoxic), prilocaine, ropivacaine (longer-acting)

-Sensory and motor nerve fibers are both sensitive to LA and sens. determined mainly by the diameter of the fibres- smaller fibers are more sensitive than large fibers
Sensitivity: Types B and C> A and s> A B and y> A a

-Addition of vasoconstrictor like epinephrine or phenylephrine prolongs duration of anesthesia, reduces systemic toxicity of LA, and remains in wanted area does not get washed away by venous flow

SE: CNS: dizziness, confusion, tremors, convulsions
CVS: arrhythmias, hypotension
Bupivacaine is esp. cardiotoxic
Hypersens. rxns. w/ ester-linked LAs

Procaine

Ester- lasts 30-60 mins.
Low potency
PABA formed so may have hypersens. rxns

Prilocaine

Amide- lasts 60-120 mins.
-Less vasodilation

SE: methemoglobinemia

Lidocaine

Amide- lasts 60-120 mins.
-Good tissue distribution n

SE: CNS effects

Bupivacaine

Amide- lasts 180-360 mins
No motor block

SE: Cardiotoxic

Ropivacaine

Amide- lasts 180-360 mins
No motor block

SE: Less cardiotoxic

Tetradotoxin (Puffer Fish) and Saxitoxin (Red Tide)

Block Na channels in both cardiac and nerve cell membranes- prevents conduction

Skeletal Muscle Relaxants
-Cisatracurium (non-depol. competitive)
-Succinylcholine (depol. non competitive)
-Dantrolene (direct-acting)
-Botulinum (direct-acting)

Peripheral skeletal muscle relaxants block nicotinic receptors of Ach at the NMJ
Types:
Competitive (Non-depolarizing)
Non-competitive (Depolarizing)
Directly acting: Dantrolene and botulinum

-Most are quaternary compounds and are not absorbed orally
-Admin. IV
-do not cross BBB or placenta


Use as adjuvant in general anesthesia
Reduction of fractures in brief procedures

-Nicotinic (Muscle) receptor blockers- Skeletal muscle relaxants
-Nicotinic (Nerve) receptor blockers- Ganglion blockers

Non-depolarizing Competitive Peripheral Skeletal Muscle Relaxants
-Long acting: 40-100 mins.
-Pancuronium
-Pipecuronium
-d-tubocurarine

-Intermediate: 20-40 mins.
-Vecuronium
-Rocuronium
-Cisatracurium

-Short-acting: <20 mins.
-Mivacurium

Block Nicotinic Nm receptors at the muscle end plates but have no intrinsic activity.

If using a non-depol. (competitive) blocker, can reverse effects w/ neostigmine

SE: flaccid paralysis

Cisatracurium

-Inactivated in plasma by spontaneous non-enzymatic degradation (Hoffman elimination)
-Not dependent on kidney or hepatic metabolism

-Depolarizing Blockers ~5 mins.
-Succinylcholine (Suxamethonium)

Depolarizing Blocker
-opens Na+ channels which cause initial twitching and fasciculations followed by desensitization of receptor

Met. by plasma pseudocholinesterase
-no ganglionic blockade
Not reversed by neostigmine

SE: causes muscle pain, fasciculations, and flaccid paralysis malignant hyperthermia, apnea in plasma pseudocholinesterase deficiency
If malignant hyperthermia, use Dantrolene

Exaggerates or has no effect w/ neostigmine

Dantrolene

For: DOC in malignant hyperthermia
reduces spasticity in hemiplegia and in cerebral palsy

Directly-acting skeletal muscle relaxant
Inhibits the release of Ca2+ from the sarcoplasmic reticulum of skeletal muscle by binding to ryanodine receptor (RyR)
-Reduces skeletal muscle strength by interfering with excitation-contraction coupling in muscle fibers.

Botulinum Toxin
-Onabotulinum toxin A (Botox)
-Abobotulinum toxin A (Dysport)
-Rimabotulinum toxin B

For: strabismus, blepharospasm, cervical dystonia, fissure, and hyperhidrosis

Directly-acting skeletal muscle relaxant

MOA: degrades SNAP-25 protein which is required for vesicle fusion and release of Ach
-produces flaccid paralysis of skeletal muscle and diminished activity of parasympathetic and sympathetic cholinergic synapses.
*effect can last weeks- 4mos. and can be renewed with readmininstration.

SE: respiratory paralysis

Central Skeletal Muscle Relaxants

-Methocarbamol
-Chlorzoxazone
-Cyclobenzaprine

-Diazepam-GABA-A receptor
-Baclofen- GABA-B receptor (less sedation)

-Tizanidine- central-acting alpha-2 agonist

Drugs Affecting Uterine Contraction

Oxytocic drugs are uterine-stimulating
-oxytocin
-ergometrine
-prostaglandins

Tocolytics are uterine-relaxing
-B2- adrenergic agonists
-MgSO4
-NSAIDs

Oxytocin

For: induction or augmentation of labor, prevention and tx of postpartum hemorrhage

MOA: oxytocin acts at oxytocin receptors (IP3) and there is intracellular release of Ca2+ from SR

Low doses cause amplitude and frequency of contractions to increase w/ complete relaxation in between

High doses cause sustained contractions, interferes w/ blood flow through placenta, and fetal distress

Ergot Alkaloids
-Ergometrine
-Ergonovine

For: postpartum atony and hemorrhage
-also for subinvolution of uterus
used to DX variant Prinzmetal's angina

MOA: reduces adenylate cyclase w/ mod. vasoconstriction action
-IV, IM, or oral

-Causes strong contractions + increased resting tone (sustained contracture) so unsuitable for facilitation of labor

SE: N/V (D2 in CTZ) spasm of coronary arteries

Prostaglandin Analogs
-PGE1 Misoprostol
-PGE2 Dinoprostone
PGF2alpha Carboprost

For: promoting labor by ripening and dilation of cervix
-PGE1- Misoprostol: cervical ripening or w/ mifepristone for abortion also used in gastric ulcer TX
-PGE2- Dinoprostone and PGF2alpha- Carboprost are used for cervical ripening and to facilitate contractions

MOA: ON FP RECEPTORS: generate IP3 and increase cytosolic Ca2+
ON EP RECEPTORS: inhibit adenylate cyclase and decrease c-AMP

-Cause coordinated contractions of the body of the uterus along w/ relaxation of the cervix
-High dose increases uterine tone and may produce prolonged uterine contractions--> fetal distress

Tocolytics
-B2 adrenergic agonists
-Ritrodine (Yutopar)
-Terbutaline (Bricanyl)

Ca2+ channel blockers
-Nifedipine

MgSO4

Oxytocin receptor antagonist: Atosiban

NSAIDs
-Salicylates
-Indomethacin

For: delay or prevent premature labor and buy time for admin. of betamethasone/dexamethasone to increase fetal lung maturity

Magnesium Sulfate

DOC for prevention and TX of convulsions from pre-eclampsia/eclampsia
(different than what is given for diarrhea)

MOA: inhibits neuromuscular transmission and decreases contractility of smooth muscle by acting as Ca2+ channel blockers

Safe and does NOT suppress CNS of mother or fetus

NSAIDs: Salicylates and Indomethacin as Tocolytics

Can block prostaglandin which may close ductus arteriosus, so muct monitor w/ ultrasound

Glaucoma Treatment
-Prostaglandins
-Beta adrenoceptor blockers: Timolol, Metipranolol, Betaxolol
-Alpha-2 Adrenoceptor Agonists- Apraclonidine and Bromonidine
-Carbonic anhydrase (Type-2) inhibitors: Acetazolamide, Topical Dorzolamide

Must reduce intraocular pressure by increasing outflow of aqueous humor and decreasing production of aqueous humor
Intraocular pressure= fluid input-drainage out of globe
-Aqueous humor produced by ciliary epithelium and drained at the filtration angle of the anterior chamber.
-Have progressive optic nerve cupping and visual field loss
-RFs: family Hx, AA, myopia

2 pathways AH can go
-Conventional: 90% through Canal of Schlemm (trabecular route)
-Unconventional: 10% Uveoscleral flow- passes within the ciliary muscle into the episcleral vessels
Increase unconventional % w/ drugs

2 Types of Glaucoma
Open-angle chronic simple, 95% of glaucomas, painless, TX w/ drugs

Closed angle glaucoma acute-congestive type. appears suddenly and is often painful. Emergency because it can cause blindness Need surgery Can use Mannitol and Acetazolamide to reduce intraocular pressure until surgery.

Prostaglandin Analogs for Glaucoma
-Latanaprost
-Bimatoprost
-Travoprost

DOC- 1st choice PGF2alpha analogs
-Efficacy: 1x/day admin. and lack of SE

MOA: increases uveoscleral outflow (unconventional-accessory pathway)

SE: conjunctival hyperemia, darkening (pigmentation) of iris, and increased eyelash growth

Beta Blockers for Glaucoma
Timolol (B1 and B2)
Metipranolol
Betaxolol (B1 selective)

2nd choice

-don't get headaches or changes in pupil size

MOA: decreases aqueous production may also increase outflow

SE: severe bronchospasm in asthmatics

Alpha2 Agonists for Glaucoma
Apraclonidine
Bromonidine
Dipivefrin

2nd choice ADD ON short-term adjunctive TX

MOA: decreases aqueous production and may enhance uveoscleral outflow

Carbonic Anhydrase (Type 2) Inhibitors
Acetazolamide
Topical Dorzolamide

2nd choice ADD ON

MOA: decreases aqueous production Blocks formation of aqueous humor by blocking CA2
-oral acetazolamide can still be used by combo. topical Tx fails

Cholinomimetics:
-Pilocarpine
-Carbachol

-Increase trabecular outflow
Rarely used now, unwanted side effects- miosis, spasm of eye muscles

Migraine Treatments
Drugs for Stopping Migraines
5HT 1B/D receptor agonists
-Ergot Alkaloids:
-Dihydroergotamine
-Ergotamine

-Triptans:
-Sumatriptan
-Rizatriptan
-Naratriptan
-Zolmitriptan

-Benign and recurring w/ headache, N/V, and other neurological dysfunction
-Activators: wine, menses, hunger, lack of sleep, worry, estrogens, glare
-Deactivators: sleep and pregnancy

2 Types:
-Migraine without aura: Common migraine- pure menstrual migraine

-Migraine w/ aura: Classic migraine- familial hemiplegic migraine

Can use Acetaminophen and NSAIDs for mild*- occasional throbbing, no functional impairment

Oral, nasal, or SC 5HT-1 agonists for moderate- nausea w/ some impairment of functioning

SC, IM, IV 5HT agonists and prophylactic meds for Severe- >3x month, significant functional impairment and marked N/V

Acute Migraine Abortives:
5HT 1B/D receptor agonists- Ergot alkaloids
-Ergotamine
-Dihydroergotamine

Block vasodilation, relieve pain and inflammation

MOA: since 5HT 1B/D are predominantly presynaptic autoreceptors, activation by agonists inhibits release of 5HT and other NTs like substance P and CGRP
-also post-synaptically, 5HT 1B/D agonists mediate vasoconstriction in cerebral blood vessels

Ergotamine- most effective when given early in migraine attack for mod- severe
-sublingual, oral, and rectal

Dihydroergotamine- weaker vasoconstrictor than ergotamine
-intranasal, SC, IM, IV

SE: N/V (but can be prevented w/ pre-tx antiemetics- prochlorperazine or metoclopramide Fetal distress and miscarriage Tingling/numbness in extremities

Contra: Can't use w/ protease inhibitors and macrolide ABX (CYP3A4 inhibitors)
-Don't use in pregnancy
-Don't use in pts. w/ ischemic heart disease or peripheral arterial disease

Triptans: 5HT-1 Agonists
-Sumatriptan
-Rizatriptan
-Naratriptan
-Zolmitriptan

Very effective acute anti-migraine agents, not intended for prophylaxis
Decrease N/V

SE: coronary vasospasm esp. in pts. w/ ischemic heart disease
-Serotonin syndrome in pts. taking SSRIs or SNRIs at the same time

Contra: don't use concurrently or within 24 hrs. of ergot or other triptans Don't use while taking MAOI or within 2 wks. of stopping one.

Prophylactic Tx for Chronic Migraines
-Beta-adrenergic receptor blockers
-Anti-convulsants
-Anti-depressants
-Ca2+ channel blockers
-Onabotulinumtoxin A
-5HT-2 receptor antagonists: Methylsergide- NOT USED

-Use in pts. who have >3 attacks/month, have 2+ days of headache-related disability/ month.
-Pts. who are unresponsive to, or cannot use migraine abortives
-have frequent headaches of any intensity

Onabotulinumtoxin A

Prophylaxis of headache in adult patients w/ chronic migraine >15 headaches/ month for 3 mos.

Methylsergide

Reserved for refractory migraine prophylaxis
Can't be used continuously for >6 mos.

5HT-2 receptor antagonist

SE: RARELY USED-Life-threatening retroperitoneal, cardiac, and pleural fibrosis

Beta-adrenergic receptor blockers for Migraine Prevention
-Propranolol
-Timolol
-(Others)

...

Anti-convulsants for Migraine Prevention
-Valproate
-Topiramate

Pts taking any of these are at increased risk of suicidal ideation or behavior

Ca2+ channel blockers for Migraine Prevention
-Verapamil

...

Anti-depressants for Migraine Prevention
-Amitriptyline

...

Bowel Motility Disorder Tx

Prokinetic agents
-Dopamine receptor antagonists
-Metoclopramide
-Domperidone

5HT receptor modulators
-Prucalopride

Cholinergic Agents
-Bethanechol

Others
-Erythromycin

...

5HT Receptor Antagonists for GIT
Metoclopramide
Domperidone

MOA: activate D2 receptors which causes suppression of release of Ach from the myenteric plexus, thus, D2 antagonists will INCREASE ACH RELEASE

Metoclopramide
For: symptomatic GERD, gastroparesis and emesis due to GI dysmotility
acts as a 5HT4 receptor agonist, 5HT3 antagonist, D2 receptor antagonist
-increases LES tone and antral and small intestine contractions

SE: acute dystonias, parkinsonism effects (tx w/ anticholinergics or antihistamines) and hyperprolactinemia

Black Box Extrapyramidal symptoms: usually in 1st 1-2 days of tx, more frequent in peds. and >30
Parkinsonian-Like symptoms usually in 1st 6 mos.
Tardive Dyskinesia potentially irriversible, involuntary dyskinetic movements with chronic or high dose, mainly in elderly and in women

Domperidone- mainly D2 receptor antagonist outside BBB

5HT receptor Modulators for GIT
Prucalopride
Tegaserod

MOA: 5HT4 agonist causes excitatory motor neuron stimulation enhancing ACH release

Prucalopride is a partial 5HT-4 agonist that stimulates motility in the colon- for chronic constipation

Tegaserod is a 5HT-4 agonist
WITHDRAWN- CARDIOTOXIC

Cholinergic Agents for GIT
-Bethanechol

MOA: enhances contractions in a relatively uncoordinated manner

Erythromycin (lower dose) for GIT

MOA: mimics motilin (a potent contractile peptide hormone in upper GI)- used in gastroparesis

Lubiprostone

MOA: activates chloride channels and promotes motility and used in constipation

Constipation TX

-Use
laxatives (mild)- evacuate formed fecal material from the rectum
cathartics (strong)- evacuate unformed, usually watery fecal material from the entire colon

Bulk-forming Laxatives
Bran
Methylcellulose Citrucel
Psyllium Metamucil

MOA: fiber resist enzymatic destruction and reach colon where bacteria ferment fiber resulting in short-chain fatty acids and increased bacterial mass

Act in: 1-3 days

SE: can hinder absorption of vitamins, minerals, and drugs like warfarin and aspirin

Stimulant (Irritant) Laxatives
Bisacodyl Dulcolax
Senna Senokot
Castor oil

MOA: produce low-grade inflammation in the intestine to promote accumulation of water and electrolytes and stimulate motility through activation of cAMP and CMP pathways and inhibition of Na+/K+ ATPase

Act: in 6-8 hrs.

SE: pregnant women should avoid these laxatives as it may stimulate contractions

Osmotic (Saline) Laxatives
Magnesium hydroxide
Polyethylene glycol
3350 Mirilax
Lactulose Constulose

MOA: cathartic action is due to osmotically mediated water retention and increased CCK

Acts: 1-3 hrs.

SE: can cause electrolyte imbalances, avoid in renal failure

Surfactant "Stool Softener" Laxatives
Docusates Colase

MOA: Emollient laxatives- anionic surfactants reduce surface tension of the stool to allow mixing of aqueous and fatty substances. These agents also stimulate intestinal fluid and electrolyte secretion by increasing cAMP

Acts: 1-3 days

Lubricant Laxatives
Glycerine suppositories
Liquid Paraffin Agarol
Mineral oil

MOA: used by patients who need to avoid straining for example after a hernia repair, hemorrhoid surgery, or heart attack.

Acts: 6-8 hrs.

SE: interferes w/ vitamin absorption
Mineral oil must be taken in upright position because it can cause lipid pneumonitis

Osmotic (Saline) Laxative: Lactulose

For: Chronic constipation
TX of hepatic encephalopathy- helps draw out NH3 from body.

MOA: metabolites of lactulose draw water into the bowel and cause cathartic effect through osmotic action
-metabolized in the colon by bacterial flora to short-chain FA's which acidifies colonic contents. Favors the formation of nonabsorbable NH4+ from NH3 and trapping NH3 in the colon and effectively reducing plasma NH3 concentrations.

Non-Specific Tx of Diarrhea

Opioid agonists: Diphenoxylate,Loperamide
Bismuth salts- pepto-bismol
Kaolin and pectin
Octreotide in carcinoid syndrom and VIPoma

Irritable Bowel Syndrome TX
Alosetron

5HT-3 antagonist for diarrhea in IBS

Antiemetics

-Vomiting is a protective reflex coordinated by the emetic center in the brainstem CTZ center and solitary tract nucleus of the vagus nerve
-Emetic center receives info. from the gut principally by the vagus nerve.
-CTZ center has a high concentration of receptors for 5HT3, dopamine D2, histamine H1, Acetylcholine M, Substance P, NK1 and opioids

5HT3 Receptor Antagonists
Ondansetron
Granisetron
Dolasetron

For: most widely used for chemo. induced vomiting
also postop. emesis
NOT good for motion sickness

SE: headache, GIT motility disorders

Dronabinol/Nabilone

For: appetite stimulant in chemo. and anorexia
prevention of vomiting in chemo

MOA: CB1 agonist antiemetic due to stimulation of CB-1 of the cannabinoid receptors on neurons in the vomiting center

SE: paranoid reactions, abnormal thinking

Scopolamine

For: motion sickness
anti-cholinergic

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