73 terms

SLM - Pharm Ex 3 Specific

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AED: Prolong rate of recovery/inactivation of voltage gated Na channels --> INCR inactive state --> DECR neuronal activity
Phenytoin
Valproic acid
Carbamazepine
Oxycarbazepine
Lamotrigine
AED: block T-type Ca channels on post-syn membrane
Ethosuximide
Valproic acid
3 Ways to INCR inhibitory effecs of GABA
1) INCR GABA effects at GABAa posy-syn receptor: Phenobarbital

2) Inhibit reuptake at presynaptic terminal

3) Irreversible inhibitor of GABA transaminase (INCR pre-syn [GABA])
Phenobarbital
1st AED (Barbiturate)

Monotherapy: gen. Ton-Clon, Partial, iv: status epilepticus

INCR Inhibitory effects of GABAa @ post-syn receptor

SE: skin rash, INCR drug metab. (BCP)
Phenytoin
Monotherapy: gen. Ton-Clon, Partial, iv Fosphenytoin (prodrug) statius Epi.

PROLONG inactivation of voltage gated Na+ channels

Zero Order: [drug] INCR disproportionately as INCR dosage

INCR drug metab. (BCP, Warfarin)

SE: Gingival hyperplasia,SJS --> discontinue drug
Carbamazepine
Monotherapy: gen. Ton-Clon, Partial, Manic depressive, neurpathic pain (carbaMaZePain)

PROLONG inactivation of voltage gated Na+ channels

Takes 3 weeks for consistent plasma [ ]

INC metab. by Phenobarbital, Phenytoin, Val Acid

SE: Acute - stupor, coma, hyperirritability convolsions
Chronic - drowsiness, vertigo, ataxia, blurred vission, INCR drug metab. (BCP)
Oxycarbazepine
Monotherapy/Adjunctive: Partial seizures

PROLONG inactivation of voltage gated Na+ channels

Prodrug activated in liver
Does NOT autoinduce! (Carbamazepine does!)

SE: dizziness, nausea, somnolence, ataxia, INCR drug metab. (BCP)
Ethosximide
Monotherapy: absence seizures

Inhibit T-type Ca channels

SE: nausea, vomiting, anorexia, CNS drowsiness, lethargy, euphoria, SJS, aplastic anemia
Valproic Acid
"Broad spectrum AED"

Monotherapy: absence, myoclonic, partial, & Ton-Clon

*Inhibit T-type Ca channels
PROLONG inactivation of voltage gated Na+ channels
INC GABA synthesis (in vitro)

SE: GI nausea, anorexia, CNS sedation, ataxia, tremor, INCR hepatic blood enzymes (40%), hepatic toxicity< 2 yo, Inhibits CYP2C9 --> INCR [phenytoin] and [phenobarbital]
Newer AEDs - 4 facts
1. lack serious side effects (less SJS)
2. NO liver enzyme induction: fewer drug-drug interactions
3. less efficacious than traditional AEDs, mostly adjunctive therapy
4. Less known about the MOA
Gabapentin
GABA bound to lipophillic hexane ring to cross BBB

Adjunctive: Partial seizures w/ & w/o generalized secondary seizures, mostly neuropathic pain

Binds to L-type Ca channels

Not metabolzed, excreted unchanged in urine --> must have good renal fcn.

SE: fatigue, ataxia
Lennox-Gustaut Syndrome (LGS)
- Childhood onset epilepsy (2-3 yo)
- Severe cognitive dysfunction
- Multipe seizure types including atonic "drop" seziures
- Resistant to drug therapy
- Mortality rates 3/7%
- TRX: Ketogenic diet can help, Felbamate
Lamotrigine
Monotherapy/Adjunctive: LGS, partial & generalized Ton-Clon seizures, "braod spectrum AED"

PROLONG inactivation of voltage gated Na+ channels

SE: dizzy/nausea, ataxia, blurred vision
Additional AED's --> rash/SJS
Topiramate
Monotherapy/Adjunctive: Partial & generalized ton/clon, LGS

Inhibit Na channels/enhance GABA receptors

SE: Ataxia, fatigue, somnolence, weight loss. DECR plasma [BCP]
Levetriacetam
Adjunctive: Adult - partial & Ton-Clon, Kids - myoclonic, IV - status epilepticus

Highest saftey margin in animal studies (NO drug-drug interactions) Rapid dose titration makes useful for adj. trx.

SE: asthenia, somnolence, dizziness
Midrin
Abortive/Analgesic: MILD-MODERATE migraine

As effective as oral ergotamine tartrate w/ fewer SE.

Isometheptene (SNS, A and B --> vasoconstrict) Dichloralphenazone (sedative)
Acetominophen (analgesic)
Ergotamine Tartrate
Abortive/Acute of MODERATE/SEVERE migraine

Interacts w/ Serotonin/Dopamine/Adrenergic receptors

Activates 5-HT1B recptors, vasoconstriction, DECR neurogenic inflammation

max oral/sublingual dose shouldn't exceed 6 mg/attack or 10 mg/week. half life 2 hrs, vasoconstriction for 24 hrs. comes from rye contaminated with fungus, can cause "ergotism"
side effects: GI upset due to activation of central dopamine receptors in the chemoreceptor trigger zone treat with metoclopramide. ergot toxifity if given with erythromycin. contraindicated with cardiovascular disease
dihydroergotamine (D.H.E. 45)
acute treatement of moderate to severe migraine. admin parenterally, incompletely absorbed by GI tract.
MOA: similar to ergotamine (5HTa stimulation, direct vasoconstriction and decreased neurogenic inflammation).
side effects: GI upset transient bradycardia, leg weakness, vasospasms (this is less likely than with ergotamine due to less arterial vasoconstrictor activity and more alpha adrenergic activity.
sumatriptan (imitrex)
acute treatement of moderate to severe migraine. derivative of serotonin. subcutaneous injection, oral tables, or nasal spray. metabolized by MAO-A, excreted in urine.
Pharmacodynamics - also relieves nasua, vomiting, photophobia, and phonophobia.
contraindicated in coronary artery disease. can cause MI, don't give IV - can cause vasospasms, don't use with other ergots.
triptan symptoms: chest and throat tightness, dif. breathing, panic, anxiety, parathesias, etc.
don't use with MAO inhibitors!
second generation triptans
greater bioavailability versus sumatriptan, also work at peripheral components of trigeminovascular system, but act centrally to inhibit pain transmission in the trigeminal nucleus.
zolmatriptan
second generation triptan - oral, disintegrating, nasal. eliminated by MAO-A and liver CYP 1A2. greater bioavailability than oral and nasal sumatriptan, but subq sumatriptan has 97% bioavailability. see table 27-9
prochlorperazine (compazine)
treatment of acute migraine unresponsive to sumatriptan, DHE or oral analgesics.
relives headaches and anti emetic.
methysergide (sansert)
migraine and cluster prophylaxis if normal therapies not working of if being used more than twice a week.
chemistry: metabolized in liver to active metabolite., methylergometrine.
MOA: multiple because acts at 5HT2 receptor antagonist and 5HT1 receptor agonist. effects take a few days to develop.
adverse effects: fibrosis and fibrotic complications of various organs. to avoid, d/c for 4 weeks every 6 months. angina pectoralis due to vasoconstriction and coronary insufficiency, GI problems, give with food. LSD like effects
beta blockers
first choice for migraine prophylaxis. best if lack partial agonist activity: atenolol, metropolol, nadolol, propanolol, timolol (NOT acebutolol, pindolol, and penbutolol). not good if patient has asthma or diabetes.
amitriptyline (elavil)
antidepressant for migraine prophylaxis
MOA: down regulation of central 5-HT2 and adrenergic receptors.
side effects: anticholinergic effects (dry mouth, blurred vision, urinary retention, cardiac arrhythmia)
valproic acid: valproate sodium 1:1 (Depakote)
antiseizure drug, prophylaxis for migraines.
MOA: unclear. facilitating GABA neurotransmission, modulating glutamate and inhibiting sodium and calcium channel activity.
side effects: nausea, vomiting, weakness (asthenia) weight gain, tremor, hair loss, rarely hepatic toxicity. teratogenic and can cause neural tube defects.
topiramate
anticonvulsant, prophylaxis for migraines. similar to valproate but adverse effects include paresthesia, fatigue, anorexia, diarrhea, wight loss, memory problems, nausea.
gabapentin (neurontin)
anticonvulsant, prophylaxis for migraines. adverse effects include somnolecense, astehnia (weakness) and dizziness
μ receptors
opioid receptors located primarily in the brainstem, spinal cord, and limbic areas and are thought to mediate supraspinal analgesia, some spinal analgesia, sedation, respiratory depression, euphoria and dependence. Also located in periphery and modulate sensitivity of nociceptors.
κ receptors
located mainly in brainstem and spinal cord, and to a lesser extent, the limbic system. thought to mediate some spinal analgesia, some supraspinal analgesia, meiosis, sedation, and dysphoria.
δ receptors
located in brainstem and limbic system, and mediate dysphoria and hallucination. also appear to play role in development of tolerance to μ agonists
pharmacologic actions of morphine
analgesia; sedation and mental clouding; relief of anxiety and apprehension; euphoria (usually); dysphoria (occasionally); nausea; depression of respiration; constriction of pupils; antitussive effect; lowering of seizure threshold; endocrine disturbances; increased tone of circular smooth muscle; decrease in propulsive movements of longitudinal muscle; cardiovascular effects; skeletal muscle rigidity; immunosuppression
standard therapeutic dose of morphine
10 mg SC or IM
characteristic symptom triad of opium poisoning
1. CNS depression
2. depressed depth and rate of respiration
3. pin point pupils (if pt is severely hypoxic (close to death) pupils may be dilated
Morphine (sulfate salt)
roa: absorbed from GI tract, but not as effective orally because of first pass metab; usually IM or IV
use: more severe pain
dose: 10 mg SC or IM; or 10-30 mg PO
codeine (phosphate or sulfate salt)
roa: orally effective
dose: 1/12 potency of morphine; common doses are 30-60 mg PO
uses: analgesic for mild-moderate pain; antitussive
hydromorphone (dilaudid, palladone)
similar to morphine but more potent
oxycodone (roxicodone, percodan, oxycontin)
sort of a cross between morphine and codeine.
roa: orally alone or in combo with acetaminophen
use: mild-moderate pain
hydrocodone (lortab, lorcet, vicodin, norco)
similar to codeine and oxycodone
roa: orally in combo with acetaminophen
use: mild-moderate pain; antitussive
currently one of the most widely prescribed opioids
meperidine (demerol)
synthetic drug
roa: oral and parenteral
dose: 1/10 potency of morphine
use: moderate-severe pain; also in obstetrics
reputed to have weaker effects on smooth muscle than morphine; short acting (1-3 hours); not appropriate for chronic pain because of buildup of active metabolite that can cause seizures
heroin (diacetylmorphine)
more potent and more euphoric than morphine; duration of action 4-6 hours
roa: injection, snorting, smoking
use: abuse
methadone (dolophine)
use: analgesic and Tx of opioid addiction
duration of action: (12-24 hrs)-less euphoric and longer acting than heroin or morphine
*when used acutely as analgesic, duration of action is 4-6 hrs
propoxyphene (darvon)
much less potent than other opioids; little analgesic activity at therapeutic doses; IT DOES have POTENTIAL for serious TOXICITY at high doses
fentanyl (sublimaze)
very potent μ agonist (100x morphine)
roa: given parenterally to supplement surgical anesthesia; transdermal preparation is available for chronic pain
neuroleptic analgesia
in this state, various diagnostic or minor surgical procedures may be carried out even though the patient might not completely lose consciousness; combo prep with fentanyl plus droperidol (innovar) can induce this state
neuroleptic anesthesia
induced by combo of nitrous oxide with innovar
opioid combination preparations (5 of them)
1. codeine/ acetaminophen
2. codeine/ aspirin (empirin and generics)
3. hydrocodone/ acetaminophen (vicodin, norco, lortab, others)
4. hydrocodone/ ibuprofen (vicoprofen)
5. oxycodone/ acetaminophen (percocet, percodan, tylox, and others)
pentazocine (talwin; talwin NX)
opioid agonist effects are dominant; acts as κ agonist, but only as partial agonist at μ receptors; acts as μ antagonist at high doses.
-less effective than morphine for severe pain
-sedation and respiratory depression less than morphine
-CNS stimulation and hallucination are more common than with morphine
-potential for physical dependence less than morphine
butorphanol (stadol)
similar to pentazocine; must be given parenterally, but this one is unique because it can be given intranasally
buprenorphine (buprenex, subutrex, suboxone)
partial agonist at μ receptors; very high doses have μ antagonist actions. Analgesic effect slightly less than morphine, but abuse potential is MUCH lower.
uses: treats heroin addiction
roa: injection, sublingually, or intranasally
suboxone
new combo product containing buprenorphine plus nalaxone designed for sublingual use.
what is primary agent used for "office-based" treatment of opioid addiction?
buprenorphine
tramadol (ultram)
use: mild-moderate pain
supposedly weak μ agonist. also inhibits synaptic reuptake of NE and serotonin, much like tricyclic antidepressants; claims that drug has very low abuse and addiction potential, but that is debatable
naloxone (narcan)
"pure" opioid antagonist
use: drug of choice for opioid poisoning
roa: must be given parenterally
duration: 1-2 hours
can precipitate withdrawal in addicts
naltrexone (ReVia)
roa: orally effective, long acting (24 hr) opioid antagonist
use: originally used in "immunizing" addicts (preventing high produced by opioid agonists); also approved for Tx of alcoholism
drawbacks: hepatotoxicity; patient compliance is a problem
*opioid addict must first be detoxified before this drug therapy can be initiated
methylnaltrexone (relistor)
roa: parenteral (subcutaneous)
use: treatment/ prevention of opioid-induced constipation-only appropriate for serious constipation resulting from opioid use in more severe types of pain; also may be useful to Tx of post-op paralytic ileus
therepaeutic uses of opioid antagonists
1. treat opioid induced overdose toxicity
2. diagnose opioid physical dependence
3. treat compulsive opioid abusers
4. reduce craving for alcohol in recovering alcoholics
NSAIDS: Indomethacin (indocin) and Ibuprofen (motrin)
these agents have good antiinflammatory activity and, in many cases, can stop the acute gout attack.
MOA: inhibition of prostaglandin synthesis
Side effects/ tox: GI irritation; one of the drugs causes CNS side effects in many patients
which NSAID should be avoided in treatment of gout...and WHY?
Aspirin- because of its biphasic effect on uric acid excretion
colchicine
naturally occurring alkaloid isolated from the autumn crocus; has unique antiinflammatory activity that is specific for gout
MOA: binds to tubulin and prevents its polymerization to microtubules. this leads to a reduction in leukocyte migration, phagocytosis and mitosis; also inhibits production and release of proinflammatory glycoproteins from neutrophils
SIDE EFFECTS: diarrhea, GI upset (N/V)
*preferred drug for alleviating acute gout attack, but GI side effects can be quite severe
allopurinol (xyloprim)
inhibits enzyme xanthine oxidase and reduces formation of uric acid. does not stop acute gout attack, but over time it can greatly reduce the potential for future attacks.
side effects: increased frequency of gout attacks during early stages of therapy; elevation of LIVER enzymes; allergic rxn's (mainly dermatologic)
febuxostat (uloric)
newer xanthine oxidase inhibitor; generally similar to allopurinol, but touted as causing fewer skin problems and allergic reactions (that is debatable); elevation of liver enzymes as with allopurinol
probenecid (benemid)
Uricosuric agent that inhibits both secretion and reabsorption of organic acids. since more uric acid is reabsorbed than secreted by the tubule, the net effect of this drug is to increase uric acid excretion. CAUSES INCREASED RISK OF KIDNEY STONE FORMATION, so it is contraindicated in patients with kidney stones (gouty nephropathy). NOT effective for treating acute attacks.
what would you use to treat acute gout attacks?
1. indomethacin, ibuprofen or related NSAIDs
2. add an oral corticosteroid (prednisone or methylprednisolone)
3. colchicine is also primary option, but side effects can be a problem
4. acetaminophen and opioids
how to treat hyperuricemia of chronic gout?
1. dietary and lifestyle modification (low purines, avoid alcohol, increase fluids)
2. uricosuric agents (probenecid or sulfinpyrazone) work best in patients who do not normally excrete lg. amounts of uric acid
3. allopurinol works best in patients who are synthesizing excess uric acid; also preferred in treatment of patients with existing kidney stones
4. in patients with severe, chronic gout/ hyperuricemia, it may be necessary to use several drugs
normal values for plasma urate/ uric acid
2.0-7.0 mg/ deciliter or 120-140 μM
factors that contribute to the development of hyperuricemia and gout
heredity, diet, alcohol, low fluid intake, cancer, radiation therapy, drugs (aspirin, diuretics, sulfonamide antimicrobials, antineoplastics, L-DOPA)
four stages of gout
1. asymptomatic hyperuricemia
2. acute gouty arthritis
3. intercritical (interval) gout
4. chronic tophaceous gout w/ or w/out complication of progressive renal failure resulting from deposition of urate crystals in the kidney and renal calculi
lamotrigine (lamictal)
use: monotherapy and adjunctive treatement of partian and generalized tonic/clonic seizures, LGS.
moa: prolong recovery of voltage gated Na channels from inactivation, inhibit Ca to lesser extent
pharmacokientics - long T1/2 - 24-35 hrs. but decreased by phenytoin, carbamazepine, phenobarbital, primidone.
side effects: dizziness, ataxia, blurred vision, nausea. rash and SJS if used with othe AEDs.
fosphenytoin
water soluble prodrug of phenytoin. given to pts IV in status epilepticus after treatment with diazepam or lorazepam.
does not irritate veins as does phenytoin because it has higher pH and doesn't contain alcohol.
AED and pregnancy. females on oral birth control are ___ times momre likely to have failure rate of oral contraceptive. and what fold in birth defects? what causes birth defects?
3 times higher failure rate, 2-3 fold increase in birth defect due to neural tube formation abnormalities resulting in facial and cranial deformities. most associated with phenytoin.
what should women on AED do if pregnant?
reduce t omonotherpay, carefully monitor drug plasma concentration, give folate (0.4 mg/day) throughout pregnancy to reduce risk of neural tube defects. also vitamin K during last month of gestation to reduce newborn coagulation problems/ vitamin K deficiencies that may be associated with AED
drugs used to treat status epilepticus
diazepam IV, if no response lorazepam IV. preferable becuase longer acting. aftere these, monitor closely. avoid hypoventilation and hypotension. once seizure is controled give IV fosphenytoin (cerebyx), a water soluble prodrug of phenytoin.