pharm neuro info.txt

l-dopa is a dopamine precursor. its adadministered with the peripheral decarboxylase inhibitor carbidopa (otherwise metabolized prior to crossing BBB, incerases SE incl N/V, ortho hypo). also allows for lower doses of levodopa (75%) and more rapid/even titration.

mimic dopamine.

l-dopa has short plasma T1/2 (1-3h), competes for absorption c its inactive metabolite. however therapeutic effect is often extended by neuron's ability to store dopamine. full therapeutic effect w/i weeks-months.

metabolized by COMT (more peripherally), MAO (more centrally).

parkinsons. pramipexoke restless leg syndrome. parlodel/cabergoline (ergots) endocrine (acromegaly, amenorrhea-galactorrhea, prolactin-secreting adenoma).

parkinsons

pergolide/cabercoline (ergots) should no longer be used due to risk of valvular heart disease.

l-dopa/DA + phenothiazine antiemetics (prochlorperazine/metoclopramine -- they are dopamine receptor blockers)

more common in DA than l-dopa. nausea, peripheral edema, ortho hypotension, hallucinations/vivid dreams. serious sudden sleep onset (driving?). ergots require slower titration due to N/V, fatigue, hypotension.

most effective SC dopamine agonist -- onset 3-20 min, duration 90 min. used in combo c l-dopa to reduce dose/minimize off time

always administered with the peripheral decarboxylase inhibitor carbidopa (otherwise metabolized prior to crossing BBB, incerases SE incl N/V, ortho hypo). also allows for lower doses of levodopa (75%) and more rapid/even titration.

advantages of dopamine agonists over l-dopa include no need for enzymatic conversion, longer duration of action, and they avoid potential neurodegeneration associated c conversion of l-dopa to free radicals

improves glycemic control in type 2 DM

catechol-o-methyl transferase

COMT breaks down l-dopa. these drugs inhibit this. (other l-dopa breakdown pathway is via dopa decarboxylase. product of breakdown is 3-OMD, which competes with L-dopa at BBB transporters -- therefore full effect of l-dopa achieved with coadministration of COMT and DDC inhibitors)

T1/2 similar to l-dopa. entacapone prolongs T1/2 of l-dopa 50%. entacapone does not cross BBB, tolcapone does.

parkinsons adjunct (decreased wearing off)

hx of neuroleptic malignant syndrome, rhabdomyolysis, pheochromocytoma. tolcapone liver disease/LFT 2xlimit.

COMT inhibitors + MAOI w/i 14 days (too much E/NE = tachy, htn, arrhythmias).

dopamine-related (N/V, ortho hypotension, dyskineasia, vivid dreams/hallucinations). also discoloration of urine (dark yellow - reddish brown)

NMDA antagonist -- relatively weak antiparkinsonian drug with low toxicity that is most useful in treating patients with early or mild PD and perhaps later when dyskinesia becomes problematic

anticholinergic -- should be reserved for younger patients in whom tremor is the predominant problem. Their use in older or demented individuals and those without tremor is strongly discouraged.

anticholinergic -- should be reserved for younger patients in whom tremor is the predominant problem. Their use in older or demented individuals and those without tremor is strongly discouraged.

nonselective MAOIs often contraindicated. MAO-B selective MAOIs become nonselective at higher doses, so caution with them as well.

loss of dopaminergic neurons in substantia nigra. Balance between D1 pathway (enables movement) and D2 pathway (inhibits movement) is disrupted in this disease (low DA levels lead to greater D2 activation).

rivastigmine available TD (compliance)

Alzheimer's, NNB reversal, postoperative intestinal ileus, urinary retention. neostigmine/pyridostigmine myasthenia gravis.

neostigmine, pyridostigmine, physostigmine, edrophonium less selective for CNS, therefore CI in bronchial asthma, urinary/GI obstruction.

SLUDGE: salivation, lacrimation, urination, defecation, GI distress, emesis.

sarin gas and pesticides

agonists at 5HT-1B and alpha1, result in vasoconstriciton. also agonists at 5HT-1B and 5HT-1D autoreceptors that are thought to decrease pain transmitter release.

low oral bioavailability, T1/2 2 h (extensive first pass metabolism) though biologic activity lasts > 24 h. ergotamine PO/SL/PR, dihydroergotamine SC/NS. ergonovine and methylergonovine are absorbed fastest (peak plasma levels < 90 min).

CYP3A4.

ergotamine/dihydroergotamine acute migraine. ergonovine/methylergonovine PP hemorrhage.

CAD, HTN, PVD, pregnancy

ergots + triptans w/i 24 h (addative effects).

N/V/D, paresthesias, angina, HTN. do not give ergotamine IV (excessive vasoconstriction / hypertension risk)

agonist at 5HT-1B (BUT NOT ALPHA-1), result in vasoconstriciton. also agonists at 5HT-1B and 5HT-1D autoreceptors that are thought to decrease pain transmitter release.

sumatriptan fastest, reaches peak plasma concentrations 12 min p SC. frovatriptan/naratriptan longest acting. sumatriptan/zolmitriptan also available as nasal sprays.

metabolism often by MAO-A (frovatriptan CYP1A2, eletriptan CYP3A4 / PGP).

CAD, HTN.

triptan + triptan (addative). triptan + MAOI w/i 14 d. rizatriptan + propranolol.

paresthesias, chest/jaw/neck tightness/pain/pressure. weight gain (except topiramate which is weight loss).

1. increase GABA activity, 2. vasoconstrictor, 3. CNS depressor

unknown. possibly Na or Ca channel blocking, GABA potentiation, NMDA antagonism, or inhibition of carbonic anhydrase.

do not need to monitor levels. do check Cr, bicarb, mental health.

migraine, epilepsy.

pregnancy (cat D, cleft palate in 1T)

topirimate + OCPs (decreased efficacy)

significant cognitive impairment, fatigue, paresthesias, taste changes, weight loss.

phentermine + ER topirimate, marketed for weight loss.

progesterone is a natural anticonvulsant, while estrogen has proconvulsant activity.

Sodium channel inhibitor, slowing recovery from inactivated state. Selectively targets channels that are opening/closing rapidly. May also enhance GABA release, inhibit glutamate release, block Ca channels.

Therapeutic levels = 10-20 mcg/mL total, 1-2 mcg/mL free. dental exam q3months.

highly protein bound. ER formulations contain 8% less drug than IR -- monitor closely when switching.

CYP2C9,2C10,2C19. Exhibits saturation kinetics: at low concentrations, first order kinetics (certain % per unit time) -- at high concentrations, zero-order kinetics (certain amount per unit time) due to saturation of pathways.

epilepsy

pregnancy (cat D)

phenytoin + OCPs (decreased efficacy). CPY P450 enzyme inducer, may also saturate metabolic pathways used by other drugs.

gingival hyperplasia, coarsening of facial features in women. BBW for cardiovascular risk c rapid infusion (>50 mg/min, >150mg PE/min).

prodrug, dosed in phenytoin equivalents (PE) to avoid need for conversion. it is better tolerated, safer, and leads to quicker therapeutic levels but is more expensive.

inhibits Na channels (slows recovery from inactive state). May also inhibit Ca channels and glutamate release.

do not need to monitor levels

at high doses, produces auto-induction.

epilepsy, bipolar disorder

reduces levels = phenytoin, carbamazepine, phenobarbital, OCPs. increases levels = valproate (can be used additively, but increases chances of skin rxns)

rash (SJS). D/C AT FIRST SIGN OF UNEXPLAINABLE RASH

okay-ish in pregnancy (cat C)

sodium channel blocker. may also have effects on adenosine receptors (inhibiting NE), GABA, and glutamate.

T1/2 is variable because they are autoinducers (T1/2 between 12 and 65 hrs reported, decreases with repeated dosing).

therapeutic levels = 4-12 mcg/mL

epilepsy, trigeminal neuralgia, bipolar disorder.

porphyria, hypersensitivity to TCAs, pregnancy (Cat D)

carbamazepine + MAOI w/i 14 days

hyponatremia due to ADH secretion. BBW for serious dermatologic reactions with the HLAB1502 allele (Asian pts) and for aplastic anemia / agranulocytosis.

a less potent analogue of carbamazepine that attempts to maintain efficacy but avoid autoinduction (fails in both departments, may have slightly less interactions).

unknown. postulated that they inhibit calcium influx at synaptic terminal, decreasing glutamate release. also might enhance synthesis of GABA.

does not undergo metabolism, excreted unchanged.

epilepsy, neuralgia, fibromyalgia

peripheral edema

gabapentin enacarbil (prodrug) is indicated for restless leg syndrome. It is more expensive, but isn't any more effective than off-label gabapentin.

an ER formulation of gabapentin indicated for post-herpetic neuralgia -- but its a brand so more expensive!

increase the binding of GABA to GABA-A receptors, increasing the influx of Cl (CNS depressants). also potentiate the binding of benzos.

redistribution effect if administered IV. They are also autoinducers (induce the same enzymes that metabolize it, resulting in increased dose requirements over time).

liver enzyme inducer (CYP2A + CYP3A)

epilepsy, sedation. antiseizure effects occur at a lower dose than sedation, however the therapeutic index difference between the two is small. phenobarbital is more selective for antiseizue than sedation, so it is the most common.

porphyria (can exacerbate accumulation of porphyrins)

sedation, addiction/tolerance, hypotension (especially IV use)

resembles alcohol intoxication (sedation, slurred speech, lack of coordination/ataxia, nystagmus, hypotension, respiratory depression)

resembles alcohol withdrawal (agitation, sleep disturbances/hallucinations, seizures, tachy/HTN, sweating).

sodium channel blocker. may also promote synthesis/inhibit breakdown of GABA, block glutamate, inhibit Ca channels.

phase II enzyme metabolism, however it is a CYP2C9 inducer (substrates = phenytoin, phenobarbital).

epilepsy, bipolar disorder, migraine prophylaxis

hepatic disease, pregnancy

GI (N/V). serious, rare hepatotoxicity (though LFT elevation relatively common), pancreatitis. carnitine supplementation may help mitigate risk

therapeutic range = 15-40 ug/mL

SR form of VPA (more commonly used)

therapeutic range = 50-125 mcg/mL