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101 Cards in this Set

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Describe Parkinson's and it's characteristic symptoms.
Most common form is idiopathic, characterized by slow, progressive degeneration of pigmented neurons in the substantia nigra pars compacta (SNpc).

Symptoms: resting tremor -disappears during sleep or purposeful movement.

rigidity- incr muscle tone.

bradykinesia- poverty of movement => akinesia.
What are the secondary Parkinson motor manifestations?
-Stooped posture
-poor righting reflex
-shuffling gait

Also difficulty in speaking(microphonia), writing(micrographia) and swallowing.

In advance stages, pts become immobile, frozen(akinetic).
What role does oxidative stress play in Parkinsons'?
Oxidation of DA => H2O2 & oxyradicals. This may lead to damage of DAergic neurons via DNA damage, peroxidation of membrane lipids, & neuronal death. In pts w/ Parkinsons, there's a deficiency of Gltathione in the striatum and incr Fe in the SNpc. This makes brain susceptible to free radical accumulation and oxidative stress.
Whats the DA Theory in Parkinson's?
Imbalance b/w Dopaminergic(inhibitory) & cholinergic(excitatory) neurons within the striatum.

*depletion of DA in the striatum is proportional to the severity of DA cell loss in the Substantia nigra.
How does depletion of DA => Parkinson's?
Loss of inhibitory DA input from the SN to the striatum shifts the balance in favor of Ach mediated excitation of:
1) inhibitory GABAergic interneurons
2)inhibitory GABAergic efferent projections.
What does MAO and COMT enzymes do?
-MAO is an enzyme involved in the oxidative deamination of monoamines like DA,NE,Epi,5HT,Histamine.

-COMT: involved in the degragation of catecholamines(DA,NE,Epi).
How is drug therapy in Parkinsons directed?
Goal of therapy is to return the system to a balanced state by:
1) increasing DA-ergic function w/ DA precursors, DA agonist, or inhibitors of enzymes which degrade catecholamines(MAO-B, COMT).

2) reduce dominance of cholinergic system w/ anticholinergic drugs.

NOTE: drug therapy is symptomatic, not curative!!!
Name the drugs used to reduce cholinergic dominance?
Benztropine- balance DA-Ach systems by reducing cholinergic dominance.

Diphenhydramine- central muscarinic blockade
Benztropine in Parkinsons?
has modest anti-parkinsonian action useful in mild to moderate dz. Has beneficial effect on tremor & rigidity but little to no effect on bradykinesia. Use in combo w/ levodopa/carbidopa for severe parkinsonism.

Used to manage drug induced parkinsonism in schizo's being tx w/ neurolepics.
Diphenhydramine in Parkinson's?
Therapeutic action via prominent anticholinergic properties.

Has common S/E of dry mouth, blurred vision, constipation & urinary retention, and Sedation, mental confusion.
When is Diphenhydramine contra-indicated?
In pts with bowel or bladder dysfunction, memory disorder, & narrow angle glaucoma.
What are the drugs which increase dopaminergic function?
levodopa + carbidopa
L-Dopa, the precursor for DA synthesis via decarboxylation. Levodopa crosses the BBB, DA doesn't.

Large doses required to cross BBB.

95% of oral levodopa is rapidly decarboxylated.
Levodopa precautions?
levodopa=>DA synthesis may cause oxidative stress and hasten degeneration of striatal neurons. For this reason, pts w/ mild dz may be started on other drugs like amantadine for starts.
S/E's of levodopa?
-cardiac arrythmias
Levodopa + carbidopa?
Carbidopa is a DOPA decarboxylase inhibitor that doesn't cross the BBB, it's used to prevent conversion of levodopa => DA in the periphery.
Benefits of using carbidopa?
-dose of levodopa need can be decreased.
-n/v is eliminated
-CV effects are diminished
-effective doses can be reached more quickly.
-antagonism of levodopa's efficacy by Vit B6 is avoided.
Psychic effects of levodopa?
apathy and depression are replaced w/ increased vigor and mood. Improvement in mental function, self interest, and relationships w/ surroundings and family.
Major S/E's of levodopa?
-Cardiac arhythmias & transit tachycardia due to DA on b-adrenergic receptors. Can be prevented w/ carbidopa and beta-blockers.

-orthostatic hypotension: occurs in early therapy then decreases w/ time.

-n/v: early in therapy and decr. w/ time. Due to action of DA on chemoreceptor trigger zone in area postrema of medulla. Minimized w/ carbidopa.

-abnormal involuntary movements(dyskinesia): dose limiting S/E.

-Mild rxn early in therapy: nervousness, insomnia, anxiety, agitation & nightmares

-psychotic rxns(confusion, delirium) are dose limiting. suicidal tendencies and depression may occur.
Pharmacokinetics considerations?
levodopa is short acting w/ half-life of 1.5 hrs. Best results are made early in tx. Tremors, rigidity, and bradykinesia are resolved nearly completely. Beneficial effects exceed lifetime of levodopa.
What is "end of dose akinesia" (wearing off)?
With time and continued degeneration, levodopa buffering capacity is lost.
What is On/OFF phenomena?
In later stage of dz, pts flucuate b/w being off having no beneficial effects and being on but w/ disabling dyskinesias.
What is done to alleviate "end of dose akinesia and On/Off fluctuations?
-smaller doses of levodopa taken more often.
-Use of sustained release formulations.
-addition of DA agonist to regimen(dyskinesia is a S/E of agonist though).
-addition of cholinergic antagonist to regimen.
-addition of MAO-B inhibitors or COMT inhibitors to regimen.
Drug-Drug interactions w/ levodopa?
-drugs which deplete brain monoamines(reserpine).
-drugs that interfere w/ DA synthesis(a-methyldopa)
-dopamine receptor antagonist.
-non-selective monoamine oxidase inhibitors.
Advantages of DA receptor agonist?
-they don't require enzymatic conversion and they don't depend on the functional capacity of the nigrostriatal neurons.

-DA receptor agonist are more selective for D2(indirect) DA receptors.
DA agonist w/ D2 selectivity.

-Use as adjunctive therapy w/ levodopa/carbidopa in pts who are experiencing On/Off and "end of dose akinesia".
Other uses of bromocriptine?
Tx of hyperprolactinemia in prolactin secreting tumors or as a S/E of antipsychotics.

Tx of Neuroleptic Malignant Syndrome(NMS). NMS is believed to result from an extremely rapid blockade of postsynaptic dopamine receptors.
DA agonist at both D1 and D2. More potent than bromocriptine. Useful in late stages of Parkinsons as adjunctive therapy w/ levodopa/carbidopa.

as with bromocriptine, duration of action of a single dose of pergolide is longer than that of levodopa.

Derived from Ergot fungus.
Non-ergot DA agonist specific for D2 subfamily with higher affinity for D3 subtype.

-Effective as monotherapy in early stages of dz.

-Useful in later stages of dz as adjunctive therapy with levodopa/carbidopa.
S/E of DA agonists?
orthostatic hypotension w/ low doses. More common w/ DA agonist than w/ levodopa.

n/v early in therapy.

Psychotic rxn are more common and severe than that w/ levodopa.

MAO-B inhibitor. Slow the degradation of DA via irreversible inhibition of MAO-B. May have neuroprotective effect via anti-Oxidative stress.

Does not inhibit peripheral metabolism of NE or 5HT or interact with food containing tyramine like non-specific MAOI's do.

Attenuates mild On/Off and "end of dose" akinesias. Thus useful as adjunctive therapy w/ levodopa.

In advanced dz, levodopa induced dyskinesias may be exacerbated by Selegiline.
What is Selegiline metabolized to?
Amphetamine. Leads to S/E of anxiety and insomnia.
COMT inhibitor. elevates DA levels by inhibiting degradation and may provide neuroprotective effects.

Use as adjunctive therapy w/ levodopa/carbidopa.

No liver toxicity w/ entacapone.
Antiviral. MOA is unclear but thought to release DA from nerve terminals.

use as monotherapy in mild dz and adjunctive therapy in fluctuating response to levodopa.

Less effective than levodopa but w/ less S/E.
What is MPTP induced parkinsonism?
MPTP is a byproduct in illicit drug prep know to cause parkinsonism. MPTP is converrted by MAOB to MPP+ which is extremely toxic to dopaminergic neurons leading to selective destruction in the substantia nigra.
Tourettes Syndrome?
Characterized by multiple, complex involuntary movements including respiratory and vocal tics. Probably a dysfunction involving both basal ganglia and limbic structures.
Tx of Tourettes Syndrome?
For BJE, drug of choice is haloperidol, a typical antipsychotic but the tardive dyskinesia is a serious concern.

Use Clonidine, a-adrenergic receptor agonist in pediatric pts to avoid tardive dyskinesia associated w/ haloperidol.
heterogeneous symptom complex - chronic disorder characterized by recurrent seizures. Seizures are finite episodes of brain dysfunction.
Where do seizures originate from?
From hyperexcitable cells (the focus) from which discharges periodically spread to limited areas of the brain = partial seizures or to large areas = generalized seizures.

Seizures are believed to involve the cerebral cortex and limbic system and not other areas of the brain.
Describe Partial seizures?
Focal seizures who's symptoms depend on area of brain effected.

Simple partial seizures - not accompanied by a change in consciousness.

Complex partial seizures - accompanied by loss of consciousness

Partial seizures w/ secondary generalization - focal seizures spread until it generalizes.
Describe Generalized Seizures?
Tonic Clonic(grand mal) sudden loss of consciousness with tonic contraction of body muscles w/ rhythmic jerking then depression of CNS function for varying periods.

Absence(petit mal) - brief loss of awareness but w/o loss of consciousness. may have eye-blinking or lip-smacking. Seen in young children.

Myoclonic - sudden jerks of limb, trunk or whole body. Seen in children to adolescence.

Atonic seizures - sudden loss of postural tone

Infantile spasms - not a seizure type. brief recurrent myoclonic jerks of body. Most pts are mentally retarded.
How is absence seizures treated?
How is infantile spasms treated?
BZ like clonazepam. These seizures are refractory to usually antiseizure agents.
How is generalized tonic clonic seizures and partial seizures treated?
What drugs have a wide spectrum of antiseizure activity?
What drugs are approved for treatment of status epilepticus?
What are the MOA of anti-seizure medication?
-they depress excitability of epileptic focus and prevent spread of seizure

-They enhance the inhibitory GABA neurotransmission.
What are the mechanisms which excitatory neurotransmission is inhibited?
-alteration of ion channel conductance => prolonged Na channel inactivation => reduced action potential frequency. OR reduce low threshold Ca++ currents(T currents).

-Blockade of excitatory glut receptors.
What are T currents implicated in?
Absence seizures
What are mechanisms which inhibitory GABA neurotransmission is enhanced?
-act at allosteric binding sites to enhance GABA mediated Cl- conductanace.

-increase GABA levels via glutamic acid decarboxylase stimulation.

-promote release of GABA

-inhibit degradation of GABA
Pharmacokinetics of anti-seizure drugs?
-Absorption is good (80-100%) w/ exceptions of phenytoin & carbamazepine.

-they are not highly bound to plasma proteins.

-Cleared via hepatic mechanisms which contributes to induction of liver microsomal enzymes and many drug interactions

-Plasma clearance is slow

-many are converted to active metabolite by the liver.
What drug is eliminated by renal excretion?
What are two important drug interactions in the liver?
-Acute interactions: drugs compete for hepatic microsomal enzymes => decrease metabolism of each other.(phenobarbital, diazepam decrease metabolism of phenytoin).

-Delayed interactions: drugs induce hepatic microsomal enzymes w/ chronic use => increase metabolism of drugs metabolized by the same enzymes(carbamazepine, phenobarbital may increase phenytoin metabolism)
Prolongs state of Na channel inactivation. DOC for generalized tonic clonic seizures. Also effective in tx of partial seizures but not effective for absence seizures.

-Given IV for status epilepticus.

-at therapeutic doses => liver enzymes are saturated. thus, small incr in dose = large incr in plasma concentration.
S/E's of Phenytoin?
-Hair growth(hirsutism)
-gingival hyperplasia
-osteomalacia(give vit-D)
-megaloblastic anemia(give folate)

A hydratoin related to phenytoin. DOC generalized tonic clonic seizures and complex partial seizures.

-like phenytoin, blood dyscrasias S/E.

-Use in children since it lacks hirsutism and gingival hyperplasia S/E's.
WIDE SPECTRUM of anti-seizure activity. DOC for atonic & myoclonic seizures or for pts with multiple seizure types.

-effective for absence seizures.

-hepatotoxicity: valproate metabolism produces toxic intermediates.
DOC for all partial seizures.

-very effective in tx of grand mal seizures but not in absence seizures.

-DOC for tx of trigeminal neuralgia

-10,11 epoxide metabolite of carbamazepine has anticonvulsant activity.
What are the serious S/E's of Carbamazepine?
-Bone marrow depression
-aplastic anemia
-water retention(prob w/ elderly w/ CV dz)
WIDE SPECTRUM of antiseizure activity.

-Effective in tx of partial, generalized, and absence seizures(2nd DOC).

-use for refractory partial seizures in combo w/ other anti-epileptics.
WIDE SPECTRUM of activity. Effective in a wide variety of seizures, especially those refractory to other drugs.
S/E's in Zonisamide tx?
-Cognitive impairment and drowsiness
-Oligohydrosis(low sweat production) & hyperthermia in pediatric pts => heat stroke
-nephrolithiasis: related to carbonic anhydrase inhibition
Drugs that reduce low threshold Ca++ currents (T currents).
-Ethosuximide: DOC for absence seizures(T currents indicative of). S/E's Bone marrow depression and blood dyscrasias


Enhances GABA-mediated increase in Cl- conductance => increase DURATION of channel opening.

-Effective in tx of generalized tonic clonic seizures and all partial seizures.

-INEFFECTIVE in absence seizures.

-maximal antiseizure action dose is below that of hypnotic effects.
Pharmacokinetics of Phenobarbital?
Lipid solubility: Phenobarbital has a low lipid solubility. High lipid solubility => increase rate of distribution => termination of CNS effects.

Hepatic metabolism: transformation to water soluble metabolites for renal excretion. Liver dz and old age can affect rate of metabolism.

Renal excretion: some is excreted unchanged w/ a pKa of 7.3 so making urine alkaline will increase its elimination rate. Useful in phenobarbital overdoses.
S/E's of longterm barbiturate use?
-osteomalacia(Give Vit-D)
-megaloblastic anemia(give folate)
-hemorrhage in newborns(give vit-K)
-Severe CNS depression when combined w/ other depressants(alcohol, antihistamines, BZ, antipsychotics, narcotics, sedative antidepressants).
BZ's: Clonazepam?
effective in tx of absence seizures & myoclonic seizures

-widely used in tx of infantile spasms.
BZ's: Diazepam?
DOC for management of status epilepticus.

-increases the frequency of the chloride channel opening!!
What else does Valproate do?
It's a drug that increases GABA levels by stimulating the synthetic enzyme, glutamic acid decarboxylase.

Valproate also inhibits the degradation of GABA.
A drug that promotes release of GABA via an unknown mechanism.

-adjunctive therapy for tx of partial seizures and generalized tonic clonic seizures.

-also effective for postherpetic neuralgia.

-excreted unchanged via kidneys. RENAL!!!

-S/E's: dizziness, drowsiness
Anti-epileptic drugs which cause cognitive impairment?
Anti-epileptic drugs which cause little to no cognitive impairment?
Teratogenicity in anti-epileptic drugs?

Drugs that do NOT decrease the effectiveness of oral contraceptives?


What are the MOA's of CNS stimulants?
-indirect action releasing endogenous monoamines(NE,DA,5HT)
-prolonging action of monoamines at synapse by preventing their reuptake.
-direct agonist action
-inhibit degradation of intracellular second messengers produced as a result of receptor activation by an agonist.
Name sympathomimetic amines used as anorexiants?
Name anorexiants that are inhibitors of monoamine reuptake ?
Name drugs used to tx ADHD?
Name drugs used to tx narcolepsy?
Name drugs used to tx neonatal apnea syndrome?
Sympathomimetic amine that produces mood elevation, increases wakefulness, alertness, concentration and physical performance.

-Schedule II controlled drug: high potential for abuse.

-anorexic effect due to action in lateral hypothalamus combined w/ increased energy expenditure.
MOA of amphetamines?
Indirect acting sympathomimetics. They act to release catecholamines from their stores and to prevent their reuptake.
Amphetamine S/E's?
-increased CV s/e due to catecholamine release => increased systolic and diastolic BP + tachycardia.

-Acute toxicity(I.V.): marked CNS stimulation, paranoid psychosis, CV effects above, hyperthermia, convulsions & coma.

-Chronic Toxicity: tolerance develops and pt becomes psychological and physiological dependent. Amphetamine psychosis develops=> hallucinations, delusions of persecutions, feelings of omnipotence
Withdrawal effects from Amphetamines?
Withdrawal syndrome => fatigue, prolonged sleep, apathy, PROFOUND LONG LASTING DEPRESSION(suicide?),

-Confusion, memory loss & delusional ideas may remain for months.
Amphetamine derivative. Lower abuse potential(schedule IV).

-Same MOA as amphetamine
-FDA approve for short-term use in obesity tx.
-was one of the drugs in "fen-phen".
MOA: blocks reuptake of NE, 5HT, DA.
-No CNS depression, abuse potential, drug dependence or valvular pathology.
-Metabolized to active form in liver.
-Not an Amphetamine but still schedule IV.
-Once daily dosing and FDA approved for long term use.
-No tolerance to anorexiant effect!!!
ADHD treatment?
-D-amphetamine *DOC*
-methylphenidate *DOC*

-action of these drugs seems paradoxical as they act to increase persistence, attentiveness and concentration but decrease excessive motor activity in ADHD children.

-MOA: drugs release NE and DA from neurons and block the reuptake back into the neuron.
Methylphenidate in ADHD tx?
Duration of action is 4-5 hrs, so children require a second dose at lunch to control behavior in school throughout the afternoon.

-Schedule II drug

-generally less peripheral effects & more prominent CNS effects.(PSYCHOMOTOR VS. sympathomimetics)

-The Sustained Release version hasn't proved to be better than regualar Methylphenidate.
mixture of amphetamine and dextroamphetamine.

-Has longer duration of action(8-10hrs).
Slow release methylphenidate

-Duration of action = 12hrs

-outer coat has small dose of methylphenidate which rapidly achieves a therapeutic plasma concentration. remainder is released at a constant rate from inside tablet.
transdermal methylphenidate.

-patch placed on hip for 9 hrs.
-low abuse potential.
-Dosage is proportional to size of patch.
Metadate CD?
Extended release methylphenidate.

-30% is immediate release beads and 70% is extended release beads.
Ritalin LA?
extended release methylphenidate.

-Uses Spheroidal Oral Drug Absorption System (SODAS) technology. IR beads w/ half enteric coated ER beads.
Atomoxetine in ADHD tx?
MOA: selective NE reuptake inhibitor.

-pts don't like this med.

-Black box label for suicide


-S/E's: headache, aggression, irritability, palpitations, insomnia, urinary retention.
What is Narcolepsy?
recurrent, uncontrollable, sudden episodes of sleep under conditions not normally conducive to sleep.

-Accompanied by hallucinations, cataplexy(sudden loss of muscle tone), and sleep paralysis.

-Treat cataplexy w/ TCA Imipramine & MAOI's
Treatment of Narcolepsy?
Amphetamines has risk of abuse, tolerance development, and fact that they may disturb normal sleep rhythm.

-Methylphenidate is an alternative.
Modafinil in Narcolepsy?
Amphetamine substitute approved for use in narcolepsy.

-S/E's headache, nausea, nervousness, anxiety, insomnia.

-Schedule IV drug (Amphetamine is schedule II)
Neonatal Apnea treatment?
Pathological apnea is apnea exceeding 20 seconds.

-attributed to neuronal immaturity of the brainstem.

-treat w/ caffine, theophylline
Theophylline in apnea tx?
DOC for neonatal apnea tx.

MOA: inhibition of phosphodiesterases => increasing intracellular cAMP.

-Direct effects on intracellular Ca++ concentrations.
-antagonism of adenosine receptors

Therapeutic actions =>Stimulate contraction of diaphragmatic muscle, stimulates central respiratory drive centers, and increases ventilatory centers sensitivity to CO2.

-Theophylline can eliminate apnea episodes of greater than 20 seconds and reduce the # of episodes as a whole.

-Caffeine is now preferred by some MD's due to simpler and more predictable dosing regimens
Theophylline S/E's?
Rapid iv infusino can result in severe toxicity or sudden death, drug should be injected slowly over 20-40 min period.

S/E's: headache, tachycardia, severe restlessness, nausea, emesis, abdominal pain.

Theophylline plasma concentrations should be measured during therapy.
What does caffeine and/or theophylline use do?
-relax smooth muscle(brochial muscle)
-Stimulate CNS
-Stimulate cardiac muscle
-Act on kidney as diuretic.