New Pharm Drugs

what pathway is affected in PD?

nigrostriatal

By the time PD symptoms emerge, ____% of SN neurons are gone?

60-80

remaining SN neurons in PD that are filled with clumps of proteins are called

lewy bodies

What are hallmark PD symptoms?

TRAP

tremor, rigidity, akinesia/bradykinesia, postural instability

Which PD drug increases dopamine synthesis?

carbidopa/levodopa

Which PD drug is a dopamine agonist?

ropinirole

Which DP drug decreases breakdown of dopamine?

MAO-B inhibitor - rasagiline
COMT inhibitor - tolcapone

advantage of ropinirole vs levodopa in PD treatment?

fewer motor fluctuations with ropinirole but lower efficacy

What is rasagiline?

MAO-B inhibitor, PD

reduces breakdown of dopamine by monoamine oxidase-B

used alone, but effect is small and not seen in all pts

adverse effects of rasagiline (MAO-B inhibitor, PD)?

may cause confusion in older pts

mechanism of action of tolcapone?

reduces breakdown of levodopa and dopamine

not as effective as individual agent

extends action of levodopa in pt who experience "wearing off" phenomenon

how does levodopa work?

taken up by dopaminergic neurons and converted into dopamine

Why is carbidopa added to levodopa?

levodopa is extensively metabolized in the body by peripheral decarboxylase enzymes (AADC)

peripheral conversion of levodopa into dopamine causes systemic side effects and limits the desired therapeutic effect

carbidopa is a AADC inhibitor

side effects of levodopa?

nausea, drowsiness, dizziness, headache most common

older pt: delusions, hallucinations, orthostatic hypotension

movement related - motor fluctuations (wearing off and on), dyskinesias (involuntary abnormal movements)


dopamine dysregulation syndrome (addictive-like behavior toward dopaminergic drugs, mood and behavioral change, compulsive behaviors, funding)

duration of levodopa therapy?

3 to 5 years is optimal therapeutic effect

positive effects diminish overtime

Alzheimer's disease is accumulation of

amyloid beta plaques outside neurons and neurofibrillary tangles of tau protein inside neurons

anti cholinesterase to treat Alzheimer's disease

donepezil

What is donepezil?

AchE Inhibitor.
generally more beneficial early in disease
modest effect
typical AchE side effects (sludge)

What is a NMDA antagonist drug for Alzheimer's?

memantine

What is memantine?

NMDA receptor antagonist for Alzheimer's
approved for moderate to severe disease
modest effect
fewer side effects compared to AchE drugs

treatment of schizophrenia?

Antipsychotics - block dopamine and serotonin (5-HT) receptors

What are the typical antipsychotics?

haloperidol, chlorpromazine

What are the atypical antipsychotics?

quetiapine, risperidone

mechanisms of action of typical antipsychotics

efficacy is directly correlated with amount of D2 receptor blockade

primarily alleviate the positive symptoms of schizophrenia

DA release increased at first to compensate blockage, effects take weeks to develop

mechanisms of action of atypical antipsychotics?

block D2 receptors less than typicals, also block serotonin 5-HT2a receptors

less serious effects on nigrostriatal DA signaling

alleviate positive and negative symptoms

generally fewer adverse effects

typical antipsychotics require __% of D2 blockage to achieve effect?

80

atypical antipsychotics require __% of D2 blockage to achieve effect?

60

What is clozapine?

30% resistant to other antipsychotics will respond to this

not first line due to side effects

good for positive, negative, and cognitive deficits

side effects of clozapine?

orthostatic hypotension, agranulocytosis, sedation, seizures

adverse effects are more common in which type of antipsychotics?

typical (1st gen)

adverse effects of antipsychotics?

extrapyramidal symptoms

galactorrhea

metabolic syndrome

neuroleptic malignant syndrome (autonomic NS collapse)

What are some benzodiazepines used for anxiety?

diazepam, alprazolam, triazolam, midazolam

What is a barbiturates used for anxiety?

pentobarbital

What is a non-benzodiazepine hypnotic?

zolpidem

mechanism of action of benzos?

bind to allosteric site on GABAa receptor that increases channel affinity for GABA

positive allosteric modulator that increases frequency of channel opening

produces CNS depression but with a ceiling effect

What is midazolam?

BZD

best given i.v, onset within minutes and duration

What is diazepam?

BZD

can be taken orally 30 min before procedure, duration 2-3hr

what is lorazepam?

BZD

longer onset time and duration of several hours

adverse effects of BZD?

CNS depression (excess sedation, ataxia, amnesia)

resp depression (not serious with BZD alone, but when combined with alcohol, opioids or other depressants)

tolerance and physical dependence

What can reverse overdose of BZD?

flumazenil

BZD antagonist

mechanism of action of pentobarbital (barbiturates)

bind GABAa at a site distinct from BZD

cause increase in opening duration of channel

adverse effects of barbiturates (pentobarbital)

more powerful CNS depressant effects compared to BZDs

uses for barbiturates?

anxiety/insomnia

emergency treatment of seizures

mechanism of action of zolpidem (non-BZD hypnotics)

bind a more restricted set of GABAa receptors compared to BZD, leading to hypnotic effect

use restricted to insomnia

less alteration of sleep cycles and hangover effects compared to BZD

adverse effects of non-BZD hypnotics (zolpidem)

amnesia, sleep-walking/driving/eating

mechanism of action of buspirone?

5-HT1a partial agonist

found in several brain regions, pre-and post- synaptic

moderate anxiolytic

no sedation or abuse potential

What is ramelteon?

first approved insomnia treatment that targets melatonin receptors

advantages of ramelteon?

no affinity for GABA receptors: limited abuse potential, limited interactions with CNS depressants

disadvantages of ramelteon?

postmarking reports of reduced testosterone or elevated prolactin

overall effect is modest

What is a MAOIs example?

phenelzine

What is a tricyclic antidepressants ex?

imipramine

What are SSRI ex?

fluoxetine, citalopram

What are SNRI ex?

duloxetine, venlafaxine

What are some atypical antidepressant drugs?

bupropion, mirtazapine

mechanism of action of MAOI?

inhibit MAO-A and MAO-B irreversibly

adverse effects of MAOIs?

serious potential for hypertensive crisis with sympathomimetics and tyramine-containing foods (processed meat, hard cheese, red wine)

two week washout required before using sympathomimetics or other classes of antidepressants

mechanism of action of tricyclic antidepressants (imipramine)

block monoamine reuptake

specific TCAs preferentially block either NE or 5-HT but clinically efficacy similar

adverse effects of tricyclic antidepressants (imipramine)

most serious: blockade of cardiac Na channels leading to conduction blockage

blockage of muscarinic, histamine, and adrenergic receptors

mechanisms of action of SSRIs? (fluoxetine, citalopram)

blockade of serotonin reuptake

efficacy similar to TCAs, but better tolerated and less severe side effects

side effects of SSRIs?

sexual effects (decreased libido, delayed orgasm)

GI symptoms: diarrhea, constipation

drug interactions: inhibit CYP enzymes

serotonin syndrome (if combined with MAOI or other 5-HT drugs) - hyperthermia, muscle rigidity, myoclonus, rapid fluctuations in mental status and vital signs

suicide risk when starting out

when to use SNRI over SSRI?

severe depression

What is bupropion?

weak monoamine reuptake inhibitor

metabolites block nicotinic ACh receptors

lowers seizure threshold

lowest rate of sexual dysfunction for antidepressants

What is mirtazapine?

blocks alpha-2-autoreceptors and interacts with some 5-HT receptors

anxiolytic and hypnotic effects

causes slightly more weight gain compared to others

first line treatment for anxiety and depression?

SSRIs

antidepressant effects take up to ___ weeks to develop

8 weeks

What is a focal seizure?

restricted to one hemisphere

effect depends on part of brain involved

What is a focal to bilateral tonic-clonic seizure?

begins as focal seizure that spreads to the other hemisphere

full body muscle contraction followed by rhythmic shaking of limbs

What is an aura?

characteristic sensations/perceptions that vary between individuals

What is a primary generalized seizure?

involves both hemisphere

signals between thalamus and cortex

What is an absence seizure?

sudden, brief interruption of consciousness
blank stare

characterized by abnormal activity of T-type Ca channels

How to treat absence seizures?

ethosuximide

mechanism of action of ethosuximide?

blocks T type calcium channels on thalamic relay neurons that underlie absence seizures

clinical use of ethosuximide?

only effective in treating absence seizures

mechanism of action of carbamazepine? (seizures)

prolongs the inactive state of sodium channels following an action potential - decreases receptive firing of action potentials

does not alter spontaneous activity so no general depression of CNS

clinical use of carbamazepine?

first choice treatment of focal seizures as well as primary generalize tonic-clonic seizures

mechanism of action of phenytoin? (seizures)

prolongs recovery from inactivated to resting state

use dependent

clinical usage of phenytoin?

efficacious in treatment of focal or generalized tonic-clonic seizures

elicits severe and somewhat unpredictable side effects, movement and coordination problems, gingival overgrowth, anemia

mechanism of action of valproic acid? (seizures)

prolongs the inactive state of voltage-gated sodium channels

produces small reductions of activity in t type calcium channels

clinical use of valproic acid?

very effective in epilepsy with mixed seizure types

drug of choice when pt has concomitant absence and generalized tonic-clonic attacks

adverse effects of valproic acid? (seizures)

teratogenic

mechanism of action for topiramate?

prolong inactive state of voltage-gated sodium channels
inhibits voltage-gated calcium channels
activates GABA receptors and inhibits NMDA glutamate receptors

clinical usage of topiramate?

used to treat focal or generalized tonic-clonic seizures

also FDA approved for weight loss

prescribed off label for migraines

mechanism of action of benzos (diazepam, midazolam) for seizures?

primary site of action is GABA-induced influx of chloride via GABAa receptors

clinical use of benzos for seizures?

to abort seizures acutely

tolerate and side effects limit use (dizziness, drowsiness)

mechanism of action for gabapentin? (seizures)

blocking HVA calcium channels

clinical use of gabapentin?

not a first-line agent for seizures due to lack of efficacy

does have other indications - neuropathic pain, restless legs

mechanism of action of pentobarbital? (barbiturates for seizures)

enhances activity of GABAa receptor

clinical use of pentobarbital (barbiturate for seizures)?

effective in focal and tonic-clonic seizures

use limited by sedation

use has decreased as better options available

cortical spreading depression hypothesis

mechanism of migraine

slow moving wave of depolarization, followed by depressed activity, that causes migraine aura

leads to activation of trigeminal neurons in the meninges, pain, inflammation, changes in blood flow

prevention drug for migraines?

erenumab - CGRP receptor antibody

aborting migraine drugs?

sumatriptan - serotonin 5-HT receptor agonist

ergotamine - ergot alkaloids

mechanism of action of erenumab? (migraine drug)

monoclonal antibody that binds and blocks calcitonin gene related peptide (CGRP) receptor

monthly subcut injection

adverse effects of erenumab? (migraine drug)

minimal in clinical trials

long term effects of CGRP blockade unknown

effect of CGRP in migraines?

transmits pain signals

promotes release of inflammatory mediators that further increase pain and vasodilation

causes vasodilation through relaxation of smooth m

mechanism of action of sumatriptan (migraine drug)

inhibit CGRP release through action of autoreceptors

directly stimulate vasoconstriction

decrease nociceptive afferent activity

When is sumatriptan used?

top choice for severe migraine that does not respond to NSAIDS

adverse effects of sumatriptan?

contraindicated in coronary artery disease

parathesias

limit to 10 days per month because of medication overuse headache

what are ergot alkaloids?

produced by clavicles purpurea (fungus)

contains psychoactive compounds, vasoconstrictors and stimulators of muscle contraction

mechanism of action of dihydroergotamine? (migraine drug)

anti-migraine effect similar to triptans

acts on wider variety of serotonin receptors as well as other receptor types

adverse effects of dihydroergotamine (migraine drug)?

long-lasting and cumulative vasoconstriction limits dosage

pregnancy category X due to stimulation of uterine smooth muscle