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B&B Exam 1 > Pharmacology > Flashcards

Pharmacology Flashcards

1
Q

Amino acid neurotransmitter responsible for the majority of excitatory transmission in the brain (along with aspartate, small % by ACh)

Descending projections from the cortex to the striatum, thalamus, and hippocampus

It’s prevalence made it hard to identify as a neurotransmitter

responsible for most fast synaptic transmission
Too much transmission results in epilepsy

Huntington’s = neurotoxicity via subtype of receptor

A

Glutamate

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2
Q

Amino acid transmitter responsible for the majority of inhibitory transmission in the brain

Diffuse projections

Too little activity can result in epilepsy, anxiety, Huntington’s

A

GABA

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3
Q

Biogenic amine neurotransmitter that is often inhibitory in the CNS

Ascending projections

Cell bodies in the substantia nigra and project to the striatum

These neurons die in Parkinson’s disease

Cell bodies in the ventral tegmental area project to the nucleus accumbens (important in addiction)

These neurons are hyperactive in schizophrenia

Neurons from the ventral tegmental area also project to the frontal cortex

A

Dopamine

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4
Q

Biogenic amine that is excitatory in the CNS

Accounts for 6% of excitatory CNS transmission but may also be inhibitory

Cell bodies are in the septal nuclei and nucleus basalis

Ascending projections go to the cortex, amygdala, and hippocampus

neurons degenerate in Alzheimer’s

Avoid drugs that block transmission in the elderly because they cause confusion and mental slowness

As dopaminergic (inhibitory) neurons die in Parkinson’s, this NT’s tone predominates the outflow from the striatum GABAergic neurons

drugs that block neurotransmission are used to treat Parkinson’s along with dopamine replacing or mimicking drugs

A

Acetylcholine

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5
Q

Inhibitory biogenic amine

Cell bodies in the locus coeruleus

Ascending projections from the locus coeruleus to the neocortex, hippocampus, and cerebellum

responsible for regulating attentiveness, mood, and hyperactivity in withdrawal from addictive drugs

Antidepressants raise synaptic levels

Addictive drugs suppress the locus coeruleus, when the drug is removed there is increased activity

A

Norepinephrine

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6
Q

Biogenic amine

Widespread projections arising from cell bodies in the raphe nucleus

Ascending projections to the hippocampus, cortex, and cerebellum (and others)

Monoamine but not a catecholamine

activity is too low in depression
SSRIs are used to elevate synaptic levels

Triptans (receptor agonists selective for 1B and D types) are used to treat migraines

5-HT1a partial agonists are used to treat anxiety

increasing the precursor tryptophan increased production and drowsiness

A

Serotonin

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7
Q

biogenic amine

diffuse ascending projections that arise from the tuberomedullary nucleus of the hypothalamus

responsible for wakefulness

blockers that penetrate the BBB cause drowsiness

A

Histamine

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8
Q

Antidepressants that selectively block SERT inhibiting reuptake of serotonin

Acutely increases 5HT in the synapse, 5HT remains in synapse longer
With time neuronal pathways adapt resulting in enhanced serotonergic transmission
Requires tryptophan to synthesize serotonin

1st line because they are well tolerated

do not affect other amines or act directly at NT receptors

good absorption – lipophilic and crosses BBB readily, largely protein bound in blood

variety of effects on CYP enzymes (drug-drug interactions)
p450 inhibitors can inhibit metabolism
renal excretion
kinetics are not critical for the therapeutic response but may be important for toxic responses

Adverse effects
CNS stimulation – insomnia, agitation
GI problems – nausea, diarrhea, bleeding
Sexual dysfunction – decreased libido, anorgasmia (tolerance does not develop)

Most adverse effects can be minimized by starting with lower doses, and will often resolve with time

High therapeutic index, fatalities are rare
Dangerous if combined with MAOIs or serotonin enhancers

Overdose – serotonin syndrome (hyperthermia, muscle rigidity, myoclonus, hyperreflexia, fluctuating vital signs and mental status)

Delayed therapeutic response (1-6 weeks)
Gradual improvement of most depressive symptoms
Positive response in 70-80% of patients

Indications: depression, anxiety disorders, eating disorders, PMDD, ADD/ADHD, other off-label

Associated with slightly increased risk of rare fetal malformations

A

Selective Serotonin Reuptake Inhibitors (SSRIs)

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9
Q

SSRI
long half-life
active metabolites
potential interaction with duloxetine (inhibit CYP2D6)

only drug that has been approved for children with major depressive disorder

A

Fluoxetine

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10
Q

SSRI associated with fewer drug interactions

A

Sertaline

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11
Q

Antidepressants that block SERT and are similar to SSRIs in pharmacologic profile

At medium to high doses they block reuptake of norepinephrine (NET)

Unique adverse effect: increase BP at high doses
Overdoes – hypertension

Unique indication: neuropathic pain

Shorter duration, increased risk of toxic response (discontinuation syndrome)

Patient less likely to relapse if on a tryptophan free diet

A

Selective Norepinephrine Reuptake Inhibitors (SNRIs)

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12
Q

SNRI
approved for GAD, fibromyalgia, diabetic neuropathy

potential drug interactions with fluoxetine (inhibit CYP2D6)

A

Duloxetine

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13
Q

Antidepressants
Tertiary amines preferentially blocks SERT and are metabolized into secondary amines which preferentially block NET

Blocks receptors for many neurotransmitters (source of side effects)
Muscarinic cholinergic, alpha 1 andrenergic, H1 histamine

Most have long half-lives, kinetics usually not important for therapeutic response but results in long delay in onset

No evidence for systematic differences in efficacy, individual differences not uncommon

Valuable alternative but not first line

Adverse effects:
Arrhythmia, tachycardia, palpitations
Orthostatic hypotension
Autonomic – dry mouth, constipation
CNS – sedation, confusion, memory impairment
Vegetative – increased appetite, weight gain
Sexual – impotence, delayed orgasm, decreased libido

Delayed therapeutic response, positive response in 80%

Additional indications:
Anxiety disorders, enuresis, pain

Overdose toxicity
Low therapeutic index due to cardiac arrhythmias, this is not a receptor mediated effect, risk does not diminish with time
Overdose treatment is supportive (lavage, lidocaine for arrhythmias)

Dispense carefully to depressed (potentially suicidal) patients

In general low therapeutic index and dangerous in overdose

A

Tricyclic antidepressants (TCAs)

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14
Q

TCA
tertiary amine metabolized into nortriptyline

possible risk of limb malformation in pregnancy

A

Amitriptyline

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15
Q

TCA
secondary amine

secondary amines can have better side-effect profile and higher therapeutic index

A

Desipramine

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16
Q

Antidepressants
Irreversible blockage of MAO
Increased NE and 5-HT
Inhibition occurs in both periphery and brain

Valuable alternative but not first line

Contraindicated for use with serotonergic drugs or drugs that increase monoamines
Good efficacy in atypical depression

Adverse effects:
Postural hypotension
GI distress
Sexual dysfunction
Overdose is not common when taken alone, effects include agitation, delirium and can lead to hyperthermia, shock, coma, and seizures

Dietary restriction: avoid foods containing tyramine (wines, cheeses)

Behavioral effects:
Initially CNS stimulation, agitation, euphoria, appetite suppression

1-6 weeks: improvement of most depressive symptoms; somewhat less stimulation

High incidence of drug interactions
Sympathomimetics result in headache, increased BP
Tramadol, St. John’s wort, triptans
Meperidine, dextromethorphan: serotonin syndrome

Risk of serotonin syndrome with SSRIs, SNRIs, TCAs, trazodone

Must allow weeks after stopping treatment before starting a new drug

Must allow at least two weeks after stopping fluoxetine before starting treatment

Associated with significant risks, avoid in pregnancy

A

Monoamine Oxidase Inhibitors (MAOIs)

Tranylcypromine

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17
Q

Antidepressants that
block DAT and NET
May increase DA and NE

Effect on DA unique and thought to be therapeutic

Non-therapeutic mechanisms:
Weak antagonist at alpha 1 and H1 receptors: orthostatic hypotension and sedation
Potent antagonist at nicotinic alpha3beta4 receptor – use in smoking cessation

Delayed therapeutic effect (1-6 weeks), mix of initial effects

Used as adjunct in SSRI

Adverse effects:
CNS stimulation, agitation, anxiety, insomnia
Weight loss, headache, nausea
Potential seizures, may be a problem with high dose formulation

Best in patients without anxiety
Unique mechanism may help in treatment resistant patients
Far fewer sexual side effects
Can cause or exacerbate anxiety

Lower overall response rate

A

Dopamine Reuptake Inhibitors

Bupropion

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18
Q

antidepressants

Potent alpha 2 antagonist: enhances NE release
5-HT release is also enhanced indirectly
antagonist at 5-HT 2A/2C receptors

non-therapeutic mechanism:
potent histamine H1 antagonist: sedation
antagonist at other serotonin receptors including 5-HT3, 5-HT7
weak antagonist at muscarinic and alpha 1

Delayed therapeutic effect (1-6 weeks), mix of initial effects

Used as adjunct with SSRI (especially in the elderly)

Strong sedative properties can be useful, but also has anticholinergic effect, used as an appetite stimulant

Adverse effects:
Sedation is prominent
Weight gain (potent antihistamine activity)
Postural hypotension/dizziness (anticholinergic)

Few sexual side effects

Blood levels may be raised by other drugs via CYP inhibition

A

Autoreceptor antagonists

Mirtazapine

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19
Q

Antidepressants
5-HT2A receptor blockade
weak SERT blockade, and weak partial agonism of 5-HT1A may play a role

non therapeutic mechanisms:
alpha 1 receptor antagonist: sedation and postural hypotension
active metabolite mCPP: agonist at 5-HT receptors

Delayed therapeutic effect (1-6 weeks), mix of initial effects

Used as adjunct with SSRI
Sedative properties can be useful, used as adjunct in insomniacs

Adverse effects:
Sedation (off label hypnotic)
Orthostatic hypotension
headache

drug interactions due to CYP3A4 inhibition

lower overall population response rate

A

Serotonin receptor antagonist

Trazodone

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20
Q

mood stabilizer
used to treat bipolar disorder – drug of choice for maintenance therapy
effective against both poles

response is gradual, fast-acting mood stabilizers often used as adjuncts initially
can be started in manic emergencies but is generally not a good choice, acute calming affects are generally insufficient when given alone

other indications: depression, schizoaffective disorder
can be used to manage depression as an adjunct to ADDs

mechanism of action is unclear

absorbed well orally, excreted in urine (altering clearance can affect blood levels)
blood level monitoring is required due to narrow therapeutic window

slow release preparations are useful to minimize toxic peaks, may increase GI toxicity

increased excretion leads to decreased blood levels due to coadministration with mannitol, acetazolamide, theophylline

increased sodium excretion leads to decreased drug excretion and increased drug levels leading to toxicity

sodium depleting diuretics, dehydration, NSAIDs, ACE inhibitors

adverse effects:
sedation, fatigue, diarrhea, nausea, tremor (treated with beta blockers), edema, polydipsia, polyuria, nephrogenic diabetes insipidus, acne, psoriasis

toxicity: therapeutic index is low, overdose can occur with normal therapy (often due to changes in renal clearance)
acute overdose – confusion, ataxia
even higher doses – hypotension, arrhythmias, convulsions, coma
treatment – supportive, dialysis, osmotic diuretics

A

Lithium

21
Q

mood stabilizer, atypical antipsychotic

mechanism unclear

used to treat bipolar disorder, adjunct with lithium or monotherapy for maintenance
becoming first line for bipolar II, used in bipolar I

significant sedation makes it useful for manic emergencies

weight gain/diabetes type 2 risk are potential problem with all atypical antipsychotics

compared to lithium: quicker responses, useful in emergencies, safer, lower efficacy in severe disease, drugs of choice in milder disease, better in mania than depression

A

olanzapine

22
Q

mood stabilizer, anticonvulsant

mechanism unclear

used to treat bipolar disorder, adjunct with lithium or monotherapy for maintenance
becoming first line for bipolar II

side effects: GI distress, sedation, weight gain

useful in rapid cycling and mixed states

compared to lithium: quicker responses, useful in emergencies, safer, lower efficacy in severe disease, drugs of choice in milder disease, better in mania than depression

A

Valproate

23
Q

anticonvulsant
used to treat bipolar disorder

mechanism unclear

significant anti-depressant activity, use with lithium which is especially effective in mania

side effects: nausea, dizziness, headache, mild rash (Stevens-Johnson is serious but less common)

compared to lithium: quicker responses, useful in emergencies, safer, lower efficacy in severe disease, drugs of choice in milder disease

A

Lamotrigine

24
Q

Antianxiolytics

binds to sites on GABAa receptor to enhance duration of GABA-mediated chloride flux
causing hyperpolarization of neuron (neuronal inhibition)

at higher concentrations, directly open GABAa Cl- channel (no GABA need be present)

suppresses glutamate transmission via AMPA receptors

direct membrane effects to inhibit neurons

full dose-dependent range of sedative effects, linear dose response curve

respiratory depression at increased doses

relatively low therapeutic index, dangerous in overdose

high incidence of dependence and addiction

induce CYPs causing drug interactions

sedative/hypnotic rarely used today
current uses: anesthesia, seizure disorders

physiological dependence

A

Barbiturates

25
Q

barbiturate anxiolytic

schedule IV

A

phenobarbital

26
Q

Anxiolytics that bind to sites on GABAa receptor to facilitate GABA-mediated Cl- influx (positive allosteric modulator)
found only on certain GABAa receptors (alpha 1, 2, 3, or 5) and requires presence of gamma subunit and presence of specific GABAa subunits
cause hyperpolarization of neuron and neuronal inhibition
no direct effect, cannot open Cl channel without presence of GABA – this limits toxicity
only one binding site per receptor

difficult to separate anxiolytic action from sedative-hypnotic effects
sedation – calming effects with relatively minimal depressant effects on psychomotor and cognitive functions; higher doses cause cognitive impairment (anterograde amnesia)
hypnosis – sleep
amnesia – useful for anesthetic use
anticonvulsant
skeletal muscle relaxation at high doses

respiratory inhibition – significant respiratory depression with pulmonary disease, contraindicated in sleep apnea, fatalities with other CNS depressants
decrease blood pressure, increase heart rate at high doses

tolerance occurs and is thought to involve change in receptors (tolerance to anxiolytic effects is uncertain)

dependence to lesser extent than barbiturates; caution in patients with history of substance abuse

many are converted to active metabolites, many of which have long half-life
flatter dose-response curve, high therapeutic index, no pharmacokinetic drug interactions, relatively long duration (once daily dosing)

disadvantages:
addiction liability
physiological dependence – rebound insomnia, rebound anxiety
potentiate CNS depression from alcohol
impairs psychomotor skills (falls, especially in the elderly)

generally safe with high therapeutic index
rarely fatal unless there is another sedative to potentiate the effect (ethanol)
can cause respiratory problems in patients with COPD or obstructive sleep apnea

use limited to up to three weeks; with longer continuous use, tolerance is likely, possible dependence

kinetic parameters are important for optimal hypnotic utility
quick onset to help with sleep latency, long duration to last through the night without problems the next day

A

Benzodiazepines

27
Q

Benzodiazepine
Full BZ agonist
bind receptor to enhance GABA channel opening, Cl- influx
rapid onset, rapidly absorbed, long-acting
anticonvulsant
higher abuse liability

effective in GAD: long term utility complicated by tolerance, dependence; useful in situational anxiety
used in epilepsy and muscle relaxation in neurological disorders

A

Diazepam

28
Q

Benzodiazepine
Rapid onset, rapidly absorbed, short acting
Effective in sleep disorders

A

Triazolam

29
Q

Benzodiazepine
Full BZ agonist
bind receptor to enhance GABA channel opening, Cl- influx
rapid onset, rapidly absorbed, intermediate duration
higher abuse liability

long term utility complicated by tolerance, dependence; useful in situational anxiety
effective in GAD, panic disorder and agoraphobia but can cause rebound anxiety if discontinued

A

Alprazolam

30
Q

Benzodiazepine
Anticonvulsant
Long-acting
Effective in social phobia, epilepsy, muscle relaxation in neurological disorders

A

Clonazepam

31
Q

Benzodiazepine
Rapidly absorbed, short acting
Higher abuse liability
Used for anesthesia

A

Midazolam

32
Q

Benzodiazepine receptor antagonist
Full BZ agonist selective for alpha 1 subunits
Risk of anterograde amnesia and sleep walking

A

Zolpidem

33
Q

Benzodiazepine receptor agonist

Less tolerance, not restricted for short term use

A

Eszopiclone

34
Q

BZ antagonist
competitively binds to receptor but does not change GABA effects – no effects given alone
competitively inhibit effects of both full agonists, and hypnotics (zolpidem) and inverse agonists

A

Flumazenil

35
Q

chemically distinct from BZs but bind the same site (GABAa with alpha 1 subunit)
effects reversed by flumazenil
no anxiolytic, anticonvulsant or muscle relaxing activity; minimal effect on sleep stages
treatment of sleep disorders
less amnesia or day after sedation vs BZs
favorable kinetic profile (rapid acting, short duration)
day after psychomotor effects
less dependence
clearance is decreased in the elderly
respiratory depression at high doses or with other depressants
risk to fetus cannot be ruled out

A

Benzodiazepine receptor agonists (BRA)

36
Q

antagonist available in case of overdose
competitive antagonist at BZ site on GABAa receptor
reverses most effects of BZs, hypnotics like zolpidem
rapid acting but short duration
does not work against alcohol or barbiturates
adverse effects: agitation, confusion, dizziness, nausea, precipitates severe withdrawal

A

Benzodiazepine receptor antagonist

37
Q

OTC, activity not established, used for jet lag
Approved for long-term use for insomnia, no demonstrated changes in sleep stages
Best against delayed onset sleep, circadian rhythm problems
Adverse effects: dizziness, hyperprolactinemia

A

Melatonin receptor agonist

Ramelteon

38
Q

different pharmacology from sedative-hypnotics
no sedative, hypnotic, anti-seizure or euphoric effects (no loss of coordination)
partial agonist at CNS 5-HT1A receptors
minor effects at other receptors: alpha 1, alpha 2, D2
not useful for acute anxiety; efficacy requires 1+ weeks
best for GAD, not as effective with panic disorders
has some anti-depressant efficacy

rapidly absorbed, first pass metabolism (several active metabolites)
no tolerance, dependence or abuse liability
slow to act, poor efficacy in panic disorders

adverse effects: non-specific chest pain, tachycardia, palpitations, dizziness, headache, nervousness, tinnitus, GI distress
do not use with MAOIs
drug interactions: CYP3A4 inducers and inhibitors

few data on safety in pregnancy

A

Non-sedative anxiolytic

Buspirone

39
Q 
Beta blocker used for migraine prophylaxis
Most commonly used and best established class of prophylaxis

Therapeutic mechanism unknown but likely related to reduction in overall adrenergic tone

Many side effects but usually not limiting
Fatigue, exercise intolerance, GI, depression, insomnia, nightmares

Contraindicated with asthma, depression, heart failure, calcium channel blocker use

Abrupt withdrawal can cause CV distress

A

propranolol

40
Q

Anticonvulsant used for migraine prophylaxis

Increases GABA mediated neurotransmission suppressing inflammation and attenuating nociceptive transmission, modulates 5HT (suppressing rostral brain stem modulator)

CSD is likely suppressed by reduced glutamtergic activity

Modest efficacy, better than 50% improvement in about half of patients

Numerous side effects – nausea, weight gain, fatigue, tremor, hair loss

Avoid in pregnancy

A

valproate

41
Q

migraine prophylaxis

adults with chronic migraine with 15+ headaches per month, each lasting 4+ hours

injected every 12 weeks, takes 2 treatments to determine effect in patient

cleaves SNARES preventing release of CGRP from the peripheral trigeminal sensory nerve terminals which mitigates development of peripheral sensitization and secondarily inhibits central sensitization

side effects: neck pain, muscular weakness, ptosis

A

onabotulinum toxin

42
Q

anticonvulsant used for migraine prophylaxis

blocks sodium and calcium channels, inhibits glutamate receptors, enhances GABA activity, inhibits activation of trigeminal nucleus

modest efficacy, better than 50% improvement in about half of patients

numerous side effects – paresthesias, fatigue, cognitive impairment, weight loss, abnormal taste

A

topamirate

43
Q

used as acute treatment of mild to moderate migraines

cerebral vasoconstriction

aids in absorption of and can potentiate analgesics – common adjuvant

A

caffeine

44
Q

may be used as migraine prophylaxis, best with predictable onset

used for acute treatment of mild to moderate migraines

analgesic/anti-inflammatory

avoid rebound headaches

A

NSAIDs

45
Q

older acute treatment for severe migraines

cerebral vasoconstrictors
non-selective 5HT agonists at trigeminal nerves

often used with caffeine and sedatives

response rate varies and is poor unless taken early in attack, oral route has worst response

drug interactions with triptans, beta blockers, nicotine

A

ergots

46
Q

ergot

Side effects: nausea, vomiting, cramps, vertigo, ischemia, sold extremities, gangrene, diarrhea

Risk of dependence with use for more than 3 weeks

Contraindicated in pregnancy, sepsis, and vascular disease

A

ergotamine

47
Q

ergot

Parenteral/nasal
Fewer side effects
Weaker vasoconstrictor

A

dihydroergotamine

48
Q

Triptan – mainstay of acute treatment for severe migraines

Serotonin derivative
Agonist at 5HT1B, 5HT1D, and 5HT1F receptors

Multiple routes (PO, IM, sublingual, nasal)

Rapid-acting, can work after onset
High rate of response
Rebound migraine common

Mostly minimal adverse effects but caution in coronary artery disease (vasoconstriction)
Receptor selectivity decreased side effects

Avoid MOAIs

Stratified care – mix routes, injection for rescue dose, short and long acting drugs together, add NSAID

A

sumitriptan

49
Q

Used for acute treatment of mild to moderate migraines

Antagonist at 5HT3 and D2 receptors

Anti-emetic, enhances gastric emptying

Little significant analgesic effect alone, typically used as an adjuvant

A

metaclopromide

B&B Exam 1 (7 decks)

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