Pharmacology Flashcards by Maggie Berrigan

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

Glutamate

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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

GABA

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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

Dopamine

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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

Acetylcholine

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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

Norepinephrine

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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

Serotonin

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biogenic amine

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

responsible for wakefulness

blockers that penetrate the BBB cause drowsiness

Histamine

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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

Selective Serotonin Reuptake Inhibitors (SSRIs)

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

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

Fluoxetine

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SSRI associated with fewer drug interactions

Sertaline

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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

Selective Norepinephrine Reuptake Inhibitors (SNRIs)

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SNRI
approved for GAD, fibromyalgia, diabetic neuropathy

potential drug interactions with fluoxetine (inhibit CYP2D6)

Duloxetine

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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

Tricyclic antidepressants (TCAs)

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TCA
tertiary amine metabolized into nortriptyline

possible risk of limb malformation in pregnancy

Amitriptyline

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TCA
secondary amine

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

Desipramine

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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

Monoamine Oxidase Inhibitors (MAOIs)

Tranylcypromine

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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

Dopamine Reuptake Inhibitors

Bupropion

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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

Autoreceptor antagonists

Mirtazapine

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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

Serotonin receptor antagonist

Trazodone

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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

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Lithium

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

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olanzapine

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

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Valproate

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

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Lamotrigine

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

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Barbiturates

barbiturate anxiolytic | schedule IV

phenobarbital

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

Benzodiazepines

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

Diazepam

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

Triazolam

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

Alprazolam

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

Clonazepam

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

Midazolam

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

Zolpidem

Benzodiazepine receptor agonist | Less tolerance, not restricted for short term use

Eszopiclone

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

Flumazenil

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

Benzodiazepine receptor agonists (BRA)

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

Benzodiazepine receptor antagonist

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

Melatonin receptor agonist | Ramelteon

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

Non-sedative anxiolytic | Buspirone

``` 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

propranolol

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

valproate

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

onabotulinum toxin

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

topamirate

used as acute treatment of mild to moderate migraines cerebral vasoconstriction aids in absorption of and can potentiate analgesics – common adjuvant

caffeine

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

NSAIDs

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

ergots

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

ergotamine

ergot Parenteral/nasal Fewer side effects Weaker vasoconstrictor

dihydroergotamine

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

sumitriptan

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

metaclopromide

Pharmacology Flashcards

(49 cards)