Pharmacology Flashcards
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
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
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
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
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
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
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
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)
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
SSRI associated with fewer drug interactions
Sertaline
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)
SNRI
approved for GAD, fibromyalgia, diabetic neuropathy
potential drug interactions with fluoxetine (inhibit CYP2D6)
Duloxetine
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)
TCA
tertiary amine metabolized into nortriptyline
possible risk of limb malformation in pregnancy
Amitriptyline
TCA
secondary amine
secondary amines can have better side-effect profile and higher therapeutic index
Desipramine
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
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
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
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
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
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
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
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
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
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
