Brain and Behavior Flashcards
Partial agonist
They produce a lower overall effect when all receptors are occupied, than say a full agonist would. On a concentration-effect curve, it looks like a full agonist in the presence of a noncompetitive (irreversible) antagonist (the Km is unchanged but the Vmax is lowered)
Pharmacodynamic
The biochemical and physiological effects of drugs on the body and the mechanisms of drug action and the relationship between drug concentration and effect.
Pharmacokinetic
Describes how the body affects a specific drug after administration through the mechanisms of absorption and distribution, as well as the chemical changes of the substance in the body (e.g. by metabolic enzymes such as cytochrome P450 or glucuronosyltransferase enzymes), and the effects and routes of excretion of the metabolites of the drug
median effective dose (ED50)
The dose at which 50% of individuals exhibit the specified quantal effect.
median lethal dose (LD50)
The dose required to produce a lethal effect in 50% of individuals.
Selective Serotonin Reuptake Inhibitor
Inhibit the serotonin transporter (SERT)
Adverse effects: due to inhibition of serotonergic tone: nausea, GI upset, diarrhea but generally improve after first week. Level of spinal cord: diminished sexual function/ interest. Increase in headaches and insomnia, weight gain. Sudden discontinuation of short half-life SSRI (paroxetine/ sertraline)- dizziness, paresthesias
fluoxetine is the prototype. Also in this class: sertraline, citalopram, paroxetine, fluvoxamine, Escitalopram
Indications for GAD, PTSD, OCD, panic disorder, PMDD, and bulimia
Popular because of their tolerability, safety in overdose, cost, and broad spectrum of use
Pharmacokinetics: interactions with CYP2D6, CYP3A4, or others depending on which drug used
Contraindicated in combination with MAOIs
Serotonin-Norepinephrine Reuptake Inhibitors
Bind the SERT and NET transporters, but unlike the TCA’s the SNRI’s dont have much affinity for other receptors
venlafaxine, desvenlafaxine, duloxetine, and milnacipran
Used for major depression, pain disorders like neuropathies and fibromyalgia, generalized anxiety, stress urinary incontinence
Adverse effects (SNRI and TCA): many of same as SSRI. Noradrenergic effects- increased blood pressure and heart rate, CNS activation like insomnia and anxiety, discontinuation syndrome. TCA: anticholinergic effects most common like dry mouth, blurred vision and confusion
*****Contraindicated with MAOI’s
Tricyclic antidepressants
imipramine (more anticholinergic), desipramine (stronger selective norepinephrine reuptake inhibitors but less anticholinergic)
amitriptyline, nortriptyline
Long half lives and well absored. Dosed once at night because of sedating effects. Doses titrated over several weeks.
Used primarily in depression that is unresponsive to more commonly used SSRIs and SNRIs.
Less popular due to poor tolerability and lethality in overdose.
Adverse effects: dry mouth, constipation (antimuscarinic effects), also sexual effects and a prominent discontinuation syndrome that feels like the flu.
Can be used in pain conditions, enuresis, and insomnia
Substrates of CYP2D6 (which is inhibited by fluoxetine)
5-HT2 antagonists
trazodone and nefazodone
trazodone’s primary metabolite, m-chlorphenylpiperazine, is a potent 5HT antagonist most commonly used as a hypnotic b/c it’s highly sedative and not associated with dependence.
nefazodone’s primary metabolite, hydroxynefazodone, inhibits 5HT receptor as well. Black box warning-hepatotoxicity.
Both drugs used in major depression but also have been used in anxiety disorders.
The 5-HT receptor is a G protein coupled receptor located in neocortex.
Adverse effects: sedation and GI disturbances
Tetracyclic and Unicyclic Antidepressants
buproprion (Unicyclic and resembles amphetamines- CNS stimulant), mirtazapine (no sexual side effects), amoxapine and maprotiline (both share resemblence to TCA’s and have comparable side effects- therefore not used often)
Monoamine Oxidase Inhibitors
phenelzine, isocarboxazid, tranylcypromine, selegiline (parkinson’s)
Rarely used due to toxicity and potentially lethal food and drug interactions
Primary use in depression resistant to other classes.
Bind irreversibly and nonselectively with MAO-A and -B
MAO-A is present in both dopamine and norepinephrine neurons and found in brain, gut, placenta, and liver
MAO-B found in serotonergic and histaminergic neurons and found in brain, liver, and platelets. Acts on tyramine
Extensive first pass effect so decreased bioavailability. They are well absorbed from GI tract
Adverse effects: orthostatic hypotension and weight gain, highest sexual effects of all antidepressants.
Causes Serotonin syndrome when taken with SSRI, SNRI and TCAs. This is caused by overstimulation of 5-HT receptors in central gray nuclei and medulla. Mild to lethal and include delirium, coma, hypertension, tachycardia, hyperreflexia, tremor.
Fluoxetine (Prozac)
SSRI
metabolized to an active product, norfluoxetine, which may have plasma concentrations greater than itself. Elimination half life for norfluoxetine is 3X longer than fluoxetine. Very long half life!
Inihibits CYP2D6- drug interactions with TCA
Because of long half life, discontinue for 4-5 weeks before starting MAOI to mitigate risk of serotonin syndrome.
Used in treating GAD, PTSD, OCD, panic disorder, PMDD, and bulimia
Paroxetine (Paxil)
An SSRI
Minimum dose for effective treatment of panic disorder is higher than minimum dose for treatment of depression.
Associated with cardiac septal defects in first trimester exposures; weight gain.
Fluvoxamine
SSRI
CYP3A4 inhibiting effects- be careful in elderly. elevate levels of diltiazem (dont memorize) and induce bradycardia or hypotension
Venlafaxine (Effexor) and Desvenlafaxine (Pristique)
SNRI (weak inhibitor of NET) Like most SNRIs, binds SERT with higher affinity
Extensively metabolized in liver by CYP2D6 to become desvenlafaxine
desvenlafaxine is conjugated and doesnt undergo much oxidative metabolism (45% unchanged excreted in urine)
half life of 11 hours
Venlafaxine and desvenlafaxine have lowest protein binding of all antidepressants (27%).
Approved for Social anxiety disorder
At higher doses, cardiac toxicity
substrate for CYP2D6 (not inhibitor) so some drug interactions. Dont give with MAOI- serotonin syndrome
Duloxetine (Cymbalta)
SNRI
Well absorbed and half life of 12 hours
Dosed once daily and tightly bound to protein (97%) and undergoes extensive ox metabolism via CYP2D6 and inhibits this cytochrome so there are drug interactions (increased TCA’s)
Desipramine (Norpramin)
TCA
Imipramine
TCA
Adverse: anticholinergic effects most common like dry mouth, blurred vision and confusion
Amitriptyline
TCA
Adverse: anticholinergic effects most common like dry mouth, blurred vision and confusion
Nortriptyline
TCA
Adverse anti-muscaranic effects
Used in smoking cessation
Trazodone
5-HT2 Antagonist
(also nefazodone) are rapidly absored and undergoes extensive hepatic metabolism. Extensively bound to protein.
short half-life requires split dosing although trazodone is often given at night due to sedative effect.
weak but selective inhibitor of SERT with little effect on NET
Also modest H1 receptor antagonist
Adverse: sedation and priapism, GI disturbances
Substrate of CYP3A4 and so inhibitors of this (ketoconazole and ritonavir) will lead to increased levels of trazodone.
Nefazodone
5-HT2 Antagonist
weak inhibitor of SERT and NET but mainly potent antagonist of postsynaptic 5-HT receptor
Adverse: hepatotoxicity (rare fatalities)
Inhibits CYP3A4 so it can raise the levels of drugs dependent on this for metabolism.
Buproprion
Tetracyclic and Unicyclic Agents
Rapidly absorbed and has a mean protein binding of 85%
Extensive hepatic metabolism and substantial first pass effect
modest inhibitor of norepinephrine and dopamine reuptake. More significantly, is presynaptic release of catecholamines (no effect on serotonin)
used in smoking cessation, winter depression, ADHD
Metabolized via CYP2B6 so altered by drugs whose metabolism are also substrates for this (cyclophosphamide)
Contraindicated in patients taking MAOIs
Mirtazapine
Tetracyclic and Unicyclic Agents
half-life of 20-40 hours
MOA: enhance monoamine tone by binding presynaptic autoreceptors. Antagonist of presynaptic alpha2 autoreceptor and enhances release of both NE and serotonin. 5-HT2 and 3 receptor antagonist and H1 antagonist (sedative effects)
Adverse: seizures, TCA like effects
Overdose: sedation, disorientation, tachycardia
Metabolized by many CYP450 enzymes and so concentration will be altered by interacting drugs. Sedating effects also with depressants such as alcohol and benzodiazepines.
Amoxapine
Tetracyclic and Unicyclic Agents
Rapidly absored with mean protein binding of 85%.
Its metabolite is a potent D2 blocker and has antipsychotic effects
NET inhibitor and less potent SERT inhibitor. Anticholinergic effects and moderate inhibitor of postsynaptic D2 receptor (antipsychotic properties)
Adverse effects: associated with parkinsoniam syndrome due to D2 block
Amoxapine and maprotiline are substrates to CYP2D6 and should not be used with inhibitors such as fluoxetine.
Maprotiline
Tetracyclic/ Unicyclic
Phenelzine
irreversible, nonselective MAOI
More sedating than either selegiline or trancypromine
Tranylcypromine
irreversible, nonselective MAOI
prolonged inhibition
Selegiline
irreversible MAO-B agent at low doses
Treat Parkinson’s disease at low doses and becomes nonselective MAOI at higher doses.
St. John’s Wort
Antidepressant action: hyperforin inhibits reuptake of serotonin, NE, and DA in vitro. Also upregulates the 5-HT2 receptor in rodent model. IL-6 production is reduced and GABA binding using commercial extract.
Also used for Premenstrual dysphoric disorder, climacter complaints, somatoform disorders, and anxiety.
Photoacticated hypericin used to investigationally treat HIV and basal/ squamous cell carcinoma and inhibits other virus
Adverse: photosensitization due to hypericin and pseudohypericin so sunscreen and eyewear should be used. Hypomania, mania, arousal.
Isocarboxazid (Marplan)
MAOI
Escitalopram
SSRI
Relatively free of pharmacokinetic interactions
enatiomer of Citalopram
Cocaine
local anesthetic with peripheral sympathomimetic action via inhibition of transmitter reuptake at noradrenergic synapse
amphetamine-like psychological effect that is shorter lasting and more intense than amphetamine
Inhibits DA reuptake into neurons in the “pleasure centers” of the brain giving you a wild ride
Cocaine is a hell of a drug
Highly addictive (relative risk of 5/5). heated in an alkaline base to become “crack cocaine” which can be smoked producing an instant “rush”
In PNS, inhibits voltage gated Na channels. In CNS, cocaine blocks reuptake of DA, NE, serotonin. The DAT block increases DA in nucleus accumbens is the rewarding aspect of the drug
By blocking NET, causes increase in arterial pressure, tachycardia, ventricular arrhythmia
Toxicities: intracranial hemorrhage, ischemic stroke, MI, seizures, coma, death
Amphetamine
Indirect-Acting Sympathomimetic
Displasces stored catecholamine transmitters.
Important chiefly because of its use and misuse as a CNS stimulant
Readily enters the CNS; effects mediated through the release of norepinephrine and dopamine
Methamphetamine
Indirect-Acting sympathomimetic
Similar to amphetamine with a higher ratio of central to peripheral effects
Methylphenidate (Ritalin)
Indirect-Acting Sympathomimetic
amphetamine variant used in treatment of ADHD
Blocks the reuptake of DA and NE into presynaptic neuron
d- enantiomer is more active and can be given in short (3-5), intermediate (3-8), and long-acting formulations (10-12)
High propensity for diversion and abuse (schedule II controlled substance)
Pseudoephedrine
Mixed-Acting Sympathomimetic
A B-receptor agonist
Used in over the counter decongestant medicine and has been abused in the synthesis of methamphetamine
Tyramine
Amphetamine-like Indirect-Acting Sympathomimetic
normal by product of tyrosine metabolism and produced from diets rich in proteins
Readily metabolized by MAO in liver and inactive when taken orally due to first pass effect.
MOA: causes release of stored catecholamines (similar to NE MOA)
*contraindicated with MAOIs
Modafanil (Provigil)
Indirect-Acting Sympathomimetic
psychostimulant with unclear MOA; it inhibits NE and DA transporters and increases synaptic concentrations of NE, DA, serotonin, and glutamate, while decreasing GABA.
Treatment for ADHD. Improves wakefulness in narcolepsy. Potential use for appetite suppressant. Fewer negative side effects than other amphetamines (no mood changes, insomnia, abuse potential)
Adverse: increase in blood pressure and heart rate
Atomoxetine (Strattera)
Indirect-Acting Sympathomimetic
Catecholamine reuptake inhibitor
selective inhibitor of NET. Non-stimulant compound. No increase in psychomotor activity. Does not induce DA release in the nucleus accumbens (unlike methyphenidate/ amphetamine) so it has a low potential for abuse
Used to treat ADHD
little cardiovascular effects due to clonidine (alpha2) like effects in CNS, but NE effects in periphery. However, may increase blood pressure in some patients.
Adverse: orthostatic tachycardia, abdominal pain, decreased appetite, vomiting, nausea, diarrhea, dizziness and somnolence, and height/ weight percentiles declined in children.
Contraindications: MAOIs should not be used within two weeks of taking atomoxetine (fatal hypertensive crisis). Metabolized by CYP2D6 so dont use with potent CYP2D6 inhibitors like paroxetine/ fluoxetine.
Not a controlled substance
Dexmethylphenidate (Focalin)
The D-enantiomer of Methylphenidate
Given in half the dose of the parent drug, a racemic mixture
Dextroamphetamine (Dexedrine)
The D-enantiomer of Amphetamine
Lisdexamfetamine (Vyvanse)
Pro-drug amphetamine consisting of a d-amphetamine covalently bonded to L-lysine.
Hydrolysis breaks the drug apart
Less potential for abuse and toxicity than amphetamine, although still a schedule II
Amphetamine (Adderall)
Indirect-Acting Sympathomimetic (this class of drugs enter the sympathetic nerve ending and displace stored catecholamines; they also can inhibit the reuptake of neurotransmitters by interfering with NET and DAT)
Adderall is the racemic form of amphetamine whereas dextroamphetamine is the d- enantiomer.
CNS stimulant, marked effects on mood and alertness, and appetite depressant.
Effects are mediated through the release of NE and DA
Adverse effects: insomnia, anorexia, weight loss, motor or vocal tics and headaches, visual hallucinations and emotional lability, growth retardation. Use caution in those with alcohol/ drug abuse.
Contraindications: Don’t use with sympathomimetic compounds (will increase heart rate and blood pressure). MAOIs will cause hypertensive crisis. Phenobarbital, phenytoin, TCAs (amphetamine will inhibit the metabolism of these drugs). Causes pupillary dilation (alpha receptor) so don’t use in closed-angle glaucoma.
Phenylpropanolamine
Mixed-Acting Sympathomimetic
Over the counter appetite suppressants but has been removed due to hemorrhagic strokes in young women.
Can increase blood pressure in patients with impaired autonomic reflexes.
Also a decongestant
Phenytoin (Dilantin)
Effective against all types of partial and tonic-clonic seizures but not absence seizures.
Exerts anti-seizure effects without causing general depression of the CNS.
MOA: slows the rate of recovery of voltage-activated Na+ channels from inactivation. At low doses it is very selective, at high doses it may reduce spontaneous activity and enhance responses to GABA
Kinetics: bound (90%) by serum proteins (mainly albumin). Small variations in the percentage of phenytoin that is bound dramatically affect the absolute amount of free (active) drug (increased in neonates, patients with hypoalbuminemia, and uremic patients). Phenytoin has a non-linear rate of elimination and can overwhelm the capacity of the liver to metabolize it, leading to disproportionate increases in plasma drug concentration following a small increase in dose. This is due to changing of metabolism from first order to zero order.
Interactions: Interacts with valproate (increases free conc. of phenytoin) and warfarin (inhibits breakdown leading to bleeding disorders)
Toxicity: Can cause cardiac arrhythmias on rapid administration, also can effect cerebellum at higher doses
Phenobarbital (Luminal)
First effective organic anti-seizure agent; relatively low toxicity and is easily affordable. Effective for generalized tonic-clonic and partial seizures. Not effective for absence seizures. Used to be used for anxiolytic properties, but at high doses becomes a hypnotic
MOA: works through potentiation of synaptic inhibition through an action on the B-subunit of GABAA receptor (increases duration of currents, not frequency of firing). At high doses, GABA is not needed to activate receptor
Kinetics: does not reach peak concentrations in plasma until several hours following administration. Induces UDP-glucuronosyltransferase as well as CYP2C and CYP3A
Toxicity: Sedation is most frequenct, nystagmus and ataxia occur at excessive dosage. Can cause irritability and hyperactivity in children, agitation and confusion in elderly. Has a low therapeutic index
half life of 4-5 days
Carbamazepine (Tegretol)
A primary drug of treating both simple and complex partial and tonic-clonic seizures; also used for trigeminal neuralgia
Related to the tricyclic antidepressants.
MOA:Same as phenytoin, limits the repetitive firing of action potentials by slowing the rate of recovery of Na+ channels from inactivation.
Kinetics: Complex; influenced by limited aqueous solubility. Slowly and erratically absorbed after oral administration. Peak plasma concentrations can occur 24 hours following dosage. Induces CYP2c, CYP3A, and UGT (like phenobarbital) which induces its own breakdown
Toxicity: Acute intoxication leads to stupor/coma, hyperirritability, convulsions, and respiratory depression. Long-term therapy lcan lead to drowsiness, vertigo, ataxia, diplopia, and blurred vision. Frequency of seizures may increase with overdosage. Watch for aplastic anemia
Mood stabilizer: can be used as an alternative to lithium when it is not efficacious. MOA unclear
Ethosuximide (Zarontin)
Primary agent for treatment of absence seizures
MOA: reduces low threshold Ca2+ currents (T-type currents) in thalamic neurons (thalamus is important for absence seizures).
Kinetics: Complete absorption, peak concentrations around 3 hours following dosage (more predictable than Carbamazepine)
Toxicity: GI complaints and CNS effects (drowsiness, lethargy, euphoria, dizziness, headahe, and ?hiccough) Several deaths have resulted from bone marrow depression
Valproic Acid (Depakene)
Effective against absence, partial, and tonic-clonic seizures
Drug of choice for myoclonic seizures
MOA: slows recovery from inactivation of Na channels (like phenytoin) and at slightly higher doses produces reductions of T-type Ca2+ currents (like ethosuximide). It may also generally increase GABA levels by preventing breakdown
Kinetics: Absorbed rapidly and completely, broken down by CYP2C9 and CYP2C19
Toxicity: Transient GI symptoms (anorexia, nausea, and vomiting) CNS (sedation, ataxia, tremor). A rare complication is potentially fatal fulminant hepatitis. Can also caused neural tube defects
Interactions: Displaces phenytoin from albumin, slows metabolism of phenytoin and phenobarbital
Mood stabilizer: antimanic effect like lithium. First line treatment for mania although only lithium is used for maintenance therapy.
Clonazepam (Klonopin) and Diazepam (Valium)
Used primarily for sedative-anti-anxity drugs.
MOA: enhance GABA-mediated synaptic inhibition by increasing frequency, but not duration, of GABAA channel openings. Causes hyperpolarization of target neurons.
Toxicity: drowsiness and lethargy occur in 50% of patients initially, but tolerance often develops.
Used for treatment of absence seizures as well as myoclonic seizures in children.
Diazepam is used for treatment of status epilepticus, not used for treatment of seizure disorders. Used for catatonic forms of schizophrenia. Clonazepam used for mild bipolar affective disorder.
Allosteric modulators (GABA has to be present for this agonist to work)
Gabapentin (Neurotonin) and Pregabalin (Lyrica)
Effective for partial seizures
Gabapentin is also used for treatment of migraine, chronic pain, and bipolar disorder
Anti-seizure drugs that consist of a GABA molecule covalently bound to a lipophilic cyclohexane ring or isobutane, respectively. Gabapentin was designed to cross the BBB
MOA: Neither mimic GABA when iontophoretically applied to neurons in primary culture. Effects may be mediated by alpha2delta-1 protein
Toxicity: well-tolerated, may lead to somnolence, dizziness, ataxia, and fatigue
Kinetics: not metabolized, not protein bound, excreted unchanged in the urine
Lamotrigine (Lamictal)
A phenytriazine derivative used for partial and secondarily generalized tonic-clonic seizures in adults and Lennox-Gastaut syndrome in both children and adults
Like valproate, can be used for any type of seizure
MOA: Same as phenytoin and carbamazepine, but is effective against a broader spectrum of seizures
Toxicity: dizziness, ataxia, blurred or doublt vision, nausea, vomiting, and rash. A few cases of Stevens-Johnson syndrome and DIC have been reported
Tiagabine (Gabitril)
Used as add-on therapy of refractory partial seizures with or without secondary generalization
MOA: inhibits the GABA transporter, GAT-1, and thereby reduces GABA uptake into neurons and glia
Toxicity: can cause seizures in patients without seizure disorders. Principal adverse effects are dizziness, somnolence, and tremor
Contraindicated in patients with generalized absence epilepsy
Topiramate (Topamax)
Used for partial-onset or primary generalized tonic-clonic seizures, for Lennox-Gastaut syndrome in patients 2 years of age and older, and for migraine headache prophylaxis in adults.
MOA: Similar to phenytoin, plus it activates a hyperpolarizing K+ current, enhances postsynaptic GABAA-receptor currents, and limits activation of the AMPA-kainate-subtypes of glutamate receptor.
Can lead to increased breakdown of oral contraceptives (can cause unwanted pregnancies)
Toxicity: well tolerated. Has been associated with cognitive impairment and patients may complain about a change in the taste of carbonated beverages
Zonisamide (Zonegran)
Approved as adjunctive therapy of partial seizures in adults, not effective against myoclonic seizures
MOA: inhibits the T-type Ca2+ currents, also has a similar one to phenytoin and carbamazepine
Well tolerated, but 1% of patients developed renal calculi
General Rules of Seizure Meds
- The less drugs, the better. Avoid multi-drug therapies if you can
- After 2 years of being seizure free, taper off the drugs
Failure can be brought by using the wrong drug for the type of siezure, drug interactions, drug induced toxicity leading to non-compliance, and unusual pharmacokinetics (like with phenytoin)
