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)
Primidone (Mysoline)
Primidone is metabolized to phenobarbital and phenylethylmalonamide.
Although metabolized to phenobarbital, the MOA is closer to phenytoin
It is used against partial seizures and generalized tonic-clonic seizures
Drowsiness occurs when initial dose is too large
Chlorpromazine (Thorazine)
Dopamine-receptor antagonist
Aliphatic derivative antipsychotic
side effects: sedation and weight gain, orthostatic hypotension and tachycardia, seizures
Pharmacokinetics: significant first pass metabolism. Oral doses have systemic availability of 25-35%. Metabolites may be excreted in urine weeks after last dose was administered. D2 blockade may occur 3-6 months after last injection.
Adverse actions are traced to blocking effects at alpha adrenoceptors, muscarinic, H1, and 5-HT2 receptors.
Least amount of EPS in the phenothiazine class
Inexpensive
Thioridazine (Mellaril)
piperidine derivative antipsychotic (more potent than chlorpromazine, but not necessarily more efficacious)
side effects: sedation and weight gain, orthostatic hypotension and tachycardia, abnormal EEG recordings, overdoses are fatal
Pharmacokinetics: significant first pass metabolism. Oral doses have systemic availability of 25-35%
Fluphenazine (Prolixin)
- Antipsychotic that blocks post-synaptic D2 receptors (D2 receptor antagonist)
Thiothixene (Navane)
Typical Anti-psychotic
Dopamine-receptor antagonist
decreased tardive dyskinesia (most important unwanted effect of antipsychotic drugs, similar to choreoathetosis). parenteral form also available
Haloperidol (Haldol)
Dopamine-receptor antagonist
Butyrophenone derivative antipsychotic
most widely used typical antipsychotic drug, despite its high level of EPS (extrapyramidal side effects which is a blockade of D2 receptors in nigrostriatal pathway (voluntary movement) and typically EPS occurs when a DA antagonist binds to about 80% of D2 receptors )
Used to treat Tourette’s syndrome
more potent and fewer autonomic effects than phenothiazines (chlorpromazine and thioridazine)
Pharmacokinetics: less first pass metabolism than chlorpromazine/ thioridazine; availability of 65%
Risperidone (Risperdal)
Inverse agonist of 5-HT2A receptor (blocks consitutive activity); these receptors modulate the release of DA, NE, Glu, GABA in limbic, striatum, and cortex.
Adverse: elevations of prolactin
Can be used to treat Tourette’s
Clozapine (Clozaril)
Atypical Antipsychotic (generalization: most atypical antipsychotics inhibit 5-HT2A receptors just as well as they do D2)
Clozapine is the prototype atypical antipsychotic: the class in general mostly act as partial agonist at 5-HT1A receptor which produces synergistic effects with the 5-HT2A receptor antagonism
Relapse after discontinuation is rapid and severe. Should never be discontinued abruptly (adverse effects of myocarditis and agranulocytosis-must get blood counts every week for 6 months); seizures in 2-5%, severe weight gain
only atypical antipsychotic used to reduce risk of suicide
Olanzapine (Zyprexa)
Atypical Antipsychotic
This goes for Clozapine as well: they both are more efficacious than other antipsychotics that block D2 because they only have to bind the about 30-50% of the receptors. Most others need to bind 60% of D2 receptors for effect. This may be due to their concurrent occupancy of 5-HT2A receptors.
Olanzapine, quetiapine, and aripiprazole cause no increase in prolactin and less EPS, reflectinga diminished D2 antagonism
adverse: severe weight gain (like Clozapine); dose-related lowering of seizure threshold
treatment of bipolar disorder when used in combination with fluoxetine (SSRI)
Quetiapine (Seroquel)
Atypical Antipsychotic
low doses used to promote sleep
short half life
No weight gain
Ziprasidone (Geodon)
Atypical Antipsychotic
Inverse agonist of 5-HT2A receptor (blocks consitutive activity); these receptors modulate the release of DA, NE, Glu, GABA in limbic, striatum, and cortex.
Can be used to treat bipolar disorder.
adverse: QT prolongation
Aripiprazole (Abilify)
Atypical Antipsychotic
partial dopamine receptor agonist, but in the presence of endogenous DA it will act as a DA receptor antagonist
Blocks postsynaptic D2 receptors in the CNS, especially in the the mesolimbic and striatal-frontal system. Does not cause EPS even though it binds D2 with high affinity- this is because it is a partial agonist.)
Has been approved for treating bipolar disorder
long half life and lower weight gain liability
Adverse effects of Antipsychotics
ANS: loss of accommodation, dry mouth, difficulty urinating, constipation: muscarinic blockade. Also, because of alpha adrenergic blockade, orthostatic hypotension, impotence, failure to ejaculate.
CNS: Parkinson’s syndrome, akathisia, dystonia via DA receptor blockade.
Endocrine: Amenorrhea-galactorrhea, infertility, impotence via DA receptor blockade (Dopamine keeps prolactin at low levels, an antagonist of dopamine leads to increased prolactin secretion)
other: weight gain from H1 and 5-HT2 blockade
Atypical antipsychotics
AKA Serotonin-DA Receptor Antagonists
Includes: risperidone, olanzapine, quetiapine, clozapine, ziprasidone
atypical because they have higher ratio of 5-HT2: D2 blockades than typicals. Blockade of 5-HT2 modulates DA neurons in nigrostriatal, mesolimbic, and mesocortical pathways. This is why there is less EPS and fixes negative symptoms of schizophrenia.
any antipsychotic can treat positive symptoms (mesolimbic system) of schizophrenia, however, only atypicals can treat negative symptoms (mesocoritcal pathway) like inexpressive faces, blank looks, monotone and monosyllabic speech, few gestures, seeming lack of interest in the world and other people
augments antidepressant effects in major depression
used for acute mania and Tourette’s disorder, reduces risk of suicide in schizophrenic patients
suppresses the abnormal movements of tardive dyskinesia
Interactions b/t DA and Serotonin systems: 2 mechanisms as to why there is less EPS. This is a summary of the mongraph:
Mechanism 1: atypical antipsychotics bind D2 receptors with lower affinity than the typical antipsychotics so that when voluntary movement is initiated in nigrostriatal pathway, release of DA at synapse can outcompete the D2 receptor antagonists (atypical antipsychotic drugs) and stimulate the inhibitory DA neurons that will inhibit the indirect pathway so no parkinson’s like symptoms and a net excitation will occur at caudate/ putamen)
Mechanism 2: Serotonergic neurons in raphe nucleus talk to DA neurons of the substantia nigra pars compacta (part of the nigrostriatal pathway). These DA neurgons have 5-HT receptors on their dentrites/soma/ axon termimals. When serotonin binds these 5-HT receptors, an inhibitory effect is initiated so that less DA is released to the caudate/ putamen. Now, when atypical antipsychotics bind 5-HT receptor as an antagonist, this net inhibition is prevented and therefore a net excitation occurs.
Lithium (Eskalith)
Treatment for bipolar disorder and recurrent endogenous depression, schizoaffective disorder, and unipolar depression
Inhibits inositol signaling and glycogen synthase kinase-3. Reduction in PIP2 so not IP3 and DAG made. Manic episodes are associated with an increase in these messengers. Also has been shown to inhibit NE sensitive adenylyl cyclase attributing to its antidepressant/ antimanic effects.
pharmacokinetics: 6-8 hours for full absorption. no metabolism and virtually all of it is extreted in urine. half life of 20 hours. Renal clearance is reduced by about 25% by diretics (thiazide), newer NSAIDS
adverse: nausea and tremor, ataxia, aphasia, decreased thyroid function (take serum TSH conc. every 6-12 months), diabetes insipidus (polydipsia), edema, bradycardia-tachycardia (contra-indicated due to T-wave flattening), acne
Recurrent endogenous depression is controlled by lithium or imipramine
Chlordiazepoxide (Librium)
- Benzodiazepine used to treat Delirium Tremens in alcohol withdrawl emergencies
Desmethyldiazepam
Benzodiazepine
More of a sedative
Active form of diazepam, prazapam, and chlorazepate
half life of over 40 hrs is an active metabolite of diazepam
Oxazepam (Serax)
Benzodiazepine
used for alchohol withdrawals
causes less drowsiness due to short half life
Flurazepam (Dalmane)
used as sleep aid but causes daytime sleepiness due to biotransformation to active metabolites
hypnotic
Benzodiazepines decrease REM, stage 3 and 4 sleep and increase stage 2 (decreases latency)
Triazolam (Halcion)
rapid oral absorption. undergoes alpha hydroxylation and metabolites are metabolized rapidly.
short half life of 3 hrs accounts for its use as hypnotic rather than sedative, but because of short half life, withdrawals occur the next day.
Binds to GABA A receptor (like all benzodiazepines). Binds the BZ site which is between the alpha and gamma subunits.
**Very important concept about benzodiazepines: they do not substitute for GABA; they allosterically enhance GABA’s effects resulting in an increase in the frequency of channel opening events.
Alprazolam (Xanax)
anxiolytic drug
used for treatment of panic disorder and agoraphobia
more toxic in overdose than other benzodiazepines
Zolpidem (Ambien)
Hypnotic
lipophilicity allows entry into CNS. Rapidly metabolized to inactive metabolites via CYP450. half life of 1.5- 3.5 hrs
A nonbenzodiazepine that binds GABA A receptor causing Chloride to rush in causing an IPSP. Binds at BZ site that has alpha 1 subunit
decreases REM sleep but minimal effects (increases) on slow-wave sleep. Shortens sleep latency and increases total time spent in sleep.
Abrupt discontinuation causes rebound insomnia. Less risk of tolerance and dependence
Zaleplon (Sonata)
Hypnotic
lipophilicity allows entry into CNS. shorter half life than Zolpidem (1 hr)
A nonbenzodiazepine that binds GABA A receptor causing Chloride to rush in causing an IPSP, GABA does not have to be present. Binds at BZ site that has alpha 1 subunit
decreases latency of sleep with no effect on total sleep time. less amnesia or day after somnolence than zolpidem or benzodiazepines.
Valerian root
herbal remedy useful as sedative-hypnotic and anxiolytic
most biological activity is attributed to sesquiterpene
Used for treating mild insomnia by reducing sleep latency (time it takes to fall asleep)
adverse: withdrawals similar to benzodiazepines when taken long term in high doses, migraine and GI effects, dizziness (these adverse were only seen in a few patients from small trials)
more effective when used over the course of time instead of acutely
Ramelteon (Rozerem)
melatonin receptor agonist used as a hypnotic. Binds MT1 and 2 receptors in suprachiasmatic nuclei
No associated dependence
Associated with endocrine changes
rapidly absorbed orally and undergoes extensive first pass metabolism
Contraindicated with inhibitors of CYP1A2 (ciprofloxacin, fluvoxamine) or fluconazole. CYP inducer Rifampin will reduce its levels.
Eszopiclone (Lunesta)
Hypnotic
absorbed rapidly into blood following oral administration. lipophilicity allows entry into CNS. half life of 6 hours and metabolized by CYP3A4
A nonbenzodiazepine that binds GABA A receptor causing Chloride to rush in causing an IPSP. Binds at BZ site that has alpha 1 subunit
increases total sleep time. less amnesia or day after somnolence than zolpidem or benzodiazepines (unusual because it can increase stage 2 sleep).
At high doses it decreases REM sleep
Thiopental
barbituate
very lipid-soluble, penetrates brain and useful for anesthesia but has been largely replaced by propofol.
Should not be used in patients with acute intermittent porphyria
Does not produces analgesia (might even cause hyperalgesia)
Decreases blood pressure on infusion (but not as bad as propofol)
Accidental injection into arterial circulation results in excrutiating pain, intense vasoconstriction, and can lead to gangrene
Secobarbital (Seconal)
Like most barbituates, they get metabolized by hepatic enzymes and little drug remaines unchanged when excreted
half life of 18-48 hours
In normal barbituate fashion, Secobarbital binds GABA A receptor but barbituates only bind to alpha 1 receptor so they are more selective in action.
**Very important concept for barbituates: they increase the duration of GABA channel openings, They can activate the channels at high concentrations.
*Absolutely contraindicated in patients with porphyrias due to enhancement of porphyrin synthesis.
- Used to treat insomnia and make one sleepy/less anxious before surgical procedures
Buspirone (Buspar)
slow-onset anxiolytic agent
No sedative, hypnotic or euphoric effects.
Unlike benzodiazepines, Buspirone has no anticonvulsant or muscle relaxant properties.
Acts on 5-HT1A and D2 receptors
No rebound anxiety or withdrawal from discontinuance.
Used in general anxiety states but not in panic disorders
Rapidly absorbed orally and undergoes extensive first pass metabolism. half life of 2-4 hours.
Toxicities: chest pain, tachycardia, palpitations, dizziness, nervousness, tinnitus, GI distress, paresthesias, pupillary constriction.
Flumazenil (Romazicon)
synthetic benzodiazephine derivative. Serves as an antagonist at GABA A receptor, blocking the actions of benzodiazepines, eszopiclone, zaleplon, and zolpidem; does not block effects of barbituates and alcohol.
used as treatment of benzodiazepine overdose
acts rapidly but has short half life of about an hour due to hepatic clearance, this is important for getting people awake from benzodiazepine anesthetics.
Adverse effects: agitation, confusion, dizziness, nausea. seizures and cardiac arrhythmias if previously taken TCAs + benzodiazepines
Sedative-Hypnotics
Sedative: antianxiety and calming effects
Hypnotic: drowsiness and state of sleepiness
These agents cross placenta and cause respiratory depression in fetus
Propofol (Diprivan)
Most frequently administered drug for induction of anesthesia (has replaced barbituates)
Kinetics: allows for continuous infusions, used during maintenance of anesthesia. Poorly water soluble, formulated as an oil emulsion that can lead to allergic reactions. Rapidly metablized in the liver, metabolites excreted in kidneys. Extrahepatic metabolism is thought to occur in the lungs (up to 30%). Elimination is like other IV anesthetics: redistributed from highly perfused (brain) to less-well-perfused (skeletal muscle) compartments.
MOA potentiation of the chloride current mediated through the GABAA receptor complex
Acts as a hypnotic without analgesic properties, causes pronounced decrease in systemic blood pressure due to vasodilation in both arterial and venous circulations, causes apnea after an induction dose, and can lead to tachycardia in the case of propofol infusion syndrome.
Benzodiazepines
Midazolam, Lorazepam, Diazepam
Unique among the group of IV anesthetics in that their action can readily be terminated by adminstration of their selective antagonist, flumazenil
Highly lipid-solube; rapidly enter CNS
Midazolam is considered to have a slower effect-site equilibration than propofol. It also has the shortest context-sensitive half-life, meaning it is the only one of the three benzodiazepines suitable for continuous infusion.
Cuases decrease in systemic blood pressure, minimal depression of ventilation (although transient apnea may follow rapid IV administration), may produce pain on injection
Lorazepam has a slow onset and prolonged duration that limit its usefulness for preop medication or induction of anesthesia
Midazolam is the most commonly used oral premedication for children
Etomidate (Amidate)
IV anesthetic with hypnotic but not analgesic effects and is often chosen for its minimal hemodynamic effects. Endocrine side-effects limit its use for continuous infusions
MOA: appears to have GABA-like effects and seems to act primarily through potentiation of GABAA mediated chloride currents, like most other IV anesthetics.
Because of etomidate’s minimal effects on hemodynamics and short context-sensitive half-time, larger doses, repeated boluses, or continuous infusions can safely be administered
May cause myoclonic activity in 50% of patients, causes cardiovascular stability after bolus injection, less pronounced respiratory depressive effects compared to barbituates, but causes adrenocortical suppression by inhibiting 11B-hydroxylase, an enzyme necessary for the conversion of cholesterol to cortisol
Not used as a continuous infusion
Often used in patients with compromised myocardial contractility
Ketamine (Ketalar)
IV anesthetic that produces significant analgesia.
MOA: complex, but associated with inhibition of the NMDA receptor complex
Ketamine is the only IV anesthetic that has low protein binding.
When using this drug, the patient’s eyes remain open and they drool.
Ketamine increases cerebral blood flow, and can increase systemic blood pressure, heart rate, and cardiac output
Can be administered by multiple routes (IV, IM, oral, rectal, epidural) which is good for uncooperative patients
Morphine
Prototypical opiod agonist. Full agonist at the mu opioid receptor, the major analgesic receptor.
- generally*, opioids act at receptor coupled to G proteins; they inhibit the influx of Calcium and reduce neurotransmitter release; secondly, they hyperpolarize and thus inhibit postsynaptic neurons by opening potassium channels.
Most opioids are well absored in all routes, but b/c of first-pass effect, a higher oral dose needs to be given
Conjugated into morphine-3-glucoronide and has neuroexceitatory effects at GABA/glycinergic system. 10% gets converted to morphine-6-glucoronide which has potent analgesic properties. These metabolites dont cross BBB and do not contribute to CNS effects of morphine
slow release morphine (oxycontin) is good for treating chronic constant pain
Tolerance and dependence MOA: Simple up-regulation of cAMP system doesn’t explain it, so two hypothesis are presented; 1.) Receptor recycling: endogenous opioids bind their receptors and cause endocytosis and eventual recycling to plasma membrane. Morphine doesn’t result in endocytosis whereas methadone does (which is used in treating opioid dependence. 2.) **Receptor Uncoupling: ** binding of opioid to receptor is normally linked to G protein. When this is no longer the case, tolerance and dependence can result. NMDA antagonists like ketamine can block this tolance mechanism.
CI: kidney failure, Probenecid can increase metabolites and cause unwanted effects
Adverse (for most opioids): disrupts REM and non-REM sleep, respiratory depression, sedation, euphoria, cough suppression, nausea/vomiting, temperature disregulation, miosis
Heroin
diacetylmorphine is metabolized to morphine
rapidly hydrolyzed by esterases to monoacetylmorphine and then morphine which is then conjugated to glucoronic acid
when given intramuscularly, more effective in relieving severe chronic pain than morphine.
potent and fast acting, but prohibited in USA
Users describe a “rush” comparable to sexual orgasm, taste, warmth. Cant distinguish between effects of hydromorphone
adverse: hypothalamic-pituitary tract messed up, abnormal menstruation, withdrawal symptoms in between dose
Toxicities: death, endocarditis, pulm infections like TB
Codeine
Oxycodone + Aspirin = Percodan
Oxycodone + Acetominophen = Percocet
partial mu opioid receptor agonist
reduced first pass metabolism (oral)
metabolism by CYP2D6, resulting in strong metabolites; codeine is demethylated to morphine. Oxycodone metabolites can accumulated in patients with renal failure.
Antitussive: suppress cough
Hydrocodone
Hydrocodone + Acetaminophen = Vicodin or Lortab
Hydrocodone + Ibuprofen = Vicoprofen
metabolism by CYP2D6, resulting in strong metabolites
Hydromorphone (Dilaudid)
Opioid gets metabolized by conjugation to H3G which has CNS excitatory properties
rectal suppositories are available
Hydrocodone is metabolized into hydromorphone via CYP2D6
Oxymorphone (Numorphan)
strong opioid agonist used in treating severe pain.
Oxycodone is metabolized via CYP2D6 into oxymorphone and so ultra rapid metabolizers need less of a dose.
Fentanyl (Sublimaze)
Adverse: truncal rigidity is especiially prominent
If GI disturbances prevent the use of sustained release morphine (oxycontin), Fentanyl transdermal patch can be used.
available via buccal transmucosal route, as a lollipop lozenge
Can be used as a primary anesthetic for surgical procedures
Meperidine (Dermerol)
Opioid
MOR agonist yielding strong analgesic effects.
Hepatic oxidative metabolism is main route kinetics. first-pass metabolism results in 50% of dose having an effect.
Adverse: A demethylated metabolite, normerperidine, can cause seizures; negative ionotropic action of the heart; tachycardia; peak respiratory depression 1 hr after administration; tremors. Can block reuptake of serotonin so can cause serotonin syndrome if used with some drugs.
CI: SSRI, TCAs, MAO, Chlorpromazine
less neonatal depression when used during labor
Propoxyphene (Darvon)
- Opiod agonist: weak opioid agonist, binding primarily to mu opiod receptors, producing analgesia and other CNS effects
Tramadol (Ultram)
Centrally acting analgesic. MOA based on blockade of serotonin reuptake. inhibits NET
weak mu receptor agonist
adverse: seizures, serotonin syndrome (esp with SSRI)
May serve as an adjunct with pure opioid agonist in the treatment of chronic neuropathic pain
CI in patients taking SSRIs for same reason as meperidine (SERT)
Nalbuphine (Nubain)
mixed opioid agonist-antagonist; agonist effect at one receptor and an antagonist effect at another
strong kappa receptor agonist and mu antagonist.
At higher doses, there appears to be a ceiling to the respiratory depressant effect although it is resistant to naloxone reversal
Pentazocine (Talwin)
mixed opioid agonist-antagonist, kappa agonist; weak mu antagonist/ partial agonist
Contraindication: weak partial agonist like pentazocine should never be used in a patient receiving a full agonist (morphine); diminishes analgesia and induces a state of withdrawal
the oldest mixed agent around. used orally or parenterally. Injection not recommended due to irritant properties
Butorphanol (Stadol)
preference for kappa opioid receptor; may cause greater analgesia in women; can cause dyphoric reactions and reduced potency from other opioids
Currently, the only opioid available in USA in a nasal formulation
produces more sedation than nalbuphine/ buprenorphine but similar analgesia
Buprenorphine (Buprenex) (Subutex and Suboxone)
mixed agonist-antagonist: binds mu receptor with high affinity and possibly used to treat withdrawal, and it also binds kappa and delta receptors antagonistically. partial mu agonist/ kappa antagonist
Combined with naloxone as a treatment plan for addiction. In high doses, it acts as a mu antagonist, limiting its analgesic properties; extremely dangerous to combine this with benzodiazepines or other CNS depressants
sublingual administration is favored to avoid first-pass metabolism. long duration of action due to slow dissociation from mu receptors and resistant to naloxone reversal
Subutex is sublingual buprenorphine.
Suboxone is buprenorphine combined with Naloxone, which inhibits patients from crushing up the Buprenorphine and injecting it. Naloxone blocks subjective high, but not when taken orally as perscribed.
Buprenorphine produces minimal withdrawal symptoms when suddenly discontinued and has a low potential for overdose, long duration of action, and can block heroin’s effects. Good long-term treatment plan.
Dextromethorphan
NMDA receptor antagonist
free of addictive properties and produces less constipation than codeine.
Antitussive and available in over the counter preps
Enhances the angalgesic effects of morphine and lowers the tolerance associated with opiates. d,m
Toxicities: powdered form can be abused and leads to death
Dissociative drug:
Naloxone (Narcan)
allyl substitution and hydroxylation of a full opioid agonist results in this strong mu receptor antagonist
Antagonist precipitated withdrawal: administer naloxone and within 3 minutes, signs and symptoms similar to those seen in abrupt discontinuance of opiates appear for about an hour
IV injection reverses coma due to opioid overdose
when administered to a morphine-treated paitent, the antagonist effects reverse morphine in 1-3 minutes. Short acting effects so need to monitor patient for relapse a few hours later.
Ethanol
CNS depressant, but also a stimulant in terms of suppression of inhibitory systems
adverse: impairs recent memory, blackouts, etc
cross-tolerance with benzodiazepines is important to know: high blood alcohol levels + benzos can be life threatening.
Acts on many receptors including GABAA and NMDA. ENT1 receptor may be involved in dependence
Withdrawal: 6-12 hours after heavy drinking may have tremor of hands, nausea, vomiting, sweating, anxiety. 12-24 hours manifest generalized seizures. 48-72 hours delirium tremens-person hallucinates and shows evidence of autonomic instability and death in 5-15%
treatment: benzodiazepines like oxazepam/ lorazepam
Nicotine
agonist at nicotinic acetylcholine receptor
Rewarding aspect of nicotine due to nAChR expressed on DA neurons in VTA and DA is released into nucleus accumbens and prefrontal cortex.
Nicotine withdrawal is mild compared to opioids and involves irritability and sleep problems. Relapse very common.
Treatment: cystine and Varenicline work by occupying nAChRs on DA neurons of the VTA, thus preventing nicotine from exerting its action. Varenicline may impair ability to drive and cause suicidal ideation.
Buproprion also approved for nicotine cessation, but seems less effective than Varenicline
3,4-methylenedioxymethamphetamine (MDMA)
“Ecstasy”
produces feelings of intimacy and empathy without impairing intellectual capacities
distributed in “raves” and taken orally
Causes release of biogenic amines by reversing the pumps, especially SERT (similar moa to amphetamines). With repeated doses serotonin may become permanently depleted
toxicities: hyperthermia + dehydration (due to dancing at the rave) may be fatal, serotonin syndrome (mental status change, ANS hyperactivity, neuromuscular abnormalities), seizures. To compensate for dehydration, dancers will drink too much water and cause hyponatremia, seizures, and death.
Opioids
activates GIO coupled receptors
mu receptors are on and inhibit GABAergic neurons causing euphoria whereas kappa receptors inhibit dopaminergic neurons and so cause dysphoria.
Treat withdrawals with clonidine and methadone. Methadone is a long acting agonist
Marijuana
Exogenous cannabinoids. THC is the main psychoactive substance.
Disinhibition of DA neurons, by presynaptic inhibition of GABA in the VTA.
half life is 4 hours
Hashish is super potent and you can hallucinate
there are withdrawals to marijuana: relessness, irritability
Dronabinol and Nabilone (older) are THC analogs
Inhalants
chemical vapors like nitrates, ketones, aliphatic/ aromatic hydrocarbons.
agents inhaled by “sniffling” “huffing” or “bagging”
Sniffing is inhaling an open container; huffing refers to soaking a cloth in volatile substance before inhalation; bagging to breathing in and out of a paper or plastic bag filled with fumes
Nitrous oxide binds NMDA receptors and fuel additives enhance GABAA
produces euphoria; increased VTA excitation is reason for toluene addiction risk.
amyl nitrite “poppers” produce smooth muscle relaxation
Toxicities: lesions in white matter of CNS
Phencyclidine (PCP) and Ketamine
dissociative anesthetic. only ketamine is still used as anesthetic
feeling of separation of mind and body. Psychedelic effects last for about an hour
at high doses, out of body “near death” experiences, causes stupor and coma, hypertension, impaired memory, visual alterations
“club drug” PCP goes by “angel dust” “Hog” and Ketamine by “special K”
non-competitive antagonist at NMDA receptor, which is present on inhibitory neurons
white crystal powders but in streets they are sold in liquid, capsules, pills which can be snorted, ingested, injected, or smoked.
Lysergic acid diethylamide (LSD), Mescaline, Psilocybin
hallucinogens; they alter consciousness and induce perceptual symtoms, including color and shape distortion
Causes dizziness, nausea, paresthesias, blurred vision, and flashbacks from previous drug exposures
Not associated with dependence or addiction. Doesn’t target mesolimbic DA system; it hits the cortical and thalamic circuites .
MOA: activates serotonic 5-HT2A receptor in prefrontal cortex, enhancing glutamatergic signals onto pyramidal neurons, enhancing perception.
LSD can induce abortion
Rohypnol
Club drug, roofies
A benzodiazepine that binds GABAA receptor and causes sedating effects. When combined with ethanol, anterograde amnesia occurs as well as an inability to protect from sexual assault.
Commonly used in raves. Associated with the same level of tolerance as other benzodiazepines
Gamma hydroxybutyrate
produced during the metabolism of GABA
used to treat narcolepsy; GHB decreases daytime sleepiness
causes euphoria, enhanced sensory perceptions, social closeness, amnesia so its a popular “club drug”
“liquid ecstasy” “grievous bodily harm” “date rape drug”
reaches maximal concnetration after 30 minutes and half life is 30 min
addictive
Disulfuram
Also known as Antabuse
Treatment of alochol dependence by inhibiting acetaldehyde dehydrogenase and therefore preventing alcohol metabolism. Unpleasant rxn if alcohol is consumed.
Patient compliance is the hardest part of treatment. Alcohol isn’t fun while taking Disulfuram, so why am I taking it?
Naltrexone
Used to reduce cravings of opioid addicts
mu opioid receptor antagonist and partial agonist is FDA aproved for both opioid and alcohol addiction by modulating endogenous opioid system.
Makes drinking alcohol less rewarding
Acamprosate
Antagonist of NMDA glutamate receptors
May interfere with synaptic plasticity that depend on NMDA receptors and useful for treating alcoholism.
Toxicities: allergic rxn, arrhythmia, change in blood pressure, impotence
Somehow acts on the GABA system. Used to get alcoholics off alcohol without withdrawals
Methadone
Used to treat opioid dependence
slow acting agonist of mu opioid receptor
similar effects to morphine/heroin but less psychoactive, and still has potential for abuse and overdose
half life ranges 4-130 hours
toxicities: respiratory depression, constipation, depression, withdrawal symptoms (but not as severe as other opioids)
Dependence vs Addiction
dependence is physical dependence. Withdrawal syndrome defines dependence. Tolerance and withdrawal are associated terms with dependence.
- Tolerence:* doses of drugs have to be increased over time as the patient gets used to them. Can occur by reduction of drug concentration or mu receptor functional changes. Unfortuante because undersirable side effects like respiratory depression dont show tolerance.
- Withdrawal:* adaptive changes once drug exposure is terminated. mu receptor activation causes inhibition of adenylyl cyclase. once drug is terminated, compensatory increase in cyclases causes negative dysporia. Also, overproduction of cAMP causes increase CREB, causing increased transcription of dynorphin. This dynorphin then leads to decreased DA release in Ventral tegmentum.
addiction is psychological dependence. Consists of compulsive, relapsing drug use despite engative consequences, triggered by cravings and cues. MOA: mesolimbic dopamine system. VTA projects to nucleus accumbens, amygdala, hippocampus, and prefrontal cortex. Drugs of abuse cause DA release into these areas and activate the mesolimbic system.
Relapse is much more common in addicts after a successful withdrawal when they are no longer dependent. Basically, addiction is much more harder to fix than dependence
Clonidine
alpha 2 adrenergic agonist that decreases NE from locus ceruleus
the withdrawals effects seen from opioid addiction stems from the loss of suppression of the locus ceruleus: vomiting, cramps, sweating, tachycardia, hypertension. clonidine reverses this
Side Effects of Anti-Convulsants
Phenytoin: CNS depression, arrhythmias
Carbemazepine: Drowsiness, stupor, coma, convulsions, respiratory depression, aplastic anemia
Valproate: GI symptoms, sedation
Ethosuximide: GI symptoms, drowsiness, lethargy
Primidone, Clonazepam, Diazepam, Phenobarbital: drowsiness
Gabapentin: somnolence, fatigue (mild)
Lamotrigine: Dizziness, GI symptoms (mild)
Topiramate: somnolence, weight loss (mild)
Tiagabine: dizziness, tremor, somnolence (mild)
Zonisamide: somnolence, fatigue (mild)
Sumatriptan
5-HT1B/1D receptor-selective agonist
Constriction of incranial blood vessels is effective in treating acute migraine attacks (with or w/ out aura)
Decreases nausea and vomiting of migraine
Classified as a triptan (indole derived) which is limited to 5-HT1 receptors
MOA: By constricting blood vessels of the arteriovenous anastomoses, shunts are closed and cerebral hypoxia and ischemia is mitigated. May also block the release of proinflammatory neuropeptides in the nerve terminal of perivascular space.
Reaches peak concentration in 12 minutes (subcutaneously) or 1-2 hours (orally). Bioavailability of 97% subQ. Half life of 1-2 hours. Metabolized by MAO-A
Adverse: coronary artery vasospasm, myocardial ischemia, MI, irritation at site of injection, bitter taste (nasal spray). Orally: paresthesia, fatigue, pain in chest, drowsy, dizzy, nausea
Contraindicated in serious cardiovascular diseases, hemiplegic or basilar migraines, hypertension
Ergotamine
Ergot and Ergot alkaloids in general are partial agonists or antagonists at DA, adrenergic, serotonergic receptors
Ergot is from a fungus that grows on rye/ other grains
Extensive first-pass metabolism. Oral administeration may result in undetectable levels. 90% of metabolites are excreted in bile. half life of 2 hours and vasoconstriction lasting 24 hours.
Acute anti-migraine effects by acting as 5-HT1B/1D agonists, similarly to Sumatriptan
Not to be used in patients with frequent, moderate migraine or infrequent, severe attacks. Only for acute migraines
Sublingual tablet, nasal spray, solution for injection, and ergotamine with caffeine as both oral and rectal suppositories.
Adverse: nausea, vomiting (CNS emetic centers), leg weakness, muscle pain, numbness/ tingling in fingers and toes, coronary vasospasm, edema and itching in hypertensive patient.
CI in pregnant women, peripheral vascular disease, coronary artery disease, hypertension, impaired renal or liver function, sepsis. Don’t use within 24 hrs of sumatriptan.
Benztropine (Cogentin), Trihexyphenidyl (Artane)
Muscarinic Receptor Antagonist
Benztropine: antagonist at M receptor in basal ganglia
Improves the rigidity and tremor of parkinsonism but has little effect on bradykinesia
Start at low dose and gradually increase until therapeutic effects are noticed. When coming off the medication, do it slowly to prevent acute exacerbation of parkinsonism.
Adverse: Poorly tolerated by the elderly, dyskinesia, acute suppourative parotitis due to dryness of the mouth, and other typical antimuscarinic effects.
Acyclovir (Zorivax)
Acyclic guanosine derivative used against HSV-1, HSV-2, and VZV but 10X more potent against Herpes Simplex than Varicella.
MOA: requires 3 phosphorylation steps for activation: converted to monophosphate by viral thymidine kinase, then to the di- and triphosphate compounds by host cell enzymes. Acyclovir triphosphate then inhibits viral DNA by competing with deoxyGTP for viral DNA polymerase (makes an irreversible complex), and chain termination following incorporation of acyclovir into viral DNA.
low oral bioavailability. Cleared by kidney. half life of 2.5- 3hrs in normal renal function
shortens duration of genital herpes by 2 days, time of lesion healing takes 4 days, duration of viral shedding is 7 days, and decreases sexual transmission.
In VZV, high doses required to decrease number of lesions
IV route is used for herpes simplex encephalitis, neonatal HSV
Resistance: viral alteration of thymidine kinase of DNA polymerase
Adverse: nausea, diarrhea, heache, IV associated with reversible renal toxicity, tremors, delirium, seizures
Rabies Immune Globulin
Passive Immunization
protection usually lasts for 1-3 months
Largely IgG (95%)
Specific immune globulin (“hyperimmune”) preparations are available for rabies. Pooled from donors who are selected for high titers of desired antibodies.
Halothane (Fluothane)
Volatile anesthetic (has low vapor pressure and thus high boiling points so that liquid at room temperature/ sea-level pressure)
The driving force for an inhaled anesthetic is the alveolar concentration. This concentration changes based on inspired concentration or partial pressure, and alveolar ventilation
Medium rate of onset and recovery
Solubility is 2X and 10X more than nitrous oxide in brain tissue and blood, respectively. Therefore, elimiantion and recovery is less rapid.
Hepatotoxicity (halothane hepatitis):
adverse: more severe depression of normal cardiac contractility than others
40% of halothane is metabolized so that elimination occurs more quickly than would be be expected based on tissue solubility.
Enflurane (Ethrane)
Volatile anesthetic
Medium rate of onset and recovery
Not really metabolized unlike halothane. Even though enflurane’s solubility is lower, it’s eliminated more slowly.
adverse: more severe depression of normal cardiac contractility than others. Only inhaled anesthetic with frank clinical seizures
Toxicities: metabolites are nephrotoxic
Isoflurane (Forane)
Volatile anesthetic
Medium rate of onset and recovery
Isoflurane, sevoflurane, halothane, enflurane produce initial activation of EEG at low doses and subsequent slowing when given doses of 1.0-1.5 MAC. Isoflurane EEG is silenced at 2.0-2.5 MAC.
Pungency makes it less suitable for patients with active bronchospasm
better choice for patients with impaired myocardial function
Sevoflurane (Ultane)
Volatile anesthetic
Rapid onset and recovery; unstable in soda-lime
better choice for patients with impaired myocardial function
Toxicities: metabolites are nephrotoxic
Nitrous Oxide
Gaseous anesthetic (high vapor pressure and low boiling point so gas at room temperature)
No metabolism; incomplete anesthetic; rapid onset and recovery
Can increase cerebral blood flow and increase intracranial pressure (SNS)
Adverse: Reduces myocardial function in a concentration dependent manner.
Toxicities: decreases methionine synthase, potentially causing megaloblastic anemia
Minimum Alveolar Concentration (MAC)
Anesthetic potency is described by the minimum alveolar concentration (MAC) required to prevent a response to a surgical incision.
Inhaled anesthetics decrease metabolic activity in the brain. Decreasing cerebral metabolic rate (CMR) reduces blood flow in the brain. Some volatile anesthetics actually increase blood flow in the brain. The net effect of either increased or decreased blood flow is what we are interested in. At 0.5 MAC, the reduction in CMR is greater than the vasodilation caused by the anesthetic, so net cerebral blood flow is decreased, a desirable effect. Increasing blood flow can be undesirable in patients with increased intracranial pressure.
Anesthetics in general either cause increased inhibition by acting on GABA/ K channels, or they can decrease excitation through AMPA/ Kainate/ etc
Three prinicipal components of anesthetics; immobility, amnesia, and consciousness
Stages of general anesthesia
Stage 1-analgesia: the patient experiences analgesia without amnesia. Later on in stage 1, amnesia is produced
Stage 2- excitement: patient appears delirous, may vocalize but is amnestic. Rapid respiration, heart rate and blood pressure increase. Duration and severity of this stage is shortened by rapidly increasing concentration of anesthetic.
Stage 3- surgical anesthesia: slowing of respiration and heart rate and extends to complete cessation of spontaneous respiration (apnea). Planes of stage 3 are described based on ocular movements, eye reflexes, pupil size.
Stage 4- medullary depression: severe depression of CNS, including vasomotor center in medulla and respiratory center in brainstem. Without support, death would ensue.
Major toxicities associated with Anesthetics
Malignant hyperthermia: genetic disorder of skeletal muscle occurs while undergoing general anesthesia. Succinylcholine may trigger it. Consists of muscle rigidity, hyperthermia, tachycardia, hypercapnia, hyperkalemia, acidoses. Rare cause of anesthetic morbidity and mortality. Treatment includes dantrolene (reduces calcium release from sarcoplasmic reticulum). Ryanodine receptor (calcium release channel in SR) mutations associated with disease.
Hepatotoxicity (halothane hepatitis): 1 in 20,000 to 35,000 get this after taking halothane. MOA is unclear but potentially caused by free radicals directly wreaking havoc. Hepatitis following enflurane and isoflurane have rarely been reported.
Donepezil (Aricept), Rivastigmine (Excelon), Galantamine (Razadyne)
Used to treat Alzheimer’s Disease
Does not modify the disease, they only alleviate symtoms
Reversible antagonists of cholinesterases (AD have deficiency of cholinergic neurons in the nucleus basalis of Meynert)
Can treat Behavioral symtoms associated with AD (paranoia, delusional thinking, anxiety, depression)
Also used to treat other neurodegenerative diseases such as dementia with Lewy bodies and vascular dementia
Well tolerated, with most common side effect being GI distress, muscle cramping, abnormal dreams.
Memantine (Nameda)
Adjunct therapy or alternative to cholinesterase inhibitors in Alzheimer’s Disease. Typically added on later in disease progression.
Noncompetitive antagonist of NMDA-type glutamate receptor (interacts with Mg+ binding site). Does not compete with glutamate directly! It interacts with the channel in a voltage-dependent manner. When the channel is depolarized, Mg is kicked out and the channel is open, allowing Memantine to enter.
Has a lower affinity than drugs such as PCP, so doesnt interfere with normal function of NMDA receptors when high concentrations of glutamate are released. Less adverse effects.
Reduces the rate of clinical deterioration in patients with moderate to severe AD. May be beneficial treatment for vascular dementia
Can treat Behavioral symtoms associated with AD (paranoia, delusional thinking, anxiety, depression) but doesn’t treat agitation. To treat agitation, use Risperidone or Olanzapine.
Adverse: headache, dizziness
Excreted in kidneys (in pH dependent manner) and should be reduced in patients with severe renal impairment. Administered orally and not metabolized by CYP450 so not many contraindications. Amantadine, dextromethorphan, and ketamine are all known to act as antagonists at
the NMDA receptor and should not be co
administered to patients receiving
memantine
Also a 5-HT3 antagonist- beneficial for memory
Serotonin Syndrome
Mild to lethal
Delerium, coma, hypertension, tachycardia, hyperreflexia, tremor
TCA, SSRI, SNRI + MOA-I leads to this
Dopaminergic Systems and Relation to Side-Effects
1) Mesolimbic: source of positive symptoms, too much dopamine/ Mesocortical: source of negative symptoms, too little dopamine
2) Nigrostriatal: Substantia nigra to dorsal striatum involved in coordination of voluntary movement (source of EPS through blockage of D2 receptors)
3) Tuberoinfundibular system: HPA axis, when you inhibit D2 receptors, you activate prolactin hormone secretion
4) Medullary-Periventricular: related to the vagas nerve, may be invovled in eating behaviors
5) Incertohypothalamic: hypothalamus and amygdala that have to do with regulating copulation
Neuroleptanalgesia and Neuroleptanesthesia
Neuroleptanalgesia: produce intense analgesia and amnesia. Neuroleptic (droperidol) + analgesic (fentanyl)
Neuroletanesthesia: produces unconciousness. Neuroleptic (droperidol)+ analgesic (fentanyl) + Nitrous oxide
