Summary of Neuropharmacology

Antipsychotic Agents (aka Neuroleptics, Major Tranquilizers)

(1) Typical Antipsychotics

Mechanism: Mesolimbic (midbrain tegmentum) D₂ receptor antagonists. Clinical potency µ plasma level (1:1 relationship)

Side Effects:

Extrapyramidal effects (EPS) - parkinsonian symptoms, akathisia, tardive dyskinesia.

Affected pathway Þ Nigrostriatal pathway

Antiemetic effect - good for nausea!

Antimuscarinic effects - blurred vision, dry mouth, sedation, confusion, inhibition of GI and urinary smooth muscle Þ constipation and urinary retention.

Pituitary effect - Ý prolactin (recall that DA normally blocks prolactin release). Tubero-infundibular pathway

Neuroleptic Malignant Syndrome - antipsychotics OD. Rigidity, autonomic instability, fever, rhabdomyolysis, coma.

Antipsychotic treatment must be stopped!!!

Drugs used for side effects:

Anticholinergic drugs - Benzotropine, Trihexyphenidyl - for EPS (except akathisia = motor restlessness)

b -Blockers - Propranolol - for Akathisia

Bromocryptine - (D₂ agonist) for Neuroleptic Malignant Syndrome

Dantrolene - (Peripheral muscle relaxant) for Neuroleptic Malignant Syndrome

Clinical Use:

Use for positive symptoms of schizophrenia (hallucinations, thought disorders, etc)

Drugs:

Thioridazine - low potency, significant antimuscarinic effects, little EPS

Perphenazine - medium potency, moderate antimuscarinic effects, moderate EPS

Haloperidol - high potency, little antimuscarinic effects, significant EPS
Low-potency antipsychotic drugs are associated with non-neurologic adverse effects (antimuscarinic)
High-potency antipsychotic drugs are associated with neurologic adverse effects (EPS)

(2) Atypical Antipsychotics

Mechanism: 5-HT_2A and D₁ receptor antagonists. No 1:1 relationship.

Side Effects: Some antimuscarinic effects. No EPS side effects!!!

Clinical Use: Use for negative symptoms of schizophrenia

Drugs:

Clozapine - may ameliorate tardive syndromes in some patients

side effect: agranulocytosis

Risperidone - most widely prescribed

Olanzapine

Quietipine

Mood Stabilizing Agents

(1) Lithium

Mechanism: Unclear. May involve: (1) inhibition of inositol monophosphatase (2) modulation of G-protein interactions (3) inhibition of Glycogen Synthase Kinase (GSK) ((1) and (2) influence gene transcription)

Side Effects: Ataxia, tremors, confusion, convulsions.

Clinical: Manic-depressive patients, manic episodes.

(2) Anticonvulsants

Mechanism: Multiple

Side Effects: Multiple

Clinical: Primarily to reduce seizures. May be used in mood disorders.

Drugs:

Carbamazepine - Na⁺ blocker; used for bipolar disease

side effect: agranulocytosis

Valproic acid - enhances action of GABA

side effect: hepatic toxicity

Lamotrigine - inhibits glutamate release, a Na⁺ blocker

Gabapentine - GABA analogue

Antidepressants

(1) Tricyclic Antidepressants (TCA’s)

Mechanism: Inhibition of norepinephrine reuptake. Minor: Inhibition of serotonin reuptake.

Side Effects:

Antimuscarinic - blurred vision, dry mouth, urinary retention, constipation.

Cardiovascular - Ý catecholamine activity Þ cardiotoxicity

Antiadrenergic - Orthostatic hypotension - blockade of a -adrenergic Rs. Most serious problem in elderly!

Antihistamine - Sedation

Clinical: Major depression, some panic disorders.

Drugs: Imipramine - prototype; all TCA's have same efficacy

others include Amitriptyline, Amoxapine, Doxepin, Maprotiline, Protriptyline, and Trimipramine

Desipramine and Nortriptyline are secondary (rather than tertiary) amines and have fewer side effects

(2) Selective Serotonin Reuptake Inhibitors (SSRIs) - atypical antidepressants

Mechanism: Inhibition of serotonin reuptake.

Side Effects: Sexual dysfunction

Clinical: Depression, anorexia nervosa, bulimia nervosa, Obsessive-Compulsive Disorder.

Drugs:

Fluoxetine (Prozac) - can cause Serotonin Syndrome (fatal drug interaction) with MAOIs

Sertraline (Zoloft)

Paroxetine (Paxil)

Citalopram (Celexa)

Fluvoxamine (Luvox) - for Obsessive-Compulsive Disorder

(3) Monoamine Oxidase Inhibitors (MAOIs)

Mechanism: Inhibits breakdown of monoamines (norepinephrine, dopamine, serotonin) by blocking mitochondrial enzyme MAO.

Side Effects: Interaction with Tyramine (in cheese, beer, wine) causes fatal hypertensive crisis. Tyramine, which mimics monoamines in action, is usually broken down by MAO in liver. Clinically not much used anymore.

Clinical: Depression in patients who are unresponsive/allergic to TCAs. Atypical depression. Phobia.

Drugs: All can cause serotonin syndrome

Phenylzine (Nardil)

Tranylcypromine (Parnate)

Isocarboxazid (Marplan)

(4) Mixed Action Antidepressants

Mechanism: Multiple mechanisms

Drug:

Venlafaxine (Effexor) - Blocks serotonin and norepinephrine reuptake

Nefazadone (Serzone) - Blocks serotonin reuptake, and serotonin receptor

Mirtazapine (Remeron) - Blocks a₂ and serotonin receptors

Buproprione (Wellbutrin) - Blocks norepinephrine and dopamine reuptake. No serotonin effects = fewer sexual side-effects. Use in ADHD!!!

Pharmacology of Anxiety Disorders

(1) SSRIs - see above. Doesn’t work for Simple Phobia Disorder. Clinically, #1 choice for Panic Disorder (#2 Benzodiazepines)

(2) Benzodiapzepines

Mechanism: bind to specific, high affinity sites on the cell membrane, which are separate from but adjacent to the receptor for GABA. Upon binding enhance the affinity of the GABA receptor to its neurotransmitter Þ Ý Cl^- ion flow. Long acting metabolites are produced. High margin of safety!!!

Side Effects: Dependence after prolonged use. Drowsiness and confusion are the two most common side effects.

Clinical: Anxiolytics, hypnotics, muscle relaxants, anticonvulsants.

Drugs:

Long Acting:

Diazepam (Valium) - Used for: Anxiety, skeletal muscle spasms, grand mal seziures, EtOH withdrawal

Flurazepam (Dalmane) - Used for: sleep disorders

Chlorodiazepoxide (Librium)

Clonazepam (Klonapin) - Used for: Anxiety, Chronic treatment of epilepsy, low abuse potential

Intermediate Acting:

Alprazolam (Xanax) - Used for: Panic Disorder

Oxazepam (Serax) - Used for: EtOH withdrawal

Short Acting:

Triazolam (Halcion)

Midazolam (Versed)

Antidote for overdose: Flumazenil Þ antagonizes benzodiazepines, and is used in benzodiazepine overdose!!!

(3) Buspirone

Mechanism: Partial agonist at serotonin (5-HT_1A) receptors, on both pre+post synaptic neurons.

Side Effects: None.

Clinical: Anxiolytic with no side effects! #1 choice for General Anxiety Disorder.

Stimulants

all Ý DA (except caffeine), all are addictive

Mechanism: Facilitate transporter mediated catecholamine release and block MAO. Block Na⁺ gradients, thus reversing transporter. Euphoria lasts 4-6 hours. Produce Addiction.

Actions: CNS - DOPAMINE Þ Ý alertness, ß fatigue, ß appetite, Ý resp center, Ý mood, insomnia.

(1) Nicotine - active component in cigarattes

Mechanism of action

(1) Activation Nicotinic acetylcholine receptor - Desensitization (acute activation followed by down regulation)

(2) Ý dopamine release via nicotinic receptors (limbic regions, intimately involved in addictive affects)

(3) Ý adrenaline (norepinephrine and epinephrine); sympathomimetic effects: Ý heart rate, Ý blood pressure.

(4) Activates all levels of the CNS especially cortex

Adverse reactions:

Low doses: nausea, dizziness, general weakness
High Doses: tremors, convulsions

Tobacco Addiction: mild state of euphoria, facilitation of learning, ß weight gain, appetite

Withdrawal symptoms: irritability, Ý appetite, dysphoria, weight gain (similar to cocaine and heroin)

(2) Caffeine - Methylxanthines: caffeine, theophylline and theobromine (in tea)

Mechanism of action:

Blockade of adenosine receptors - responsible for CNS stimulant effects

Inhibition of phosphodiesterase - Ý intracellular cAMP

Mobilization of calcium from cells (ß skeletal contractility)

Pharmacological Properties: stimulation

CNS: alertness, stimulate respiratory center (similar to amphetamines)

Tissue sensitivity: Cortex > brainstem > spinal cord

Potency: Caffeine > theophylline > theobromine

Cardiovascular: tachycardia, arrhythmias (only at high doses because of increased catecholamine release)

Potency: Theophyline > Theobromine > Caffeine

Vascular: ß peripheral vascular resistance (vasodilation) and Ý cerebrovascular resistance (treatment for headaches)

Smooth Muscle Relaxation - bronchi. (Theophylline used in the treatment of bronchial asthma)

Stimulation of Skeletal Muscle - tremors (receptor specific effect)

Diuretic: inhibition of the secretion of antidiuretic hormone (ADH)

GI: stimulates GI motility, erode intestinal lining Þ ulcers (stimulate acid secretion)

Medical Use: asthma (vasodilation of smooth muscle), apnea, relief of headache (Ý resistance in cerebrovascular circulation)

Tolerance: Tolerance occurs in the Cardiovascular system FIRST!!! Occurs later on in the CNS. Contrast this to cocaine, amphetamines where the CNS is the first to develop tolerance then the CV system (therefore with cocaine, amphetamines you are at a greater risk of vascular stroke and heart attack with chronic usage.

Adverse Reactions: nervousness, anxiety, irritability, muscle twitching, insomnia, Ý temp, panic attacks

Withdrawal symptoms: Mimic flu: ache in joints, headache, fatigue, dysphoric, irritable, nausea

(3) Amphetamines and Methylphenidate (ritalin)

Mechanism:

facilitate Norepinephrine release

block MAO Þ Ý Dopamine, Norepinephrine, Serotonin

Actions:

CNS Dopamine release Þ Stimulates entire cerebrospinal axis: Ý alertness, ß fatigue, ß appetite, Ý medullary respiratory center, elevates mood (but are NOT antidepressants), insomnia.

Sympathetic nervous system Indirect stimulation of adrenergic system via norepinephrine release.

Clinical Usage:

Narcolepsy (methylphenidate)
hyperkinetic syndromes (iattention deficit disorder), short term weight control.

Adverse effects:

Cardiovascular: Ý norepinephrine release Þ activation of a and b receptors Þ hypertensive crisis (Ý BP, Ý HR)

CNS: Dopamine release: confusion, anxiety, insomnia, psychotic episodes

Withdrawal: Withdrawal symptoms are opposite of what drug actions

(4) Cocaine

Mechanism:

Action potential mediated blockade of norepinephrine, serotonin, and dopamine reuptake into presynaptic terminals

Ý dopamine in limbic system Þ euphoria for 1-1.5 hrs

Note: Blocking AP works for Cocaine but not amphetamines.

Actions:

CNS:

Low doses: stimulation of cortex and brainstem: Ý mental awareness, feeling of well-being, euophoria, hallucinations, delusions, paranoia, Ý motor activity

High doses: tremors, convulsions, respiratory and vasomotor depression.

Sympathetic nervous system: potentiates action of Norepinephrine: Tachycardia, HTN, Pupillary dilation, peripheral vasoconstriction

Clinical Use:

Surface anesthesia (blocks voltage-gated Na⁺ channels)

vasoconstriction

Adverse effects: anxiety, depression, arrhythmias