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)
Drugs used for 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!!!
- 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
- Use for positive symptoms of schizophrenia (hallucinations, thought disorders, etc)
(2) Atypical Antipsychotics
Mechanism: 5-HT2A 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
- 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)
- Clozapine - may ameliorate tardive syndromes in some patients
- side effect: agranulocytosis
- Risperidone - most widely prescribed
Mood Stabilizing Agents
Side Effects: Multiple
Clinical: Primarily to reduce seizures. May be used in mood disorders.
- 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.
- 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
(1) Tricyclic Antidepressants (TCA’s)
Mechanism: Inhibition of norepinephrine reuptake. Minor: Inhibition of serotonin reuptake.
Clinical: Major depression, some panic disorders.
Drugs: Imipramine - prototype; all TCA's have same efficacy
- 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
(2) Selective Serotonin Reuptake Inhibitors (SSRIs) - atypical antidepressants
- others include Amitriptyline, Amoxapine, Doxepin, Maprotiline, Protriptyline, and Trimipramine
- Desipramine and Nortriptyline are secondary (rather than tertiary) amines and have fewer side effects
(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
- Mechanism: Inhibition of serotonin reuptake.
- Side Effects: Sexual dysfunction
- Clinical: Depression, anorexia nervosa, bulimia nervosa, Obsessive-Compulsive Disorder.
- Fluoxetine (Prozac) - can cause Serotonin Syndrome (fatal drug interaction) with MAOIs
- Sertraline (Zoloft)
- Paroxetine (Paxil)
- Citalopram (Celexa)
- Fluvoxamine (Luvox) - for Obsessive-Compulsive Disorder
(4) Mixed Action Antidepressants
- Phenylzine (Nardil)
- Tranylcypromine (Parnate)
- Isocarboxazid (Marplan)
- Mechanism: Multiple mechanisms
- 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)
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.
Antidote for overdose: Flumazenil Þ antagonizes benzodiazepines, and is used in benzodiazepine overdose!!!
Mechanism: Partial agonist at serotonin (5-HT1A) receptors, on both pre+post synaptic neurons.
Side Effects: None.
Clinical: Anxiolytic with no side effects! #1 choice for General Anxiety Disorder.
- 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)
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
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
- Mechanism of action
- (1) Activation Nicotinic acetylcholine receptor - Desensitization (acute activation followed by down regulation)
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)
- Low doses: nausea, dizziness, general weakness
- High Doses: tremors, convulsions
Ý intracellular cAMP
Mobilization of calcium from cells (ß skeletal contractility)
Pharmacological Properties: stimulation
- Mechanism of action:
- Blockade of adenosine receptors - responsible for CNS stimulant effects
- Inhibition of phosphodiesterase -
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)
- 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
Þ Ý Dopamine, Norepinephrine, Serotonin
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.
- facilitate Norepinephrine release
- block MAO
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
- Narcolepsy (methylphenidate)
- hyperkinetic syndromes (iattention deficit disorder), short term weight control.
Ý dopamine in limbic system Þ euphoria for 1-1.5 hrs
Note: Blocking AP works for Cocaine but not amphetamines.
- Action potential mediated blockade of norepinephrine, serotonin, and dopamine reuptake into presynaptic terminals
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
- Low doses: stimulation of cortex and brainstem:
Adverse effects: anxiety, depression, arrhythmias
- Surface anesthesia (blocks voltage-gated Na+ channels)