Dr. Laila M. Matalqah Ph.D. Pharmacology PHARMACOLOGY OF CNS 4 Antidepressant General Pharmacology M212

Definitions Affective disorders - mental illnesses characterized by pathological changes in mood 1. Unipolar disorders Depression –depressed mood Mania – excessive accelerated psychomotoric activity - opposite behavior: enthusiasm, orapid thought and speech patterns, extreme self-confidence, and impaired judgment. 2. Bipolar disorder “cycling mood“ = severe highs (mania event- hypomania) and lows (major depressive episodes) strong genetic background

Depression Mental disorder presents with depressed mood, loss of interest or pleasure, feelings of guilt or low self-worth, disturbed sleep or appetite, low energy, and poor concentration Major Depressive Episode Criteria/Core symptoms Five (or more) of the following symptoms have been present: (1) depressed mood or (2) loss of interest or pleasure must be present with 3 of: significant weight loss /gain fatigue or loss of energy feelings of worthlessness or excessive or inappropriate guilt diminished ability to think or concentrate, or indecisiveness recurrent thoughts of death or suicidal ideation without a specific plan or a suicide attempt (!)

Neurobiological theory of depression 1. Monoamine theory (1965) deficiency of monoamines, such as norepinephrine and serotonin, at certain key sites in the brain. Supported by: pharmacological effects of antidepressants (TCA, MAOI) In the past, medication of hypertension with reserpine induced depression 2. “Receptor theory” the problem is in up-regulation of post-synaptic receptors and alterations in their sensitivity The antidepressant treatment increases the amount of monoamines in CNS and gradually normalize the density/sensitivity of their receptors The precise pathophysiology of depression remains unsolved

Therapy of depression 1. Tricyclic antidepressants (TCA) 2. Selective Serotonin Re-uptake Inhibitors (SSRI) 3. Monoamine oxidase inhibitors (MAOI) Duration of treatment – 6 months after recovery (1st episode), may be even life-long treatment in recurrent depression Non-pharmacological treatment Psychotherapy Light therapy Electroconvulsive therapy (ECT)

Tricyclic Antidepressants (TCAs) Chemical structure: three-ring nucleus – lipophilic nature Principal mechanism of action: 1. Block of re-uptake of monoamine neurotransmitters norepinephrine (NE) and serotonin (5-HT) 2. Block other receptors (outside the CNS) : H1-receptor (histaminic),  -receptors (adrenergic), M-receptors (muscarinic receptors) imipramine

Most important TCAs Imipramine : also used to control bed-wetting in children Desimipramine: demethylated form, the active metabolite of imipramine Amitriptyline : (used also to treat migraine) Nortriptyline: demethylated form, the active metabolite of amitriptyline Clinical use and efficacy is relatively similar within the group The more significant difference is in their adverse effects

Pharmacokinetics Administered orally rapid absorption, extensive first pass effect  low and inconsistent Bioavailability Strong binding to plasma proteins (90-95% bound). wide distribution (high lipophilicity) = large distribution volumes Metabolism in the liver (CYP450) affected by inhibitors and inducers most of these metabolites are active! CYP450 polymorphisms Glucuronidation  inactive metabolites excreted in the urine.

Adverse effects TCA are effective antidepressants their use is complicated by numerous troublesome adverse effects Anticholinergic (atropine-like) due to M-blockade Dry mouth, blurred vision Constipation, urinary retention (more in amitriptyline, less in imipramine) Palpitations, tachycardia Postural (orthostatic) hypotension + reflex tachycardia  -blockade of adrenergic transmission (frequent in elderly) Sedation - H 1 -blockade drowsiness, difficulty in concentration (amitriptyline,) Sexual dysfunction (loss of libido, impaired erection)

Mono-Amino-Oxidase Inhibitors (MAOI) mechanism of action: Inhibition of intracellular enzyme MAO in CNS neurons (= decrease in degradation of norepinephrine, dopamine, and serotonin) when given to normal non-depressed subjects cause euphoria + excitements  risk of abuse! The MAOIs are indicated for depressed patients who are unresponsive or allergic to TCAs or who experience strong anxiety

MAOI drugs Irreversible non-selective inhibitors (hydrazides) long lasting inhibition (up to 1-2 weeks) despite of the elimination rate of a drug phenelzine tranylcypromine Reversible selective Inhibitors of MAO-A (RIMA) moclobemide Note: Reversible inhibitors of MAO-B (e.g. selegiline ) are used in the treatment of Parkinson's disease.

Adverse reactions and toxicity Hypertension Postural hypotension (in up to 1/3 patients) CNS stimulation – tremor, excitement, insomnia, convulsions in overdose. Weight gain (increased appetite) Rare severe hepatotoxicity

Interaction with food Tyramine reaction Tyramine  a natural indirect sympathomimetic produced by fermentation  some food contain high amounts  normally metabolized by MAO in the gut and liver. After MAOI treatment bioavailability of tyramine is significantly higher: pharmacodynamic synergism Tyramine causes the release of large amounts of stored catecholamines from nerve terminals, resulting in what is termed a “hypertensive crisis,”

Interaction with food Tyramine reaction hypertensive crisis: stiff neck, tachycardia, nausea, hypertension, cardiac arrhythmias, seizures, and, possibly, stroke. Dietary restrictions: maturing cheeses, wine, beer, yogurts, bananas meats, chicken liver, pickled or smoked fish This risk is minimal with modern RIMA drugs.

Interaction with drugs 1. Serotonin syndrome (with SSRI, TCA) Hypertension & hypertensive crisis confusion, agitation and excitation, tremor, fever, sweating, nausea, diarrhea, sleep disruption TCA wash-out period (2 weeks) when switching these antidepressants Managment –\ benzodiazepines (lorazepam), supportive care, 5-HT blockers, such as methysergid and propranolol may be given 2. levodopa (catecholamine precursor), sympathomimetics

Selective Serotonin Re-uptake Inhibitors (SSRI) More modern (1 st drug) and safe antidepressants fluoxetine Principal mechanism of action: selective inhibition of 5-HT (serotonin) reuptake Other indications of SSRI: anxiety disorders

Most important SSRI Fluoxetine Fluvoxamine Paroxetine Sertraline Citalopram

Pharmacokinetics Good absorption after oral administration Important biotransformation in the liver By CYP D6 and 2C19 isoforms Some CYP450 inhibitors: Fluoxetine and paroxetine Long half-lives of elimination(s) fluoxetine (T 1/2 =50h) + active metabolite (T 1/2 =240h) Drug interaction based on plasma protein binding and CYP blockade

Adverse effects GIT nausea, vomiting, abdominal cramps, diarrhea relatively frequent, higher doses? Headache Sexual dysfunctions (loss of libido, erectile dysfunction…) Anxiety - an increase in anxiety or agitation during early treatment Sleep disturbances, insomnia and fatigue Serotonin syndrome upon intoxication or drug interactions

Therapy of bipolar disorder Main aim: to eliminate mood episodes maximize adherence to therapy improve functioning of the patients eliminate adverse effects “MOOD STABILIZERS” Lithium Valproate Carbamazepine Lamotrigine Adjunctive agents (antidepressants and benzodiazepines)

Lithium Since indication as a prophylactic treatment in bipolar disorder. Effective also in 60-80% patients with mania or hypomania. Principle mechanism of action Interfer with recycling of second messenger systems (mainly IP3 is depleted) Pharmacokinetics administered orally elimination – 95% in urine only 20% of Li + filtered by GF is excreted (80% reabsorbed)

Lithium – toxicity and adverse reactions Adverse reactions : polyuria and polydipsia, weight gain, GIT disturbances (vomiting, nausea, dyspepsia), alopecia Drug interactions: thiazides – increased Li reabsorption  intoxication Acute intoxication, symptoms: GIT: vomiting, diarrhea CNS: confusion, tremor, ataxia, convulsions, coma. Heart: arrhythmias, hypotension Toxicity of long-term therapy Renal toxicity – the kidney's ability to concentrate the urine is decreased