TCAs: THE MULTIPLE EFFECTS OF A "DIRTY" DRUG FAMILY TCA REUPTAKE BLOCKER RECEPTOR ANTAGONIST NE 5-HT DA à1 à2 HIST1 Musc1 D2 3ø IMIPRAMINE + + 0 ++ 0 + ++ 0 AMITRIPTYLINE + ++ 0 +++ + +++ ++++ 0 CLOMIPRAMINE + +++ 0 ++ 0 + ++ 0 DOXEPIN ++ + 0 ++ 0 +++ ++ 0 AMOXAPINE ++ 0 0 ++ + + 0 2ø DESIPRAMINE +++ 0 0 + 0 0 + 0 NORTRIPTYLINE ++ + 0 + 0 + ++ 0 TRIMIPRAMINE + 0 0 ++ + +++ ++ + PROTRIPTYLINE ++ 0 0 + 0 + ++ 0 MAPROTILINE ++ 0 0 + 0 ++ + 0 TCA PHARMACOKINETICS: ROUTE OF ADMINISTRATION: p.o. PEAK BLOOD LEVELS: 2 - 6 hrs t1/2: around 24 hrs, so once-daily administration CLEARANCE: In liver METABOLIC PATHWAY: 3øTCA VIA DEMETHYLATION 2ø ACTIVE METABOLITE VIA P450s ACTIVE METABOLITE GLUCURONIDATION URINARY EXCRETION INDIVIDUAL DIFFERENCES: There is a 30-fold range in metabolic rates: some 10% are "slow hydroxylators" Elderly are especially likely to metabolize slowly CLINICAL INDICATIONS: No clear difference BETWEEN compounds in clinical efficacy against major depression! All TCAs take some 2+ weeks to achieve their antidepressive effect! Some consider major depression with melancholia to respond best to TCAs OBSESSIVE-COMPULSIVE DISORDER: Only clomipramine is effective ENURESIS - BED-WETTING: Responds well to imipramine, other 3ø TCAs PANIC DISORDERS: appear to respond ADHD MAY BENEFIT INSOMNIA, BULEMIA, NARCOLEPSY, CHRONIC PAIN MAY ALSO BENEFIT TCA SIDE EFFECTS: PROPERTY SIDE EFFECT MUSCARINIC BLOCKADE Blurred vision Dry mouth Tachycardia Constipation Urinary retention Cognitive dysfunction à1 BLOCKADE Postural hypotension Dizziness Drowsiness à2 BLOCKADE blockade of antihypertensives HISTAMINE BLOCKADE Sedation Weight gain DOPEY, DROWSY, DISORIENTED: Immediate effects of all TCAs, worst in the 3ø These effects do supposedly show tolerance Explain TCA efficacy in insomnia CARDIOTOXICITY: TCAs can induce potentially fatal arythmias at near-therapeutic doses: Thus have LOW therapeutic index One-week supply can be fatal if taken all at once Biiig problem in drugs used to treat suicidal tendencies! TCA DRUG INTERACTIONS: The 3ø TCAs potentiate alcohol effects Prozac, many neuroleptics reduce P450 metabolism of TCAs, to dangerous levels! Combinations of MAO inhibitors and TCAs are potentially fatal. MONOAMINE OXIDASE INHIBITORS (MAOIs) DEVELOPMENT: In the late 1950s, these drugs grew out of the recognition of an unexpected mood-elevating effect of the anti-tubercular drug IPRONIAZID ABOUT MAO: THERE ARE TWO ISOZYMES: MAO-A AND MAO-B MAO-B more common in: 1. The serotonin system 2. The striatal dopamine system DIFFERENT MAOIs AFFECT THE TWO ISOZYMES DIFFERENTLY CLASSIFICATION OF MAOIs BY STRUCTURE, SELECTIVITY AND REVERSIBILITY: The early MAOIs were hydrazines and irreversible "suicide" inhibitors of the MAOs DRUG HYDRAZINE? SELECTIVE? REVERSIBLE? PHENELZINE YES NO NO ISOCARBOXAZID YES NO NO TRANYLCYPROMINE NO NO NO SELEGILINE NO YES; MAO-B NO MOCLOBEMIDE NO YES; MAO-A YES BROFAROMINE NO YES; MAO-A YES INDICATIONS: Similar to TCAs, probably as efficacious Like TCAs, take several weeks to achieve antidepressive effects SIDE EFFECTS OF MAOIs: These compounds, especially the irreversible MAOIs, have potentially severe side effects, including: Dizziness Orthostatic Hypotension Sexual dysfunction, esp. anorgasmia Insomnia Weight Gain Hepatotoxicity Vitamin B deficiency Myoclonic jerks Dietary tyramine (in cheese, for example) metabolism is blocked; eating high-tyrosine foods can produce headache, hypertension, even stroke DRUG INTERACTIONS: Severe, especially with compounds increasing anything metabolized by MAO, such as many stimulants, TCAs and specific serotonin reuptake inhibitors such as SOME INTERESTING MAOIs: SELEGILINE (DEPRYNYL): MAO-B selectivity AT LOW DOSES provides benefit for treatment of Parkinson's Under active investigation for apparent ability to prolong life span, AND the span of sexual activity in males MOCLOBEMIDE: The MAOI of the future, because it binds with low affinity to MAO-A, easily displaced by tyramine, reversible, has far fewer side-effects SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs) DEVELOPMENT: Early 1970s: Eli Lilly begins search for anti-depressants without TCA side-effects Finds Fluoxetine=Prozac, approved by FDA in 1987 A specific serotonin reuptake blocker, not active against other (KNOWN) targets, hence far fewer side effects Sweeps to commanding heights of the psychiatric drug business by 1993 INDICATIONS: DEPRESSION OBSESSIVE-COMPULSIVE DISORDER PANIC DISORDER WEIGHT CONTROL!! BULIMIA IMPULSIVITY, ANGER, AGGRESSION WHATEVER AILS YOU! SIDE EFFECTS: CENTRAL SEROTONIN SYNDROME: Diarrhea, cramps Mania/delirium Fever Blood pressure, heart rate increased CAN result in death RARE, except when taken with MAOIs SEXUAL DSYFUNCTION (ANORGASMIA): Relatively common side-effect Can be used to treat premature ejaculation in males AGITATION, MOTOR RESTLESSNESS: mild but common side-effect SUICIDE: Brief outbreak of media hysteria about Prozac causing suicide But suicide and depression are linked AND it is well-known that as profound depression lifts, some find the energy to get up and kill themselves Link has not proved out epidemiologically DRUG INTERACTIONS: Not a problem except with MAOIs