Antidepressant drugs
Mood DisorderThe most common mood disorders are: Major depression (unipolar depression). Manic-depressive illness (bipolar disorder). Major depression and bipolar disorder are pervasive mood altering illnesses affecting energy, sleep, appetite, libido and the ability to function.
Introduction
The symptoms of depression are: Intense feelings of sadness. Hopelessness. Despair. The inability to experience pleasure in usual activities. Mania is characterized by the opposite behavior, that is: enthusiasm rapid thought and speech patterns extreme self-confidence impaired judgment the brain. .Biogenic amine Theory
Depression is due to a deficiency of monoamines such as norepinephrine and serotonin at certain key sites in the brain. Mania is caused by an over production of these neurotransmitters. It is not known which of these neurochemical systems is most responsible for the antidepressant activity All clinically useful antidepressant drugs potentiate, either directly or indirectly, the actions of norepinephrine, dopamine, and/or serotonin in the brain.Antidepressant Drugs
Tricyclic / polycyclic antidepressants (TCA). Selective serotonin-reuptake inhibitors (SSRI). Monoamine oxidase inhibitors (MAOI). Drugs used to treat mania: Lithium salts.Tricyclic/polycyclic ntidepressants
older tricyclic antidepressants Imipramine (the prototype). Amitriptyline . desipramine . Nortriptyline (a demethylated derivative of imipramine). Protriptyline . Doxepin. Amoxapine. Maprotiline second generationTricyclics/Polycyclics
Examples: Amitriptyline, imipramineMode of Action:Inhibit NE, 5-HT, DO re-uptakeAlso have muscarinic and adrenergic effectsThis is manifested in terms of side effectsClinical Effects: Elevate mood, mental alertness, reduces morbid preoccupation in 50 – 70% of patients
Mode of action
Inhibition of neurotransmitter uptake: TCAs inhibit the neuronal re-uptake of norepinephrine, and serotonin into presynaptic nerve terminals. It has been suggested that monoamine receptor densities in the brain may change over a 2 to 4 week period with drug use and may be important in the onset of activity. 2. Blocking of receptors: TCAs block serotonergic, α1-adrenergic, histamine, and muscarinic receptors.Mode of action
ActionsTCAs elevate mood, improve mental alertness, increase physical activity, and reduce morbid preoccupation in 50 to 70% of individuals with major depression. The onset of the mood-elevation is slow, requiring 2 weeks or longer. These drugs do not produce CNS stimulation or mood elevation in normal individuals.
Actions
Tolerance to the anticholinergic properties of the TCAs develops within a short time. Some tolerance to the autonomic effects of TCAs develops. Physical and psychological dependence have been reported. The drugs can be used for prolonged treatment of depression without loss of effectiveness.Therapeutic uses
severe major depression. Some panic disorders. Imipramine has been used to control bed-wetting in children (older than 6 years) by causing contraction of the internal sphincter of the bladder. Note: At present it is used cautiously, because of the inducement of cardiac arrhythmias and other serious cardiovascular problems.Adverse effects
Antimuscarinic effects Cardiovascular Orthostatic hypotension Sedation Precautions: The tricyclic antidepressants should be used with caution in manic-depressive patients. 6. The tricyclic antidepressants have a narrow therapeutic index; for example, 5 to 6 times the maximal daily dose of imipramine can be lethal. Depressed patients who are suicidal should be given only limited quantities of these drugs and should be monitored closely.SELECTIVE SEROTONIN-REUPTAKE INHIBITORS (SSRI Inhibitors)
Examples:Fluoxetine, Zoloft, PaxilMode of Action:Selectively block 5-HT reuptakeClinical Effects:Effective in treating depression, Obsessive –Compulsive Disorder Fewer side effects than TCA’s.
(SSRI Inhibitors)
The SSRI are a new group of chemically antidepressant drugs that specifically inhibit serotonin reuptake. This contrasts with the tricyclic and block muscarinic, Hl-histaminic and α-adrenergic receptors. Compared with tricyclic antidepressants, the SSRIs cause fewer anticholinergic effects and lower cardiotoxicity.Fluoxetine
It is the prototype of SSRI. Fluoxetine is as effective in the treatment of major depression as tricyclic antidepressants. The drug is free of most of the troubling side effects of tricyclic antidepressants, including anti- cholinergic effects, orthostatic hypotension, and weight gain. Fluoxetine is preferred over tricyclic antidepressantsTherapeutic uses
In depression, where it is as effective as the tricyclic antidepressants. Fluoxetine is effective in treating obsessive-compulsive disorder. The drug has been used for a variety of other indications, including anorexia nervosa, panic disorder, pain associated with diabetic neuropathy, and for pre- menstrual syndrome.Adverse affects:
Gastrointestinal symptoms. Sleep disturbance (insomnia and somnolence ) sexual dysfunction, anxiety (acutely), insomnia, tremor. Overdoses of fluoxetine do not cause cardiac arrhythmias but can cause seizures. For example, in a report of patients who took an overdose of fluoxetine (up to 1200 mg compared with 20 mg/day as a therapeutic dose) about half of the patients had no symptoms.MAO Inhibitors
Examples: Phenylzine, isocarboxazide Mode of Action of MAO enzyme : MAO inactivates excess NE, DO, 5-HT Inhibitors increase the amounts of these neurotranmitters Physiological Effects: DepressionMONOAMINE OXIDASE INHIBITORS
(MAO) is a mitochondrial enzyme found in neural and other tissues, such as the gut and liver.
MONOAMINE OXIDASE INHIBITORS
The MAO inhibitors may irreversibly or reversibly inactivate the enzyme, permitting neurotransmitter molecules to escape degradation and therefore to both accumulate within the presynaptic neuron and to leak into the synaptic space. This causes activation of norepinephrine and serotonin receptors, and may be responsible for the antidepressant action of these drugs.MONOAMINE OXIDASE INHIBITORS
Phenelzine. Isocarboxazid. tranylcypromine,. Use of MAO inhibitors is now limited because of the complicated dietary restrictions required of patients taking MAO inhibitors.Receptor
MAOIncreased NT
Mechanisms of Action of MAOI
Dopamine 5-HT NE
MAOI
-
Dopa
Mode of action
MAOI form stable complexes with the enzyme(MAO), causing irreversible inactivation. This results in increased stores of norepinephrine, serotonin and dopamine within the neuron, and subsequent diffusion of excess neurotransmitter into the synaptic space. These drugs inhibit not only MAO in brain, but oxidases that catalyze oxidative deamination of drugs and potentially toxic substances, such as tyramine, which is found in certain foods. The MAO inhibitors therefore show a high incidence of drug-drug and drug- food interactions.
Therapeutic uses
Depressed patients who are unresponsive or allergic to tricyclic antidepressants or who experience strong anxiety. Patients with low psychomotor activity may benefit from the stimulant properties of MAO inhibitors. Treatment of phobic states. Atypical depression, may respond to MAOIs. Atypical depression is characterized by labile mood, rejection sensitivity and appetite disorders.Adverse effects
Tyramine, contained in certain foods, such as aged cheeses, chicken liver, beer, and red wines, is normally inactivated by MAO in the gut. Individuals receiving a MAO inhibitor are unable to degrade tyramine obtained from the diet. Tyramine causes the release of large amounts of stored catecholamines from nerve terminals, resulting in headache, tachycardia, nausea, hypertension, cardiac arrhythmias, and stroke.Lithium Salts
Mode of Action: Affects inositol triphosphate (IP3), blocks Na+ channels Clinical Effects: Treatment of manic/depressive patients VERY TOXICLithium salts
Clinical uses Used prophylactically in treating manic-depressive patients . Treatment of manic episodes. Effective in treating 60 to 80% of patients exhibiting mania and hypomania.Lithium salts
Mechanism of action Although many cellular processes are altered by treatment with lithium salts, the mode of action is unknown. It is currently proposed that Lithium acts by altering the cellular concentration of the second messenger, inositol triphosphate (IP3)Lithium salts
Pharmacokinetic Lithium is given orally. The ion is excreted by the kidney. Lithium salts are very toxic. Their safety factor and therapeutic index are extremely low--comparable to those of digitalis.