Antidepressants Pharmacology Lecture Notes PDF

1 PM 719 Pharmacology II Chapter 30 Antidepressants Lecture Notes (LN) Major depressive disorder (MDD) depressed mood most of the time for at least two weeks loss of interest or pleasure in most activities disturbances in sleep, appetite along with deficits in cogn...

1 PM 719 Pharmacology II Chapter 30 Antidepressants Lecture Notes (LN) Major depressive disorder (MDD) depressed mood most of the time for at least two weeks loss of interest or pleasure in most activities disturbances in sleep, appetite along with deficits in cognition and energy Neuropathic Hypothesis of MDD Brain derived neurotrophic factor (BDNF) helps regulate neural plasticity, resilience and neurogenesis Loss of BDNF is associated with MDD Antidepressant drugs may promote neurogenesis and synaptic connectivity Monoamine Hypothesis of MDD (Biogenic Amine Hypothesis) Loss of 5-HT and/or DA leads to MDD Reserpine which depletes monoamines leads to depression All available antidepressant drugs effect the monoamine system Neuroendocrine Hypothesis Alterations in the hypothalamus-pituitary axis (HPA) may contribute to MDD MDD is associated with elevated cortisol levels Exogenous glucocorticoids are associated with mood symptoms and cognitive deficits similar to those seen in MDD Up to 25% of MDD patients have depressed thyroid function Basic Pharmacology of Antidepressants Selective Serotonin Reuptake Inhibitors (SSRIs) drugs inhibit the serotonin transporter (SERT) Six available in the US fluoxetine, sertraline, citalopram, paroxetine, fluvoxamine, escitalopram Serotonin-Norepinephrine Reuptake Inhibitors (1) Selective Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) SNRIs include venlafaxine, desvenlafaxine, duloxetine All selectively inhibit NE and 5-HT reuptake pumps  2 (2) Tricyclic Antidepressants (TCAs) Nine available, all with a tricyclic core Largely replaced by the SSRIs and others due to many ADRs and potential for lethal toxicity (cardiac) in overdose (3) 5-HT2 Antagonists Two in this class, trazadone and nefazodone (4) Tetracyclic and Unicyclic Antidepressants bupropion, mirtazapine, amoxapine, maprotiline (5) Monoamine Oxidase Inhibitors (MAOIs) Seldom used due to potential for ADRs when taken with certain foods phenelzine, isocarbodazid, tranylcypromine, selegiline, moclobemide Pharmacokinetics SSRIs (1) Fluoxetine differs from other SSRIs (2) metabolized to active metabolite, norfluoxetine (3) SSRI combined with an MAO inhibitor can cause serotonin syndrome Serotonin Norepinephrine Reuptake Inhibitors (1) Selectives (a) venlafaxine extensively metabolized in the liver (b) most tightly bound to protein (albumin) (c) once daily dosing for most (2) TCAs (a) dosed once per day, given at night due to sedative effects (b) serum levels useful for predicting toxicity and efficacy (unlike most other antidepressants) 5-HT2 Antagonists (a) extensively bound to proteins (b) trazodone in lower doses as a hypnotic than used for MDD Tetracyclic and Unicyclic Agents (a) amoxapine has an active metabolite which is a potent D2 receptor blocker which gives it antipsychotic effects  3 MAOIs (a) dosed in patches which reduces first pass effect and decreases food interactions Pharmacodynamcis Mechanisms used to increased neurotransmitters in the CNS (a) block reuptake (b) inhibit MAO (c) binding presynaptic autoreceptors (mirtazapine) (d) binding specific postsynaptic receptors like 5HT2 antagonists (mirtazapine) SSRIs (a) SSRIs bind and allosterically inhibit the transporter (b) at therapeutic doses about 80% of the transporters are inhibited (c) SSRI binding is specific for the serotonin transporter Drugs that Block both Serotonin and NE transporters (1) Serotonin-Norepinephrine Reuptake Inhibitors (a) affinity of most seem to be greater for serotonin over NE (b) drugs are better tolerated over the TCAs because they have no effect on histamine, alpha adrenergic blocking, and anticholinergic effects (2) TCAs (a) variable affinity for 5HT and NE reuptake pumps (b) common ADRs include dry mouth, constipation due to antimuscarinic actions (c) also potent antagonists of histamine H1 receptors (d) block of alpha adrenergics causes orthostatic effects 5HT2 Antagonists (a) nefazodone and trazodone block this receptor (b) block 5HT2 = antianxiety, antipsychotic, antidepressant (c) agonists at 5HT2A receptor with LSD = hallucinogenic and anxiogenic (d) mescaline is a 5HT2A agonist (e) nefazodone is a potent inhibitor of 5HT2A receptor as is trazodone Tetracyclic and Monocyclic Antidepressants (a) bupropion= presynaptic release of catecholamines (b) mirtazapine = antagonist of presynaptic alpha 2 autoreceptors  4 and enhances the release of NE and 5HT also is an antagonist at 5HT2A receptors also potent H1 antagonist (has sedative effects) (c) amoxapine and maprotiline actions similar to TCAs Both inhibit reuptake of NE and 5HT Both have anticholinergic properties Monoamine Oxidase Inhibitors (MAOIs) (a) MAO-A substrates are 5HT, EPI, NE, DA MAO-B substrates are DA and some 5HT (b) phenelzine and tranylcypromine are non-selective MAO inhibitors (c) selegiline is a irreversible MAO B inhibitor but at higher doses it becomes nonselective. Used in Parkinsonism Clinical Pharmacology (a) montherapy often doesn’t work and more than one drug required (b) The FDA requires a warning on all antidepressants that suicide rates increase compared to control in patients under 25 years (c) Drugs may take up to 8-12 weeks before drug effect kicks in ADRs SSRIs (a) Increased 5-HT levels in the gut causes nausea, GI upset, diarrhea, (b) Increased 5-HT levels in the spinal cord leads to sexual dysfunction 30-40% of patients report loss of libido (c) increased 5-HT levels increase incidence of headaches, insomnia, hypersomnia Serontonin-Norepinephrine Reuptake Inhibitors and the TCAs (a) When they increase 5-HT, same as SSRIs as above (b) Increased NE causes increase blood pressure, heart rate, (c) Increased NE in CNS causes insomnia, anxiety, agitation (d) For TCAs the most common ADR is anticholinergic effects dry mouth, constipation, blurred vision, confusion (e) TCAs block alpha receptors and this results in orthostatic hypotension (f) TCAs block H1 receptors and this causes weight gain and sedation (g) TCAs have adverse sexual effects 5-HT2 Antagonists (a) Most common are sedation and GI disurbaces (b) Trazodone in fact used to treat insomnia  5 Tetracyclics and Unicyclics (a) amoxapine associated with Parkinsonism due to D2 blocking Monoamine Oxidase Inhibitors (a) weight gain and orthostatic hypotension are most common ADRs (b) irreversibles have highest rate of sexual dysfunction of all the antidepressants Overdose (a) suicide is a major consequence of MDD (b) TCA causes cardiac toxicity with death resulting (this has helped lead to their limited use) (c) A seven day supply of imipramine (1500 mg) can be lethal (d) Most SSRIs are much safer, with overdose fatality very rare Drug Interactions SSRIs (a) paroxetine and fluoxetine are potent CYP 2D6 inhibitors TCAs are substrates for 2D6, TCA levels rise to toxic levels (b) fluvoxamine inhibits 3A4, diltiazem is substrate for 3A4 which causes rise in diltiazem levels and bradycardia or hypotention Selective Serotonin Norepinephrine Reuptake Inhibitors and the TCAs (a) SNRIs are contraindicated with MAOs (serotonin syndrome) (b) TCAs are substrates for 2D6, about 7% Caucasians have poly- morphism for slow metabolism of TCAs 5-HT2 Antagonists (a) triazolam levels increased because nefazodone inhibits CYP 3A4 (b) ketoconazole inhibits CYP 3A4 which raises trazodone levels Tetracyclic and Unicyclic Antidepressants (a) bupropion should be avoided in patients on MAOIs MAOIs Two types (classes) of drug interactions (1) Pharmacodynamic interactions (a) MAOIs plus SSRIs, or SNRIs, or most TCAs or meperidine can cause a “Serotonin Syndrome” (2) Food interactions (a) MAOIs plus tyramine in the diet (beer, cheese etc etc) increases NE levels to toxic levels  6 (b) can lead to malignant hypertension Chapter 30 Drugs Required in Bold including all those in the text above. (1) SSRIs fluoxetine block re-uptake 5HT, little to no NE effect citalopram escitalopram paroxetine sertraline (2) SNRIs duloxetine block re-uptake of both 5HT and NE venlafexin (3) TCAs imipramine mixed and variable block of 5HT and/or NE re-uptake amitriptyline………for many years the most widey used drug in podiatric medicine to treat diabetic peripheral neuropathy, replaced today by what drug? doxepin nortriptyline (4) 5-HT Antagonists trazadone block 5HT2A receptors nefazodone (5) Tetracyclics and Unicyclics bupropion variable actions at DA, NE and 5HT receptors amoxapine maprotiline mirtazapine (6) MAOIs phenelzine  7 selegiline PM 719 Pharmacology Chap 29 Antipsychotic Drugs BRIEF SUMMARY The operative theory for the cause of schizophrenia, bipolar disorder, and psychosis associated with dementia etc. is that certain CNS neurotransmitters (NT) are elevated in the CNS. Reducing the activity of these NTs is a major goal in drug therapy in patients with these psychotic conditions. The NTs which are in excess vary but include NE, 5HT, and DA. The drugs used in these psychotic conditions act by attaching to and blocking a specific receptor for one or more of the NTs just listed in the previous sentence. First Generation Antipsychotics D2 >>5HT (stronger block of dopamine receptors compared to 5HT (serotonin) receptors). chlorpromazine thiothixene fluphenazine haloperidol thioridazine Second Generation Antipsychotics 5HT > D2 (stronger block of 5HT receptors compared to dopamine receptors). aripiprazole lurasidone ziprasidone brexpiprazole olanzapine cariprazine quetiapine clozapine risperidone NOTE: Focus on the drugs in bold.