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Antidepressant
Antidepressant SSRI Fluoxetine, Sertraline, Paroxetine, Fluvoxamine, Citalopram, Escitalopram MOA inhibit allosterically the Serotonin reuptake transporter (SERT) by binding to the receptor at a site other than the active binding site no effects on other receptors (adrenergic, muscarinic, histamine) Highly selective blockade of serotonin transporter (SERT) Fluoxetine is notable for the long half-life of its active metabolite, norfluoxetine (79 days at steady state) little effect on norepinephrine transporter (NET) Safety & Clinical Indications Greater safety overdose, relative lack of cardiovascular and anticholinergic effects, and convenience because dosage titration is often unnecessary Adverse effect Gastrointestinal (GI) distress and sexual dysfunction, but the drugs differ in their degree of risk for activation and insomnia or mild sedation fluoxetine most likely to be activating, whereas paroxetine and fluvoxamine are likely to be the least activating Extrapyramidal- like movement disorders delayed ejaculation in men and anorgasmia DISCONTINUATION SYNDROME: dizziness, problems with balance, !insomnia, fatigue, nausea, irritability, anxiety/ agitation, mild !shocklike sensations and headache SEROTONIN SYNDROME: Triad of mental, autonomic and !neurological disoders Anticholinergic, sedation, hypertension (venlafaxine) sustained increased diastolic pressure at higher doses DISCONTINUATION SYNDROME SEROTONIN SYNDROME Drug-drug interaction CYP inhibition (fluoxetine 2D6, 3A4; fluvoxamine 1A2; paroxetine 2D6)

Major depression, anxiety disorders panic disorder! obsessive-compulsive disorder post-traumatic stress disorder perimenopausal vasomotor symptoms eating disorder (bulimia)

SNRI Duloxetine Venlafaxine

Moderately selective blockade of NET and SERT

Major depression, chronic pain disorders fibromyalgia, perimenopausal symptoms

Interactions: Some CYP2D6 inhibition (duloxetine, desvenlafaxine) Duloxetine is a moderate inhibitor of CYP2D6 (TCAs); Do not use with MAOIs (Serotonin Syndrome) TCA levels may rise when combined with CYP2D6 inhibitors; TCA and Antihypertensives (exacerbation of orthostatic hypotension) metabolized by 2 major routes: transformation of the tricyclic nucleus and alteration of the aliphatic side chain.

TCA Imipramine

Mixed and variable blockade of NET and SERT block the reuptake of norepinephrine and to some extent serotonin (5-HT), but also have prominent antagonistic effects on muscarinic, histaminic and adrenergic receptors

Major depression not responsive to other drugs chronic pain disorders incontinence obsessive-compulsive disorder (clomipramine)

Anticholinergic, -blocking effects, sedation, weight gain, arrhythmias, and seizures in overdose Initial dose- sedation, anticholinergic effects and orthostatic hypotension. Maintenance therapy- weight gain is the most common; often responsible for discontinuation of therapy DISCONTINUATION SYNDROME

5-HT2 Antagonist Nefazodone Trazodone

Inhibition of 5-HT2A receptor nefazodone also blocks SERT weakly Trazodone forms a metabolite (m-cpp) that blocks 5-HT2A,2C receptors

Major depression sedation and hypnosis (trazodone)

Modest - and H1-receptor blockade (trazodone) initial sedation and orthostatic hypotension Nefazodone can cause lifethreatening hepatic failure 5- HT-2A blocking effect is responsible for nefazodone not causing sexual dysfunction. Trazodone- sedative and orthostatic hypotensive effects priapism

Nefazodone inhibits CYP3A4 nefazodone with CYP3A4dependent drugs (triazolam, simvastatin)

extensive hepatic metabolism

Uni/Tetracyclic Antidepressant UnicyclicBupropion; TetracyclicMirtazapine, Amoxapine, Maprotiline

ncreased norepinephrine and dopamine activity (bupropion) NET > SERT inhibition (amoxapine, maprotiline) increased release of norepinephrine, 5-HT (mirtazapine) Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine, serotonin and dopamine.

Major depression smoking cessation (bupropion)! sedation (mirtazapine)! amoxapine and maprotiline rarely used

Lowers seizure threshold (amoxapine, bupropion); sedation and weight gain (mirtazepine)

CYP2D6 inhibitor (bupropion)

adjunct to SSRIs to treat the GI and sexual dysfunction effects

Bupropion: occasional agitation, insomnia and anorexia.

Bupropion is metabolized by CYP2B6- metabolism can be altered by drugs which are also a substrate of CYP2B6 (cyclophosphomide); Mirtazapine is a substrate of CYP 2D6, 3A4 and 1A2 Hypertensive crisis with tyramine, other indirect sympathomimetics! serotonin syndrome with serotonergic agents, meperidine MAOIs and serotonergic agents (SSRIs, SNRIs, some TCAs)SEROTONERGIC SYNDROME; MAOIs and tyramine in diet

Mirtazapine: serotonin and norepinephrine agonist effects coupled with postsynaptic blockade of 5- HT-2 and 5- HT-3 receptors MAOI Phenelzine ! Tranylcypromine Selegiline MAO-A - primarily responsible for NEP, serotonin, and tyramine metabolism. MAO-B- more selective for dopamine Drug of Choice: SERTRALINE 250 mg Blockade of MAO-A and MAO-B (phenelzine, nonselective) MAO-B irreversible selective MAO-B inhibition (low- dose selegiline) Major depression unresponsive to other drugs

sedation and weight gain

Hypotension, insomnia orthostasis, weight gain, dry mouth, insomnia and sexual dysfunction DISCONTINUATION SYNDROME

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All SSRIs have the same efficacy and safety profile Drug Interaction: Fluoxetine, sertraline, paroxetine and fluvoxamine are inhibitors of !cytochrome P-450 (CYP-450) isoenzymes; Citalopram and Escitalopram do not hace significant effects on p-450 isoenzymes o Paroxetine and Fluoxetine (2D6 Inhibitors) with TCAs (2D6 substrate)!o Fluvoxamine (3A4 Inhibitor) with diltiazem!o SSRIs with MAOIs (Serotonin Syndrome) : Cognitive, Autonomic and Somatic effects Fluoxetine: longest half- life (7-9 days), increased interaction with other drugs Administration: Oral form only; may be taken with or without food No special storage considerations All are available in the Philippines

MOOD STABILIZER
LITHIUM MOA inhibits the release of dopamine by reducing calcium that promotes depolarization in the presynaptic vesicles Safety & Clinical Indications first drug with proven prophylactic value as maintenance therapy for patients with bipolar disorder acute treatment of manic episodes and in the prevention of recurrent manic and depressive episodes in bipolar patients equal to antidepressants for maintenance therapy to prevent recurrence in unipolar major depression most effective of all adjunctive treatments to add to an antidepressant for treatmentresistant depression. Adverse effect most common adverse effects are polyuria, polydipsia, and weight gain. The most bothersome effects that lead to noncompliance, however, are weight gain, confusion, and mental slowness Lithium toxicity (marked tremor, severe nausea, and diarrhea), plus central effects of slurred speech, vertigo, and increased confusion. Drug-drug interaction Thiazide diuretics will reduce lithium clearance within several days, causing lithium levels to rise Nonsteroidal anti-inflammatory drugs, particularly indomethacin, naproxen, and ibuprofen decrease lithium clearance Sulindac and aspirin do not significantly affect lithium levels. Angiotension-converting enzyme inhibitors may also substantially increase lithium levels

ANTIPSYCHOTIC DRUGS (RISPERIDONE)

potent inhibitors of serotonin (5HT-2A) receptors and dopamine receptors

prevent switching into mania secondary to the antidepression therapy.

sleepiness, restlessness, and autonomic effects Amenorrhea-galactorrhea, falsepositive pregnancy tests, and increased !libido have been reported in women, whereas men have experienced decreased libido and gynecomastia Orthostatic hypotension Somnolence, dizziness, ataxia, fatigue, nystagmus, tremor, diplopia, wt gain, dyspepsia, arthralgia, purpura, leukopenia, anxiety

ANTICONVULSANTS (GABAPENTIN)

modify the synaptic or nonsynaptic release of GABA resulting in an increase in brain GABA effect is dependent on reduced 2+ presynaptic entry of Ca via voltage-activated channels.

antagonize the effect of levodopa and other dopamine agonists Fluoxetine and paroxetine, CYP2D6 inhibitors, increase the plasma concentration of risperidone Carbamazepine has been shown to decrease plasma levels of the active antipsychotic fraction of risperidone Gabapentin is not metabolized and does not induce hepatic enzymes.

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MOA PEG-Interferon alfa w/ Ribavirin Safety & Clinical Indications treatment nave for hepatitis C and chronic hepatitis C genotype 1 - sustained viral response (SVR) of 42% to 46%, genotypes 2 or 3, interferon (conventional or pegylated) plus a lower dose of ribavirin (800 mg per day) - sustained viral response in approximately 80% of patients. Adverse effect most common side effect is hemolytic anemia, which is commonly observed within the first 2 to 4 weeks of therapy. The anemia can be associated with a significant number of cardiac and pulmonary events. Central nervous system side effects such as insomnia, depression, and irritability also are common. Allergic reactions such as rash and pruritus may also occur. Ribavirin is highly teratogenic and embryotoxic. flulike symptoms such as high temperature and chills, loss of apptetite, insomnia, weight loss and shortness of breath Drug-drug interaction elimination is primarily through the urine Ribavirin is eliminated by the kidneys and not removed by dialysis. Dose reduction or discontinuation should be instituted for patients who develop anemia, leukopenia, thrombocytopenia, or depression.

Boceprevir

protease inhibitor that inhibits replication of HCV in host cells by binding to the NS3/4A protease of hepatitis C virus genotype 1a and 1b protease inhibitor that inhibits replication of HCV in host cells by binding to the NS3/4A serine protease of HCV genotype 1

treatment of chronic hepatitis C in combination with peginterferon alfa and ribavirin in patients with compensated liver disease

are taken orally 3 times daily for 12 weeks, metabolized in the liver, and excreted in the stool

Telaprevir

anemia, feeling sick, diarrhea, haemorrhoids and itchy skin rash.

Treatment of chronic hepatitis C is recommended for those at risk for developing cirrhosis. Drug of Choice: PEG-Interferon alfa w/ Ribavirin

BPH Alpha-adrenoreceptor antagonist 5-Alpha-reductase Inhibitors MOA blocks alpha receptor thus promotes smooth muscle relaxation inhibits the conversion of testosterone to dihydrotestosterone suppressing the prostate growth Clinical Indications relieves symptoms with moderate to severe BPH Adverse effect nausea, vomiting, dizziness, lightheadedness, and orthostatic hypotension ejaculatory dysfunction, erectile dysfunction and decreases libido

mainly acts on the prostate beneficial when the prostate volume is 40 ml or greater affect the clinical course of BPH, reducing the risk of acute urinary retention and surgical intervention.

DRUG CLASS OF CHOICE: Alpha-adrenoreceptor antagonist Alpha1 receptors are expressed in the base of the bladder and the prostate, and their blockade decreases resistance to the flow of urine. Alpha blockers, therefore, are used therapeutically for the treatment of urinary retention due to prostatic hyperplasia. The 3 subtypes of alpha-1 receptor include 1a, 1b, and 1c. of these, the alpha-1a receptor is most specifically concentrated in the bladder neck and prostate. MOA reversible alpha 1 selective antagonist Clinical indication effect on voiding symptoms and flow rates is dose-dependent. It improves irritative and obstructive voiding symptoms. Improvement in flow rate is the objective treatment of urinary flow obstruction and irritative symptoms associated with BPH and HPN Adverse effect D-D Interaction & metabolism extensively metabolized in the liver

Terazosin

Doxazosin

blocks alpha 1 but not alpha 2, inhibits postsynaptic alpha adrenergic receptors, resulting in vasodilation of veins and arterioles and decrease in TPR and BP. highly selective alpha 1 adrenoreceptor antagonist

Prazosin

relaxes both arterial and venous vascular smooth muscle as well as prostate muscle due to blockade of alpha 1 receptor

Tamsulosin

competitive alpha 1 antagonist drugs efficacy in BPH suggests that the alpha1A subtype may be the most important alpha subtype mediating prostate SM contraction

greater potency in inhibiting contraction in prostate smooth muscle versus vascular smooth muscle compared with other alpha 1 selective antagonist less effect on standing blood pressure in patients

Terazosin is taken once daily and minimally metabolized in the liver and undergoes first pass metabolism, which makes it most suitable for the patient

has longer half life and has moderate bioavailability and extensively metabolized with a very little parent drug excreted in urine and feces drug interaction with ACE inhibitors in which the patient is currently taking Extensively metabolized in humans because of metabolic degradation by the liver, only about 50% of the drug is available after oral administration with a half life of 3 hours metabolized extensively in the liver interacts with Sertraline, a CYP inhibitor, which may lead to Talmusolin toxicity

Drug of Choice: TERAZOSIN