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Dr. Hiwa K. Saaed, PhD, Pharmacology & Toxicology

school of Pharmacy, University of Sulaimani

Ref: Lippincott’s Illustrated Review Pharmacology, 6th edition

2014-2015

ANTIDEPRESSANTS

SSRIsCitalopram CELEXAEscitalopram LEXAPROFluoxetine PROZACFluvoxamine LUVOX CRParoxetine PAXILSertraline ZOLOFTSEROTONIN/NOREPINEPHRINEREUPTAKE INHIBITORS (SNRIs)Desvenlafaxine PristiqDuloxetine CYMBALTAVenlafaxine EFFEXORATYPICAL ANTIDEPRESSANTSBupropion WELLBUTRIN, ZYBANMirtazapine REMERONNefazodone SERZONETrazodone DESYRELTRICYCLIC ANTIDEPRESSANTS (TCAs)Amitriptyline ELAVILAmoxapine ASENDINClomipramine ANAFRANILDesipramine NORPRAMINDoxepin SINEQUANImipramine TOFRANILMaprotiline LUDIOMILNortriptyline PALMELORProtriptyline VIVACTILTrimipramine SURMONTILMONOAMINE OXIDASE INHIBITORS(MAOIs)Isocarboxazid MarplanPhenelzine NARDILSelegiline ELDEPRYLTranylcypromine PARNATEDRUGS USED TO TREAT MANIAand BIPOLAR DISORDERCarbamazepine TEGRETOL, EQUETRO,CARBATROLLithium ESKALITHValprioc acid DEPAKENE, DEPAKOTE

DEPRESSION

Depression: is the most common of affective disorders; disorder of mood rather than disturbances of thought or cognition. it may range from a very mild condition, bordering on normality, to severe (psychotic) depression accompanied by hallucinations and delusions.

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DEPRESSIONThe symptom of depression include emotional & biological:

Emotional symptoms: intense feeling of sadness, hopelessness and despair

inability to experience pleasure in usual activities,

Low self-esteem: feelings of guilt, inadequacy and ugliness

Indecisiveness, loss of energy and motivation, and suicidal thoughts.

Biological symptoms:

Retardation of thought and action

Loss of libido

changes in sleep patterns and appetite,04/10/2023 3

MANIAMania is characterized by the

opposite behavior that is enthusiasmrapid thought and speech

patternsextreme self-confidence impaired judgment.

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MAJOR TYPES OF DEPRESSION The three major types of depression are:

1. Reactive depression, a response to external event:adverse life events, grief, physical illness, and drugs (reserpine).

2. Bipolar affective (manic-depressive) disorder:expansive mood, grandiosity, inflated self-esteem,pressured speech, flight of ideas,and poverty of sleep.3. Major depressive disorder (unipolar 75%, endogenous depression 25%):

a depression of mood without any obvious medical or situational causes,

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3. MAJOR DEPRESSIVE DISORDER (MDD)

manifested by • inability to cope with ordinary events or

experience pleasure, • anorexia, with significant weight loss,• insomnia, fatigue, and inability to

concentrate.

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BIOLOGIC AMINE HYPOTHESIS

Depression is due to deficiency in neuronal and synaptic catecholamine concentration, such as NE and 5-HT at certain key sites in the brain.

Mania: excess amines

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BIOLOGIC AMINE HYPOTHESIS

This theory was based on observations that: Most clinically useful antidepressant drugs

potentiate, either directly or indirectly, the actions of norepinephrine (NE) and/or serotonin (5-HT) in the brain.

Reserpine (which was used to Rx schizophrenia and HTN) caused sever depression in ~15% of patients. This drug depletes neuronal stores of monoamines.

Iproniazide (MAOI) used to treat TB sometimes induced euphoria.

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MECHANISM OF ANTIDEPRESSANT DRUGS ACTION

Although antidepressant drugs may cause changes in brain amine activity within hours, weeks may be required for them to achieve clinical effects!!!!

Q. What is happen in depression?The monoamine in the limbic system are depleted → → upregulation of

• postsynaptic β receptor • & presynaptic α2, 5-HT2A, 5-HT2C.

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Q. WHAT IS ANTIDEPRESSANT DO?

Antidepressant drug decrease the presynaptic inhibitory receptor densities in the brain over a two-to four-week period upregulation → downregulation → greater synthesis and release of neurotransmitters into the synaptic cleft → enhanced signalling in the postsynaptic neurons, presumably leading to therapeutic response.

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DRUG CATEGORIES

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Class drugs

TCA Imipramine, Amitriptyline, Cloimpramine, Doxepin, Trimpramine

Heterocyclic Desipramine, Nortriptyline, Amoxapine, Maprotiline, Portriptyline

5-HT/NERIs Venlafaxine, Duloxetine

Atypical Bupropion, Mirtazapine Nefazodone, Trazodone

SSRIs Fluoxetine, Citalopram, Escitalopram, Fluvoxamine, Paroxetine, Sertraline

MAOIs Phenelzine, Moclobemide, Isocarboxazid, Tranylcypromine

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SSRIs

• a group of chemically unique drugs • They specifically inhibit serotonin reuptake, • They have 300 to 3000 fold greater selectivity for the

serotonin transporter as compared to the NE transporter.• They typically take 2 to 12 weeks to produce improvement in

mood• SSRI have little ability to block the dopamine transporter.• SSRI have little blocking activity at muscarinic, α-adrenergic,

and histaminic H1 receptors (fewer side effects). Thus, they are well tolerated by patients with heart disease, the elderly, who are especially sensitive to the anticholinergic and orthostatic effects of the TCA.

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THERAPEUTIC USES OF SSRIS:

1. Depression.2. Obsessive compulsive disorder (the only indication

for fluvoxamine ).3. Panic disorder .4. Generalized anxiety .5. Premenstrual dysphoric disorder .6. Bulimia nervosa (only fluoxetine is approved for this last

indication).

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PHARMACOKINETICS

• All the SSRIs are well absorbed after oral administration,

• Only sertraline undergoes significant first-pass metabolism.

• Fluoxetine (Prozac) and Sertraline (Zoloft) are given in the morning because of its potential for being activating and causing insomnia.

• The majority of SSRIs have plasma half-lives that range between 16 and 36 hours.

• Metabolism by P450-dependent enzymes and glucuronide or sulphate conjugation occur extensively.

• Excretion of SSRIs is primarily through the kidneys, except for paroxetine and sertraline, which also undergo faecal excretion.

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• Fluoxetine differs from the other members of the class in two respects :

1. It has a much longer half-life (50hrs).

2. The metabolite is as potent as the parent compound . the half-life of the metabolite is quite long, ~10 days.

• Fluoxetine and paroxetine are potent inhibitors of a hepatic CYP P450 isoenzyme (CYP2D6)

CYP2D6 responsible for the elimination of TCA drugs, neuroleptic drugs, and some antiarrhythmic and β-adrenergic antagonist drugs.

• Note; about 7% of the white population lack (CYP2D6) and, therefore matabolize fluoxetine very slowly.

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PHARMACOKINETICS

• With initiation of therapy with an SSRI, some patients describe anxiety or agitation. Insomnia

• Paroxetine and fluvoxamine are sedating, and may be useful in patients who have difficulty sleeping.

• Conversely, patients who are fatigued may benefit from one of the more activating antidepressants, such as fluoxetine.

• Sexual dysfunction: loss of libido, delayed ejaculation, and anorgasmia.

Replace with a drug having fewer sexual side effects, such as Bupropion or mirtazapine.

• The SSRIs tend to be weight neutral with the exception of paroxetine (Paxil), which is associated with weight gain.

• Use in children and teenagers: 1/50 children become more suicidal as a result of SSRIs treatment.

• SSRI+MAOIs cause Serotonin syndrome: characterized by: hyperthermia, muscle rigidity, myoclonus and changes in mental status and vital signs.

• Discontinuation syndrome: All of the SSRIs, particularly the agents with shorter half-lives and inactive metabolites. Fluoxetine has the lowest risk of causing an SSRI discontinuation syndrome due to its longer half-life and active metabolite. include headache, malaise, and flu-like symptoms, agitation and irritability, nervousness, and changes in sleep pattern.04/10/2023 17

SEROTONIN/NE REUPTAKE INHIBITOR:

Venlafaxine, desvenlafaxine, levomilnacipran and duloxetine, selectively inhibit the reuptake of both serotonin and NE.

effective in treating depression and neuropathic pain (such as backache and muscle aches) in patients in which SSRIs are ineffective.

SNRIs, unlike the TCAs, have no activity at adrenergic, muscarinic, or histamine receptors and thus have fewer side effects than the TCAs.

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VENLAFAXINE VS DULOXETINE

Venlafaxine: • Is a potent inhibitor of serotonin

reuptake and, at higher doses, is an inhibitor of NE reuptake. It is also a mild inhibitor of dopamine reuptake.

• It has minimal inhibition of the CYP P450 isoenzymes. The t1/2 of the parent compounds plus its active metabolite is approximately 11 hours.

• SE: nausea, dizziness, insomnia, sedation, and constipation. At high doses, there may be an increase in blood pressure..

Duloxetine: inhibits serotonin and NE reuptake

at all doses. It is extensively metabolized in the

liver to numerous metabolites, should not be administered to patients with hepatic insufficiency. Metabolites are excreted in the urine.

Food delays the absorption of the drug. t1/2 is ~12 hours.

SE: nausea, dry mouth, and constipation are common, Insomnia, dizziness, somnolence, sweating, Sexual dysfunction also occurs.

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ATYPICAL ANTIDEPRESSANTS

They are a mixed group of agents that have actions at several different sites.

Bupropion: (smoking cessation)

• Acts at unidentified site. It has minimal effects on NE or 5-HT systems, but blocks DA reuptake.

• Its short half-life may require more than once-a-day dosing or the administration of an extended release formulation, it decreases the craving of nicotine in tobacco abusers.

• Side effects include: dry mouth ,sweating ,tremor and seizures at high doses.

Mirtazapine:

• block 5-HT2 and α2 receptors.

• It is a sedative because of its potent antihistaminic activity, which may be used to advantage in depressed patients having difficulty sleeping,

• but it does not cause the antimuscarinic SEs of TCAs,

• Does not interfere with sexual functioning, as do the SSRIs.

• Increased appetite and weight gain frequently occur.04/10/2023 20

NEFAZODONE AND TRAZODONE:

• Nefazodone (P450 inhibitor) blocks both NE and 5-HT reuptake, and is a 5-HT2 antagonist,

• trazodone weak inhibitor of serotonin reuptake by blocking 5-HT1 presynaptic autoreceptors and thereby, increase serotonin release, and is a 5-HT2 antagonist.

• Both are sedating because of potent H1 blocking activity.

• Trazodone has been associated with causing priapism.

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TCAs• Tertiary amines; imipramine (prototype), amitriptyline, clomipramine,

doxepin and trimipramine

• Secondary amines; desipramine, and nortryptyline (N-demethylated metabolites of imipramine and amitriptyline respectively), amoxapine, maprotiline, and protriptyline.

Mechanism of Action: Inhibition of neurotransmitter (serotonin and NE) uptake: ↑adrenergic

and serotonergic neurotransmission.Blocking of four receptors: serotonergic, α-adrenergic, histaminic, and

muscarinic receptors. actions at these receptors are probably responsible for many of the

untoward effects of TCAs.

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MECHANISM OF ACTION:

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• Sever major depression,

• phobic and panic anxiety disorders,

• Neuropathic pain,

• obsessive compulsive disorder (OCD),

• nocturnal enuresis; Imipramine has been used to control bed-wetting in children (older than six years) by causing contraction of the internal sphincter of the bladder.

THERAPEUTIC USES

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Adverse effects Muscarinic blockade leads to blurred vision, xerostomia,

urinary retention, constipation, and aggravation of glaucoma and epilepsy.

Sympathomimetic: in tremor, and cardiac overstimulation, arrhythmia.

α-adrenergic receptors blockade, causing orthostatic hypotension and reflex tachycardia.

Imipramine is most likely and nortriptyline is least likely to cause orthostatic hypotension.

H1 receptors blockade; Sedation Metabolic: Weight gain is a common adverse effect of the

TCAs. Endocrine: Sexual dysfunction, as evidenced by erectile

dysfunction in men and anorgasmia in women. Drug interactions: Hyperthermia, seizures, coma, and death with MAOIs,

serotonin syndrome with SSRIs, 04/10/2023 26

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MAO INHIBITORS

Mechanism of action: They increase stores of norepinephrine ,serotonin and dopamine within the neuron and subsequent diffusion of excess neurotransmitter into the synaptic space.

Therapeutic uses:

1. Indicated for depressed patients who are unresponsive or allergic to TCAs.

2. Patient with low psychomotor activity.

3. Treatment of phobic states .

These drugs inhibit not only MAO in the brain but also peripheral oxidase, therefore MAOIs show a high incidence of drug-drug and drug-food interactions.

• Cheese reaction: Individuals receiving MAOIs are unable to degrade tyramine obtained from the diet, tyramine causes the release of large amounts of stored catecholamine from nerve terminals, resulting in headache, tachycardia, nausea, hypertension ,cardiac arrhythmias and stroke .

• Other side effects include: drowsiness, orthostatic hypotension ,blurred vision, dry mouth, dysuria and constipation .

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TREATMENT OF MANIA AND BIPOLAR DISORDER

• For more than 40 years, Lithium (Li+) has been used to treat mania.

• lithium carbonate is effective in 60 to 80% of all acute manic episodes within 5 to 21 days of beginning treatment.

• Because of its delayed onset of action in the manic patient, Li+ is often used in conjunction with low doses of high-potency anxiolytics (e.g., lorazepam) and antipsychotics (e.g., haloperidol) to stabilize the behaviour of the patient..

Mechanism of Action:

Lithium interferes with the resynthesis (recycling) of PIP2, by inhibition of the dephosphorylation of both IP2 to IP, and IP to Inositol, necessary steps in the recycling of inositol→↓ PIP2 in neuronal membranes of the CNS.

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LITHIUM, MECHANISM OF ACTION

PIP

PIP2

GIP3

IP2

IP1

InositolPI

X Li+

PLC

DAG

Ca 2+

LITHIUM

• Lithium is given orally, and the ion is excreted by the kidney like Na+;

• low Na+ diet or chronic diuretic treatment enhances toxicity, medical conditions (diarrhoea), or physical activities (those that induce sweating) that deplete the body of Na+.

• Lithium salts are very toxic. Their safety factor and therapeutic index are extremely low-comparable to those of digitalis.

Adverse Effects:

• ataxia, tremors, confusion, convulsions, acne, edema, visual dysfunction,

• goiter, hypothyroidism; nephrogenic diabetes insipidus (treat with amiloride, not thiazides), teratogenicity (cardiac malformations, neonatal cyanosis, and hepatomegaly);

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OTHER MOOD-STABILIZING AGENTS

• Several anticonvulsant; Valproic acid and carbamazepine are the best studied to date.

• In 1995, valproic acid was approved by the FDA for treatment of acute mania and is now considered a first-line agent.

• In pregnancy clonazepam or gabapentin are preferred.

• Other anticonvulsants under investigation include lamotrigine and topiramate.

• The atypical antipsychotics (risperidone, olanzapine, ziprasidone, aripiprazole, asenapine, and quetiapine) have also received FDA approval for use in acute mania and mixed episodes associated with bipolar disorder.

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