Antidepressant drugs.ppt

8/12/2019 Antidepressant drugs.ppt

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Antidepressants drugs

PharmacologyDepartment

Lecturer Genny Dominguez


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SUMMARY

Antidepressants.1. Tricyclic antidepressants.2. Selective serotonin

reuptake inhibitors.3. Serotonin/Norepinephrine

reuptake inhibitors.4. Monoamine oxidase

inhibitors.5. Atypical antidepressants.


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It is the most common of the affectivedisorders.

It may range from a very mild condition,bordering on normality, to severe(psychotic).

Its a major cause of disability andpremature death.

In addition to the significant suicide risk,depressed individuals are more likely to diefrom other causes, such as heart disease orcancer.

Depression


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Depression

Emotional symptoms:Misery, apathy, andpessimism, hopelessness.Low self esteem.

Feelings of guilt, inadequacyand ugliness.

Indecisiveness and loss ofmotivation.

Biological symptoms:Retardation of thought andaction.Loss of libido.Sleep disturbance and loss of

appetite.


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Depression

The clinical syndromes are:

Unipolar depression:Reactive depressionEndogenous depression.

Bipolar depression:Manic depressive psychosis.


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Monoamine theory for depression

Theory: Reduced monoamine transmission(NA &/or 5HT) causes depression.

EvidenceReserpine, which depletes neuronal monoaminestores, causes depression.Methyldopa, which reduces CNS NA release,causes depression.

Note: Measurements of monoamine levels donot clearly support the hypothesis.Drugs which enhance monoamine transmissionimprove depression.


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Processes to remaind

The release of a monoamineneurotransmitter from a nerve terminal.Inhibition of transmitter release by aninhibitory pre-synaptic receptor.Elimination of neurotransmitter from thesynaptic cleft by:

a high affinity reuptake mechanism. A low affinity reuptake mechanism.Passive diffusion.


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Release of Noradrenaline

1-adrenoceptor

NA

NA

- NA is released in response to

depolarization of sympatheticnerves.

- NA activates 1-adrenoceptorsof the target tissue.


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Release of Noradrenaline

1-adrenoceptor

NA

NA

2-adrenoceptor _

- NA also activates 2-adrenoceptors of thenerve terminal.

- 2-adrenoceptors inhibitrelease of NA.

- This a negative feed-

back system.NOTE: THIS NOT ASYSTEM FOR THE RE-UPTAKE OF NA


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Re-uptake of Noradrenaline

1-adrenoceptor

NA

NA

NAUptake 1

Uptake 2

- NA is released in largeamounts from sympatheticnerves, and requires to becleared from the synapse bytwo uptake systems and bydiffusion in the circulation:

Uptake 1: is a high affinity, lowcapacity system that permitsNA uptake by the nerveterminal.

Uptake 2: is a low affinity, highcapacity system that permitsNA uptake into the targettissue.


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Noradrenaline Reuptake 1 Inhibitors

1-adrenoceptor

NA

NA

NAUptake 1

Uptake 2

Anti-depressants are widelyused in medicine, and includedrugs such as amitriptyline

They stimulate nor-adrenergictransmission within the CNS byinhibiting the uptake 1 system,which increases the synapticconcentration of NA.

Amitriptyline


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Antidepressants groups

Tricyclic antidepressants (TCAs).Serotonin-selective reuptake inhibitors

(SSRIs).Serotonin/Norepinephrine reuptakeinhibitors (SNRIs).

Non-selective MAOIs. Atypical antidepressants.


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Tricyclic antidepressants

(TCAs)Tertiary amines:

AmitriptylineImipramineClomipramine

DoxepinTrimipramine

Secondary amines:

Desipramine Nortriptyline Amoxapine Aprotiline

Protriptyline


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Tricyclic antidepressants Amitriptyline, imipramine, clomipramine are non-selective inhibitors of both NA and 5HT.Nortriptyline is moderately selective for NA.Onset of antidepressant effect in 2-4 weeks, whereasthe receptor blocking effects are immediate.Effective against unipolar depression, both reactive andendogenous.

The drugs are taken orally and have a T 1/2 of 10-20 h.They are best suited to the treatment of mild ormoderate depression.In overdose, these drugs are hazardous.


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TCAs are also inhibitors of:Muscarinic cholinergic receptors:

Dry mouth, mydriasis, blurred vision, tachycardia,constipation, urinary retention.

Histamine H 1 receptors:

Sedation may help disturbed sleep if taken at night.Cardiac K + channels:

In overdose, these drugs may cause life-threateningventricular arrhythmias.

Tricyclic antidepressants provide effective treatment forneuropathic pain (results from damage to or dysfunction ofthe peripheral or CNS, rather than stimulation of pain

receptors).


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TCAs actions Elevate mood (the onset is slow 2 weeks).Improve mental alertness.Increase physical activity.Reduce morbid preocupation in individual with major

depression.Physical and psychological dependence (should beslowly withdrawal).Can be used for prolonged treatment of depression.


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TCAs therapeutic uses.

Severe major depression.Panic disorders.

To control bed-wetting inchildren (older than 6years) by causingcontraction of the internalsphincter of bladder.Chronic pain (neuropathicpain) amitriptyline.

PANIC


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TCAs ADR

Antimuscarinic effects: Blurred vision,Xerostomia (dry mouth), Urinaryretention, Constipation, Aggravation ofglaucoma and epilepsy.

Increased catecholamine activity:Cardiac over stimulation (overdose).Block adrenergic receptor: Orthostatichypotension and reflex tachycardia.

Block histamine H 1 receptors: Sedation.Weight gain.Sexual dysfunctions (erectiledysfunction in men, anorgasmia in

women).


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TCAs interactions

TCA

Direct-acting Adrenergicdrugs

MAOI

Indirect-acting

Adrenergic drugs Ethanol

CNS depressants

Toxic sedation

Mutual enhancement:HypertensionHyperpyrexiaConvulsionsComa

Block effects ofindirect-actingsymphatomimeticdrugs.

Potentiate effects ofbiogenic amine drugsby preventing theirremoval from thesynaptic cleft.


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TCAs PrecautionsShould be used with caution in manic-depressive patients, because they mayunmask maniac behaviour.They have narrow therapeutic index: 5 to 6fold the maximal daily dose of imipramine canbe lethal.


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Serotonin-selective reuptakeinhibitors (SSRIs)

These drugs include fluoxetine, paroxetine, sertraline,citalopram, escitalopram and fluvoxamine.They are highly selective for 5HT reuptake.They are taken orally and have a very long half life(>24h).SSRIs cause less anti-muscarinic effects than tricyclicantidepressants.They are much safer than tricyclic antidepressants inoverdose.They appear to cause an increased suicidal risk inchildren and teenagers, and so are avoided in these

groups.


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SSRIsThe onset of theantidepressant effect takes 2-4weeks.Maximum benefit may requiretwelve weeks or more.

3 months

2 weeks


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SSRIs Therapeutic uses.

They are effective in a variety ofpsychiatric disorders:Depression.Obsessive-compulsive disorder (theonly indication of fluvoxamine).Panic attacks.

Anxiety.Premenstrual dysphoric disorder.Bulimia nervosa.


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SSRIsFluoxetine: Longer half-life (fifty hours).Fluoxetine and paroxetine are inhibitors of the cytochromeP450 responsible for the elimination of TCA, neuroleptics,antiarrythmics and -adrenergic antagonist drugs.

Renal excretion, except paroxetine and sertraline (fecal).Hepatic impairment (dosages should be adjusted).


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SSRIs Adverse effects

They have fewer and less severe adverse effects than theTCA and MAOIs.GI effects: Nausea and diarrhoea.

Anxiety.

Weakness.Sleep disturbances: Drowsiness, insomnia; Paroxetine andfluvoxamine are sedating, may be useful in patient who havedifficulty sleeping.

Sexual dysfunction: Loss of libido, delayed ejaculation andanorgasmia, if the SSRIs induce sexual dysfunction shouldbe replaced by bupropion or mirtazapine.Rarely, SSRIs may precipitate aggressive or violent

behaviour.


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SSRIs, Overdoses and interactions.

Fluoxetine: Seizures.In combination with MAOIs, they maycause the serotonin syndrome, whichcomprises, tremor, hyperthermia andcardiovascular collapse.


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Serotonin/Norepinephrine

reuptake inhibitors (SNRIs)These drugs inhibit the reuptake of bothserotonin and norepinephrine.

They include:

Duloxetine Venlafaxine


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SNRIsMay be effective in treating depressionin patients in which SSRIs areineffective.Effective in depression accompanied by

chronic painful symptoms (neuropathicpain), backache and muscle aches, thispain is in part modulated by serotoninand norephinephrine in the CNS.

Venlafaxine is used mainly in theelderly. It is less sedative and hasfewer antimuscarinic effects than thetricyclic antidepressants.

SSRIs


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Monoamine oxidaseMonoamines are eliminated by enzymaticdegradation.There are two principle enzymes:

Monoamine oxidase (MAO).Catechol-O-methyltransferase (COMT).

There are two MAO isoenzymes:MAO-AMAO-B

The two enzymes have a different distributionwithin the body:MAO-A is found in the CNS, liver and gut wall.MAO-B is found in the CNS alone.


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Monoamine oxidase and its inhibitors

There are differences in the substratespecificity of MAO-A and MAO-B:MAO-A oxidises NA, 5HT, dopamine andtyramine.MAO-B oxidises dopamine and tyramine.

Inhibitors of monoamine oxidase divide intotwo groups:

Non-selective MAO inhibitors (used indepression).MAO-B inhibitors (used in Parkinsons disease).


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Non-selective MAO inhibitors

Non-selective MAOIs cause a rapid andsustained increase in the CNSconcentration of NA, 5HT and dopamine.They are very effective for the rapidcontrol of severe depression.They are generally long lasting, due to theirreversible inhibition of MAO.They should not be given together withtricyclic antidepressants or SSRIs.


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Adverse effects of non-selective MAOIs

Adverse effects include:Postural hypotension.

Atropine-like effects (antimuscarinic).

Weight gain.Restlessness and insomnia.Liver damage (rare, but MAOIs are avoided inpatients with abnormal LFTs).

In addition, non-selective MAOIs may cause severehypertension in the presence of tyramine-containingfoods. This is the cheese reaction .


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The effect of tyramine on noradrenergictransmission

1-adrenoceptor

NA

TyrUptake 1

Tyramine (from food) entersperipheral adrenergic nerves viathe uptake 1 system. It is taken upinto vesicles, where it displaces NA

into the cytosol.Cytosolic NA may then leak out ofthe nerve via the uptake 1 system,and activate post-synapticreceptors.

Tyramine is normally destroyed byMAO-A in the gut wall and liver.

NA

TyramineUptake 1


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The cheese reactionTyramine is a product of bacterial fermentation, and is

found in foods where such a reaction occurs (some beersand wines, soft cheeses, and aged or cure meats, etc).Tyramine is a substrate for both MAO-A and MAO-B, but astyramine does not cross the blood-brain barrier, its effects

are produced only by peripheral MAO-A.Patients who ingest tyramine while taking non-selectiveMAOIs, may develop life-threatening hypertension.

A dangerous hypertensive reaction can occur by a similar

mechanism in patients taking both non-selective MAOIs andephedrine or amphetamine.Note: MAO-B inhibitors, which are used in Parkinsons disease, do not produce a cheese reaction. They selectivelyincrease the neuronal dopamine concentration.


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Non-selective MAOIsDrugs in this class (irreversible non-selectiveinhibitors of MAO) include:

PhenelzineTranylcypromineIsocarboxazid

There is a reversible non-selective inhibitor ofMAO moclobemide.

Moclobemide appears to cause less severe cheese

reactions, but tyramine containing food is still bestavoided.The less severe cheese reaction is probably related tothe less sustained inhibition of the enzyme.


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Non-selective MAO InhibitorsThe use of these drugs is limited due to thecomplicated dietary restrictions required ofpatients taking MAOIs.


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Non-selective MAOIs therapeutic

usesDepressed patients who areunresponsive or allergic toTCAs or who experience

strong anxiety.Low psychomotor activity(have mild stimulant effect).Phobic states.

Atypical depression: Labilemood, rejection sensitivity,and appetite disorders.

TCAs


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Non-selective MAOIs

Antidepressant effectsrequired 2-4 weeks of

treatment.The enzymaticregeneration when isirreversibly inactivateoccurs several weeksafter termination ofthe drug.

2- 4 weeks

N l i MAOI ADR


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Non-selective MAOIs ADRSevere and unpredictable effects.Patients that ingest tyramine-contained foods,causes the release of large amounts ofcatecholamines (tachycardia, headache, nausea,hypertension, cardiac arrhythmias and stroke)because the tyramine normally is inactivated byMAO in the gut. Phentolamine and prazosin arehelpful in the management of tyramine-inducedhypertension.May be dangerous in severely depressed patients

with suicidal tendencies.Drowsiness, orthostatic hypotension, blurredvision, dry mouth, dysuria and constipation.Should not be coadministered with SSRIs

(serotonin syndrome) (six weeks before).

SSRI MAOI


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Atypical antidepressants

They are not moreefficacious than theTCAs or SSRIs.BupropionMirtazapineNefazodoneTrazodone


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Bupropion: Extended release formulation.

Is unique in that it decreases thecraving for nicotine in tobaccoabusers.

ADR: Dry mouth, sweating,tremor, and seizures at highdoses.


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Mirtazapine:Block 5-HT2 and 2 receptors.

Antihistaminic activity(sedative) may beused in depressedpatients having

difficulty sleeping.Increased appetiteand weight gain.


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Nefazodone and trazodone:Inhibitors of the serotonin reuptake, block the

5-HT1 presynaptic autoreceptors and increaseserotonin release.Block H1 activity (sedating).Cause priapism.


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Other antidepressant drugsFlupenthixol (a neuroleptic) has anti-depressanteffects, and is used in depression at low doses.Reboxetine, a selective inhibitor on NA reuptake.

Tryptophan, the amino acid precursor of 5HT,may be used as adjunctive therapy.St Johns wort (a plant extract). It containshyperformin, a monoamine transport inhibitor. Itis a potent inducer of cytochrome P 450 , and willinteract with the metabolism of many otherdrugs.


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P450 interactions the critical listThe plasma concentration of many drugs may beaffected by drugs that induce or inhibit cytochrome P 450 .Do not forget the following critical list is drugs whosemetabolism may be altered by P 450 inducers or inhibitors

Warfarin Anticonvulsants (phenytoin, carbamazepine, others) Anti-AIDS drugs

Protease inhibitorsNon-nucleoside RT inhibitorsCyclosporine AOral contraceptives

Sedating, useful GI Orthostatic Weight


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Sedating, usefulfor agitation

GIdistress

Orthostatichypotension

Weightgain

SSRIs Citalopram - + - -

Escitalopram - + - -

Fluoxetine - + - -

Fluvoxamine + + - -

Paroxetine + + - -

Sertraline - + - -

SNRIs Venlafaxine - + - -

Duloxetine - + - -

Atypicalantidepressants Bupropion - - - -

Mirtazapine + - - +

Nefazodone + + - -

Trazodone + - - -

TCA Amitriptyline + - + +

Amoxapine + - - -

Clomipramine + + - +

Desipramine - - - -

Doxepin + - + +Imipramine + - - +

Maprotiline + - - -

Nortriptyline + - - -

Potriptyline - - - -

Trimipramine + - - +

MAOI Phenelzine - - + -

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Antidepressant drugs.ppt