Assoc. Prof. Iv. Lambev www.medpharm-sofia.eu

Medical University of Sofia, Faculty of MedicineDepartment of Pharmacology and Toxicology

•Antidepressants•Mood stabilizers•Psychostimulants•Nootropic drugs•CNS stimulants

(Abstract)

Depression is a heterogeneous disorder. A simplified classification based on presumed origin is as follows:

(1) brief reactive or secondary depression (most common), occurring in response to real stimuli such as grief, illness, etc;(2) major depression (melancholic and recurrent depression) a genetically determined biochemical disorder manifested by an inability to experience ordinary pleasure or to cope with ordinary life events;(3) manic-depressive depression (depression associated with bipolar affective disorder)Pharmacologic treatment of depressions is very important, althougha continuing role for electroconvulsive therapy for severe forms oflife-threatening depression is also noted.

manic

Depression is one of the most common psychiatric disorders. At any given moment, about 3–5% of the population is depressed,and an estimated 10% of people may become depressed during their lives. The symptoms of depression are often subtle and unrecognized both by patients and by physicians. Patients withvague complaints that resist explanation as manifestations ofsomatic disorders and those who might be simplistically describedas “neurotic” should be suspected of being depressed. Soon after the introduction of reserpine (1948), it becameapparent that the drug could induce depression by inhibiting the neuronal storage of amine neurotransmitters 5-HT and NE.Reserpine-induced depression and depleted stores of amine neuro-transmitters. It was reasoned, depression must be associatedwith decreased functional amine-dependent synaptic transmission.

NA (noradrenaline) = NE (norepinephrine)

Rauwolfia serpentina (a small indian shrub)

•Reserpine•Ajmaline

Pathogenesis of depression The idea that depression must be associated with decreased

functional amine-dependent synaptic transmissionprovided the basis for amine hypothesis of depression.By extension, drugs that increased amine function in appropriate synaptic areas would relieve depression. The amine hypothesis has provided the major experimental models for the discovery of new antidepressants.All currently available antidepressants, except bupropion,are classified as having their primary actions on the metabolism, reuptake, or selective receptor antagonismof 5-HT, NA, or both.

The effects of DA, 5-HT and NE on the brain functions

(NE)

(DA)

(5-HT)

Raised neurotransmitter concentrations produceimmediate alterations in postsynaptic receptoractivation, leading to changes in second messenger(intracellular) systems and to gradual modificationsin cellular protein expression. Antidepressantsincrease a cyclic AMP response-element binding(CREB) protein which in turn is involved inregulating the transcription of genes that influencesurvival of other proteins including brain derivedneurotrophic factor (BDNF) which exerts effects onneuronal growth. The role of BDNF in depressionis supported by the observation that stress bothreduces its expression and impairs neurogenesis.

The monoamine hypothesis of depression is anoversimplification (only deficieny of NA, 5-HT, and

DA) of a complicated picture. Other systems thatare implicated in the etiology of depression (and which provide potential targets for drug therapy) include the hypothalamo-pituitarythyroid axis andthe hypothalamo-pituitary-adrenal axis (HPA). The finding that 50% of depressed patients have elevated plasma cortisol concentrations constitutesevidence that depression is associated withincreased HPA drive.

Structural relationships betweenvarious tricyclic antidepressants (TCAs).Their structures are similar to phenothiazines.

Selective serotonin reuptake inhibitors (SSRIs).

Pharmacokinetics

The antidepressants are generally well absorbed after oral administration. Steady-state plasmaconcentrations of TCAs show great individual variation but correlate with therapeutic effect.Antidepressants in general are inactivated princi-pally by metabolism by hepatic cytochrome P450enzymes (2D6 and 3A4). Other cytochrome enzymes are CYP 1A2 inhibited by the SSRIfluvoxamine, and induced by cigarette smoking,caffeine and the atypical antipsychotics (clozapine and olanzapine).

Several of these drugs produce active metaboliteswhich prolong their action (e.g. fluoxetine ismetabolized to norfluoxetine, t1/2 200 h). The meta-bolic products of certain TCAs are antidepressantstoo, e.g. nortriptyline (from amitriptyline),desipramine (from imipramine).Half-lives of TCAs and SSRIs are long (> 15 h).Around 7% of the Caucasian population havevery limited CYP 2D6 enzyme activity. Such “poor metabolizers” may find standarddoses of tricyclic antidepressants intolerable andit is often worth starting at a very low dose.

Clinical indicationsThe major indication is to treat depression, but a number of other uses have been established by clinical experience.Antidepressants may benefit most forms of anxiety disorder(panic disorder, generalized anxiety disorder, post-traumaticstress, obsessive-compulsive disorder, and social phobia),migraine.SSRIs are effective in milder cases of the eating disorder bulimia nervosa, particularly fluoxetine (in higher doses thanare required for depression). Antidepressants appear to beineffective in anorexia nervosa.

SSRIs (selective serotonin reuptake inhibitors) are used in:•panic disorders•chronic anxiety•depression•bulimia neurosa(fluoxetine – in higher doses)

Schematic representation of the time course of panic treatments

Adapted from Bennett and Brown (2003)Adapted from Bennett and Brown (2003)

Mode of use

The action of TCAs in ameliorating mood is usuallyabsent in the first 2 weeks of therapy and at least 4weeks must elapse to constitute an adequate trial.Where a minimal response is noted in this period, itis reasonable to extend the trial to 6 weeks to seeif further benefit is achieved. Dose titration is oftennecessary. By contrast, patients mayexperience unwanted drug effects immediatelyon starting treatment (and they should be warned), but such symptoms often diminish with time.TCAs are given either in divided doses or, for themore sedative compounds, as a single evening dose.

SSRIs have advantages over tricyclics in simplicityof introduction and use. Dose titration is oftenunnecessary since the minimum therapeutic dosecan usually be tolerated as a starting dose. Divideddoses are not required and administration is by asingle morning or evening dose. Patients commencing treatment on SSRIs aremore likely to reach an effective dose than thosestarting on TCAs.Venlafaxine is licensed for treatment-resistant depression by gradual dose titration. There issome need for dose titration when using MAOIs.

Side effects of TCAs

Anticholinergic (atropine-like): dry mouth, blurred vision, accommodation disturbances, increased ocular pressure, con-stipation, urinary retention, sweating, adynamic ileus (very rare).CNS: dizziness, tiredness, confusion, tremor, insomnia,seizures, exacerbation of psychotic symptoms.CVS: postural hypotension, sinus tachycardia, arrhythmia.Blood: leucopenia, agranulocytosis, thrombocytopenia, Haemolytic anaemia. Other ADRs: impaired respiration, libido changes, tinnitus, GIcomplaints, liver function disturbances, increased body weight.

TCAs – Interactions: Potential Results

MAOIs hyperthermia, palpitations, excitation

Adrenomimetics hypertension, hyperthermia, tachycardia

Alcohol effect of alcohol may be increased

Clonidine, Methyldopa

decreased hypotensive effects

T3, T4 enhanced potential for CV toxicity

Physostigmine antagonism

Anticholinergics additional anticholinergic activity

Neuroleptics inhibition of metabolism of antidepressants

Levodopa overreaction of levodopa

Lithium the therapeutic response is increased in some cases and suppressed in others

Precautions: close supervision, especially in early phase oftreatment (suicide risk of TCAs). The possibility of unmaskinga latent psychosis should be considered. A switch into a manicor hypomanic condition may occur (“switch process”).Caution should be exercised in CVD, history of urinary retention,narrow-angle glaucoma, and thyroid disease.

Side-effects of SSRIs(mainly during the 1st and 2nd weeks of treatment): CNS: head-ache, restleness; CVS: bradycaria; GIT: nausea, diarrhoeaThe serotonin syndrome is a rare but dangerous complicationwith features restlessness, tremor, hуperthermia, convulsions,coma and death. Risk is increased by co-administration withMAOIs, the antimigraine drug sumatriptan, and St. John’s Wort.

Side-effects of MAOIs (Moclobemide)CNS: insomnia, restlessness, confusion, dizziness.CVS: arrhythmia, tachycardia, palpitations, high blood pressure.

The following foods and beverages should be avoided – tyramine containing nutrition:maturated cheese (“cheese syndrome” – high blood pressure), broad beans, smoked orpickled fish, meat extracts containing brewer's yeast, fermented sausages (e.g. salami);red wine, sherry, beer and excessive amounts of alcohol.

Trazodone acts by antagonism of central presynaptic alpha-2-adrenoceptors. It is an option for depressed patients where heavysedation is required. Trazodone also has the advantages of lacking antimuscarinic effects and beingrelatively safe in overdose. Males should be warnedof the possibility of priapism (painful penile erections),due to the blockade of peripheral postsynaptic alpha-1-adrenoceptors.

Mianserin has the advantages of lacking antimuscariniceffects too, but can cuases aplastic anaemia.

Agomelatine (Valdoxan®) is a melatonergic agonist (MT1- and MT2-receptors) and 5-HT2C antagonist. It has no effect on monoaminereuptake and no affinity for α, β adrenergic,histaminergic, cholinergic, dopaminergic and benzodiazepine receptors. Agomelatine is indicated for the treatmentof major depressive episodes in adults. It not use in chlidren below 18 years of agedue to a lack of data on safety and efficacy.

Many patients with mild to moderate depression areaware of the benefits of the herbal remedy St. John’sWort. The major active antidepressive constituents are thought to be hyperforin and hypericin. Some believethat hyperforin is the major constituent responsiblefor antidepressant activity. It inhibits the reuptakeof 5-HT, DA, and NA.Hyperforin also has affinity for GABA and glutamatereceptors.

Hypericum perforatum L.

St. John’s WortMany patients with mild to moderate depression areaware of the benefits of the herbal remedy St. John’sWort. The major active antidepressive constituents are thought to be hyperfurin and hypericin . Some believeThat hyperfurin is the major constituent responsible forantidepressant activity. It inhibits the reuptake of5-HT, DA, and NA (NE).Hyperfurin also has affinity for GABA and glutamatereceptors.

Use of St. John’s Wort is complicated by thelack of standardization of the ingredients. Thosewho wish to take St. John's Wort should be madeaware that it may cause dry mouth, dizziness,sedation, GI disturbance and confusion.It induces hepatic CYP 1A2 and CYP 3A4with the result that the plasma concentration andtherapeutic efficacy of warfarin, oral contraceptives,some anticonvulsants,antipsychotics and HIV protease/reverse transcriptase inhibitors arereduced. Concomitant use of tryptophan and St. John’s Wort may cause serotoninergiceffects including nausea and agitation.

Electroconvulsive therapy (ECT) involves thepassage of a small electric charge across the brain by electrodesapplied to the frontotemporal aspects of the scalp with the aim ofinducing a tonic-clonic seizure. ECT requires the patient to bereceiving a general anaesthetic. It may cause memory deficit although this is generally transient. ECT is usually reserved for psychiatric illness wherepharmacotherapy has been unsuccessful for instancethe severely depressed patient who has stopped eating ordrinking. Modern-day ECT is a safe and effective alternativeto pharmacotherapy and remains a first-line option in clinicalcircumstances where rapid, response is desired, when it canbe life-saving.

Mood stabilizersIn bipolar affective disorder patients suffer episodesof mania, hypomania and depression, classicallywith periods of normal mood in between. Manicepisodes involve greatly elevated mood, ofteninterspersed with periods of irritability or undueexcitement, accompanied by biological symptoms(increased energy, restlessness, decreased need forsleep, increased sex drive), loss of social inhibitions,irresponsible behaviour and grandiosity. Psychoticfeatures may be present, particularly disorderedthinking, manifested by grandiose delusions and“flight of ideas” with rapid speech.

Hypomania is a less dramatic and dangerouspresentation but retains the features of elation orirritability and the biological symptoms, abnormalitiesin speech and in social conduct to overfamiliarity and mild recklessness.Depressive episodes include depressive symptomsdescribed before and may include psychotic features.

Lithium salts are ineffective for prophylaxis ofbipolar affective disorder in around 35% of patientsand cause severe unwanted effects. The searchfor alternatives has produced drugs that are morefamous as anticonvulsants (carbamazepineand sodium valproate, and possibly lamotrigine).

The main effect of lithium is probably to inhibit hydrolysis of inositol phosphate, so reducing therecycling of free inositol for synthesis ofphosphatidylinositides. These intracellular moleculesare part of the transmembrane signaling system thatis important in regulating intracellullar calcium ionconcentration, which subsequently affectsneurotransmitter release. Other putative mechanismsinvolve the cyclic AMP “second messenger” systemand monoaminergic and cholinergic neurotransmitters.

Action of lithium on the IP3 and DAG second-messenger system. The schematic diagram shows the synaptic membrane of a neuron. (PIP2 – phosphatidylinositol-4,5-bisphosphate; PLC – phospholipase-C; G – G-coupling protein). Result: activation of protein kinase C, mobilizationof intracellular Ca2+, etc. Lithium, by inhibiting the recycling of inositolsubstrates, may cause depletion of the second-messenger source PIP2

and therefore reduce the release of IP3 and DAG.

The therapeutic plasma concentration is close to the toxic concentration (low therapeutic index). Lithiumis a small ion that, given orally, is rapidly absorbedthroughout the gut. High peak plasma concentrationsare avoided by using sustained-release formulationswhich deliver the peak plasma lithium concentrations in 5 h.With chronic use the plasma t1/2 of lithium is 15–30 h.Lithium is usually given 12-hourly to avoid unnecessaryfluctuation (peak and trough concentrations) and tomaintain a plasma concentration just below the toxiclevel. A steady-state plasma concentration will be attained after about 5–6 days (i.e. 5 x t1/2).

Lithium carbonate is effective treatment in 75%of episodes of acute mania or hypomania. Because its therapeutic action takes 2–3 weeksto develop, lithium is generally used in combinationwith lorazepam or diazepam (or with a neurolepticswhere there are also psychotic features).

For prophylaxis, lithium is indicated when therehave been two episodes of mood disturbance intwo years.

Lithium is also used to augment the action ofantidepressants in treatment-resistant depression.The difference between therapeutic and toxic dosesis narrow and therapy must be guided by monitoringof the plasma concentration once a steady stateis reached. Increments are made at weekly intervalsuntil the concentration lies within the range of0.4–1 mmol/L (maintenance at the lower level ispreferred for elderly patients). The plasmaconcentration should be checked every 3 months.Thyroid function and renal function (plasma creatinine and electrolytes) should be measuredbefore initiation and every 3 months during therapy.

Side-effects of Lithium

CNS: ataxia, dysarthria, choreoathetoid disturbances, extrapyrimidal symptoms, confusion, tremor, epilepticseizures, spasms, stupor, sedation, lethargy.

CVS: arrhythmia, hypertension, circulatory collapse.

Other effects: weight increase, muscular hypotonia,anorexia, nausea, vomiting, thirst, rash etc.

The manic phase in bipolar affective disorderoften requires treatment with neuroleptics(chlorpromazine, haloperidol), though lithium orvalproic acid supplemented with high-potencybenzodiazepines (eg, lorazepam or clonazepam)may suffice in milder cases.

Recent controlled trials support the efficacy ofmonotherapy with atypical antipsychotics (olanzapine) in the acute phase (up to 4 weeks)of mania.

PsychostimulantsPsychostimulants have predominant cortical action. Their psychiceffects are more important than those on medullary vital centres.

(1) Methylxanthines

Three methylxanthines are pharmacologicallyimportant: caffeine, theophylline, and theobromine.All of them occur naturally in certain plants.

Only caffeine is used as a CNS stimulant. It is widelyconsumed in the form of beverages, including asinfusions or decoctions, derived from these plants.

Coffea arabica (seeds)In an averagecup of coffee:Caffeine 75 mg

Theobromacacao (cocoa)In an average cup of cocoa:Caffeine 4 mgTheobromine 200 mg

Cola acuminata(Guru nuts)In 330 ml bottleof cola drink:Caffeine 50 mg

Methylxanthines (purine alkaloids)Caffeine, Theophylline, Theobromine

Thea sinensis(leaves)In an average cup of tea:Caffeine 50 mgTheophylline 1 mg

Actions of methylxanthinesThey block adenosine-1-receptors. Adenosine acts as a localmediators in CNS, CVS and other systems. Adenosine contractsbronchial muscles, dilates cerebral blood vessels, depressescardiac pacemaker and inhibits gastric secretions.Methylxanthines inhibit phosphodiesterase which degradesintracelullarly cAMP. Theophylline-containing preparationsenhance cAMP accumulation. It results in bronchodilation,vasodilation and cardiac stimulation (including tachycardia).Caffeine and theophylline are CNS stimulants, primarily affect thehigher centres. Caffeine (150 to 250 mg) produces a sense ofwellbeing, alertness, beats boredom, alleviates fatigue; thinkingbecomes clear, improves performance and increases motoractivity.

As a CNS stimulant caffeine is more active than theophylline.In higher doses caffeine causes nervousness, restlessness, panic, insomnia, and excitement. Still higher doses produces tremor, arrhythmia, delirium, and convulsions.Methylxanthines, especially caffeine, also stimulate medullaryvagal, respiratory and vasomotor centres (analeptic effect).Vomiting in higher doses is due to both to gastric irritation and stimulation of chemoreceptor trigger zone (CTZ).

Methylxanthines directly stimulate the heart and increase forceof myocardial contraction. They tend to increase heart rate bydirect action, but also decrease it by vagal stimulation. Net effectis variable. Tachycardia is more common with theophylline.

Cardiac output is increased. This action is more marked in CHF patients. At highdoses cardiac arrhythmias may be produced.Methylxanthines, especially theophylline, dilate systemic bloodvessels, including coronaries. Cranial vessels are constrictedby caffeine: this is one of the bases of its use in migraine.Effect of blood pressure is variable and unpredictable. Usuallya rise in systolic and fall in diastolic BP is observed.

Antiasthmatic (bronchodilatation) effect of theophylline ismore potent then those of caffeine.

ATP 3’, 5’-AMPcAMP

Lipolysis

(–)

AC PD

Cholesterol synthesis

Caffeine > 300 mg/d:5–6 coffee cups daily

(+)

(+)

Hypercholesterolemia

Methylxanthines are mild diuretics. They act by inhibiting tubularreabsorption of Na+ and water. Theophylline and theobromineare more potent diuretics than caffeine.

At high dose caffeine enhances the contractile power of skeletalmuscle: it increases release of Ca2+ from sarcoplasmaticreticulum by direct action. In addition, caffeine facilitatesneuromuscular transmission by increasing ACh release. Itscentral action relieves fatigue and increases muscular work.

Methylxanthines enhance secretion of acid and pepsin in thestomach, even on parenteral application. They are gastricirritants – theophylline more than caffeine.

Caffeine is an alkaloid with pKb 0.8. It is rapidly absorbed afteroral administration. It is < 50% bound to plasma proteins. Itst1/2 is 4 h. Caffeine is nearly completely metabolized in the liver bydemethylation and oxidation, and excreted in urine. Caffeine isto be avoided in peptic ulcer patients. It is not contraindicatedin gout because it is not converted in the body to uric acid. Moderate coffee drinking does not contribute todevelopment of hypertension.

Uses of caffeine• In analgesic drug combinations: caffeine benefits headache probably by allaying fatigue and boredom.• Migraine attacks: in combination with ergotamine. • To counteract hypnotic overdose, but its value is doubtful, better not to be used.

Caffeine is an alkaloid with pKb 0.8. It is rapidly absorbed afteroral administration. It is < 50% bound to plasma proteins. Itst1/2 is 4 h. Caffeine is nearly completely metabolized in the liver bydemethylation and oxidation, and excreted in urine. Caffeine isto be avoided in peptic ulcer patients. It is not contraindicatedin gout because it is not converted in the body to uric acid. Moderate coffee drinking does not contribute todevelopment of hypertension.

Uses of caffeine• In analgesic drug combinations: caffeine benefits headache probably by allaying fatigue and boredom.• Migraine attacks: in combination with ergotamine. • To counteract hypnotic overdose, but its value is doubtful, better not to be used.

(2) Amphetamines

Amphetamines are central indirect adrenomimetics. Highercentral and peripheral activity ratio is exhibited by dextro-amphetamine and methylamphetamine (methamphetamine). Amphetamines stimulate mental than motor activity.Convulsive doses are much higher.Abuse potential of the amphetamines is very high!

Methylphenidate is chemically and pharmacologically similarto amphetamine. Both act by releasing NA and DA in the brain.Both produce increase in mental activity at doses which havelittle action on other central and peripheral functions. Methylphenidate is considered superior to amphetamine fortreatment of hyperkinetic children (attention deficit disorder)because it causes less tachycardia and growth retardation.Behaviour and learning ability are improved in 75% of cases.Methylphenenidate can also be used for concentration andattention defect in adults, and for narcolepsy. Side effects of methylphenidate are anorrhexia, insomnia,abdominal discomfort, and bowel upset.

(3) Cocaine(3) Cocaine is an alkaloid from the leaves of Erythroxylon coca, a South American plant. The natives of Peru and BoliviaPeru and Bolivia habituallychew these leaves. Cocaine is used sometimes in ocularanaesthesia as eyes drops. It should be never beinjected because it can causes tissue necrosis.After system absorption cocaine produces prominent CNSstimulation with marked effect on mood and behaviour (a senseof wellbeing, delays fatigue and increases power of endurance).In susceptible individuals it produces strong psychological,but not physical dependence. Cocaine is unique among Cocaine is unique among drugs ofdrugs ofabuseabuse, because it is does , because it is does not produce tolerance on repeutednot produce tolerance on repeuteduseuse. It also stimulate vagal, vasomotor, vomiting andthermoregulatory centres. In periphery it blocks reuptake of NAand adrenaline and acts indirectly as a sympathomimetic.

Nootropic drugs (cognition enhancers)

Piracetam is a cyclic GABA derivative withoutGABA like activity. Piracetam selective improves efficiency of higher encephalic integrative activity by:

• Enhancement of learning and memory• Facilitation of interhemisphere information transfer• Increased tonic cortical control of subcortical areas• Improves ATP/ADP ratio in encephalon• Stimulates synaptic transmission, etc.

The indications of piracetam are:• Senile dementia of Alzheimer type, multi-infarct dementia, etc.• Mental retardation and learning problems in children• Cerebrovascular accident: to hasten recovery• To reduce impairment of consciousness following brain trauma or brain surgery, memory impairment after electroconvulsive therapy, and central vertigo.The validity of evidence for drug induced cognition enhancement has not been established. ADRs: gastric discomfort, excitement, insomnia, dizziness,skin rash.

Pramiracetam has similar properties and indications.

www.medpharm-sofia.eu> 600 files& > 300 links

www.medpharm-sofia.eu> 600 files& > 300 links