Medical University of Sofia Faculty of M Department

Medical University of Sofia, Faculty of M Department of Pharmacology and Toxico • Antidepressants • Mood stabilizers • Psychostimulants • Nootropic drugs • CNS stimulants (Abstract) Assoc. Prof. Iv. Lambev www. medpharm-sofia. eu

Depression is a heterogeneous disorder. A sim classification based on presumed origin is as f (1) brief reactive or secondary depression (most comm occurring in response to real stimuli such as grief, illn (2) major depression (melancholic and recurrent depr a genetically determined biochemical disorder ma by an inability to experience ordinary pleasure or to co ordinary life events; (3) manic-depressive depression (depression associate bipolar affective disorder) Pharmacologic treatment of depressions is very important a continuing role for electroconvulsive therapy for sever life-threatening depression is also noted.

mani c

Depression is one of the most common psychiatric disord At any given moment, about 3– 5% of the population is de and an estimated 10% of people may become depressed their lives. The symptoms of depression are often sub unrecognized both by patients and by physicians. Pa vague complaints that resist explanation as manifestation somatic disorders and those who might be simplistically d as “neurotic” should be suspected of being depressed. Soon after the introduction of reserpine (1948), it became apparent that the drug could induce depression by inhibiti neuronal storage of amine neurotransmitters 5 -HT and NE Reserpine-induced depression and depleted stores of am transmitters. It was reasoned, depression must be associ with decreased functional amine-dependent synaptic tran

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 transmission provided 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

(5 -HT) (NE) (DA) The effects of DA, 5 -HT and NE on the brain fu

Raised neurotransmitter concentrations produce immediate alterations in postsynaptic receptor activation, leading to changes in second messenger (intracellular) systems and to gradual modifications in cellular protein expression. Antidepressants increase a cyclic AMP response-element binding (CREB) protein which in turn is involved in regulating the transcription of genes that influence survival of other proteins including brain derived neurotrophic factor (BDNF) which exerts effects on neuronal growth. The role of BDNF in depression is supported by the observation that stress both reduces its expression and impairs neurogenesis.

The monoamine hypothesis of depression oversimplification (only deficieny of NA, 5 -HT, an DA) of a complicated picture. Other systems are implicated in the etiology of depression (a which provide potential targets for drug thera include the hypothalamo-pituitarythyroid axis the hypothalamo-pituitary-adrenal axis (HPA) The finding that 50% of depressed patients h elevated plasma cortisol concentrations cons evidence that depression is associated wit increased HPA drive.

- - - - - - - - - - - - - - - Monoamine Reuptake Inhibitors α 2 -adrenergic blockers (1) Tricyclic antidepressants (non-selective inhibitors) (1 a) Drugs Desipramine Nortriptyline (1 b) Prodrugs Amitriptyline Clomipramine Doxepin Imipramine (3) Selective SSRIs Citalopram, Fluoxetine (2) Selective NARIs Escitalopram, Fluvoxamine Reboxetine Paroxetine, Sertraline Mianserin* Mirtazapine Trazodone MAO inhibitors Moclobemide (MAO-A) Nialamide (MAO-A & B) Selegiline (irreversible MAO-B)

Structural relationships between various tricyclic antidepressants (TCAs) Their structures are similar to phenothia

Selective serotonin reuptake inhibitors (SSRIs).

Pharmacokinetics The antidepressants are generally well absorbed after oral administration. Steady-state plasma concentrations of TCAs show great individual variation but correlate with therapeutic effect. Antidepressants in general are inactivated principally by metabolism by hepatic cytochrome P 450 enzymes (2 D 6 and 3 A 4). Other cytochrome enzymes are CYP 1 A 2 inhibited by the SSRI fluvoxamine, and induced by cigarette smoking, caffeine and the atypical antipsychotics (clozapine and olanzapine).

Several of these drugs produce active metabolites which prolong their action (e. g. fluoxetine is metabolized to norfluoxetine, t 1/2 200 h). The metabolic products of certain TCAs are antidepressants too, e. g. nortriptyline (from amitriptyline), desipramine (from imipramine). Half-lives of TCAs and SSRIs are long (> 15 h). Around 7% of the Caucasian population have very limited CYP 2 D 6 enzyme activity. Such “poor metabolizers” may find standard doses of tricyclic antidepressants intolerable and it is often worth starting at a very low dose.

Clinical indications The major indication is to treat depression, but a nu other uses have been established by clinical experi Antidepressants may benefit most forms of anxiety d (panic disorder, generalized anxiety disorder, post-tr stress, obsessive-compulsive disorder, and social ph migraine. SSRIs are effective in milder cases of the eating dis bulimia nervosa, particularly fluoxetine (in higher d are required for depression). Antidepressants appe ineffective 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 tr Adapted from Bennett and Brown (2003)

Mode of use The action of TCAs in ameliorating mood is usually absent in the first 2 weeks of therapy and at least 4 weeks must elapse to constitute an adequate trial. Where a minimal response is noted in this period, it is reasonable to extend the trial to 6 weeks to see if further benefit is achieved. Dose titration is often necessary. By contrast, patients may experience unwanted drug effects immediately on starting treatment (and they should be warned), but such symptoms often diminish with time. TCAs are given either in divided doses or, for the more sedative compounds, as a single evening dose.

SSRIs have advantages over tricyclics in simplicity of introduction and use. Dose titration is often unnecessary since the minimum therapeutic dose can usually be tolerated as a starting dose. Divided doses are not required and administration is by a single morning or evening dose. Patients commencing treatment on SSRIs are more likely to reach an effective dose than those starting on TCAs. Venlafaxine is licensed for treatment-resistant depression by gradual dose titration. There is some need for dose titration when using MAOIs.

Side effects of TCAs Anticholinergic (atropine-like): dry mouth, blurred vis accommodation disturbances, increased ocular pressu stipation, urinary retention, sweating, adynamic ileus (v CNS: dizziness, tiredness, confusion, tremor, insomnia seizures, exacerbation of psychotic symptoms. CVS: postural hypotension, sinus tachycardia, arrhythm Blood: leucopenia, agranulocytosis, thrombocytopenia Haemolytic anaemia. Other ADRs: impaired respiration, libido changes, tinn complaints, liver function disturbances, increased body

TCAs – Interactions: Potential Results MAOIs hyperthermia, palpitations, excitation Adrenomimetics hypertension, hyperthermia, tachycardia Alcohol effect of alcohol may be increased Clonidine, Methyldopa decreased hypotensive effects T 3, T 4 enhanced potential for CV toxicity Physostigmine antagonism Anticholinergics additional anticholinergic activity Neuroleptics inhibition of metabolism of antidepressants overreaction of levodopa Levodopa

Precautions: close supervision, especially in early pha treatment (suicide risk of TCAs). The possibility of unma a latent psychosis should be considered. A switch into a m or hypomanic condition may occur (“switch process”). Caution should be exercised in CVD, history of urinary re narrow-angle glaucoma, and thyroid disease. Side-effects of SSRIs (mainly during the 1 st and 2 nd weeks of treatment): CNS: ache, restleness; CVS: bradycaria; GIT: nausea, diarrhoe The serotonin syndrome is a rare but dangerous compl with features restlessness, tremor, hуperthermia, conv coma and death. Risk is increased by co-administration w MAOIs, the antimigraine drug sumatriptan, and St. John’s

Trazodone acts by antagonism of central presynaptic alpha-2 -adrenoceptors. It is an option for depressed patients where heavy sedation is required. Trazodone also has the advantages of lacking antimuscarinic effects an relatively safe in overdose. Males should be warn of the possibility of priapism (painful penile erecti due to the blockade of peripheral postsynaptic alpha-1 -adrenoceptors. Mianserin has the advantages of lacking antimu effects too, but can cuases aplastic anaemia.

Side-effects of MAOIs • Moclobemide (selective reversible MAO-A in • CNS: insomnia, restlessness, confusion, dizziness. CVS: arrhythmia, tachycardia, palpitations, • Nialamide (irreversible nonselective MAO-A & B i can cause high blood pressure. The following foods a high blood pressure beverages should be avoided – tyramine containing nu maturated cheese (“cheese syndrome” – high blood pre syndrome yogurt, broad (fava) beans, green bean pods, chocolate, or pickled fish, meat extracts containing brewer's yeast, f ausages (e. g. salami); red wine, sherry, beer and excess amounts of alcohol; bananas, avocados, pineapple, coco

OTHER ANTIDEPRESSANTS: Agomelatine (Valdoxan®) is a melatonergic agonist (MT 1 - and MT 2 -receptors) and 5 -HT 2 C antagonist. It has no effect on monoamine reuptake and no affinity for α, β adrenergic, histaminergic, cholinergic, dopaminergic and benzodiazepine receptors. Agomelatine is indicated for the treatment of major depressive episodes in adults. It not use in chlidren below 18 years of age due to a lack of data on safety and efficacy.

Many patients with mild to moderate depression aware of the benefits of the herbal remedy St. J Wort. The major active antidepressive constituen thought to be hyperforin and hypericin. Some b that hyperforin is the major constituent responsible for antidepressant activity. It inhibits the reuptake of 5 -HT, DA, and NA. Hyperforin also has affinity for GABA and glutamate receptors. Hypericum perforatum L.

St. John’s Wort Many patients with mild to moderate depression aware of the benefits of the herbal remedy St. J Wort. The major active antidepressive constituen thought to be hyperfurin and hypericin. Some That hyperfurin is the major constituent respon antidepressant activity. It inhibits the reuptak 5 -HT, DA, and NA (NE). Hyperfurin also has affinity for GABA and glutam receptors.

Use of St. John’s Wort is complicated by the lack of standardization of the ingredients. Those who wish to take St. John's Wort should be made aware that it may cause dry mouth, dizziness, sedation, GI disturbance and confusion. It induces hepatic CYP 1 A 2 and CYP 3 A 4 with the result that the plasma concentration and therapeutic efficacy of warfarin, oral contraceptives, some anticonvulsants, antipsychotics and HIV protease/reverse transcriptase inhibitors are reduced. Concomitant use of tryptophan and St. John’s Wort may cause serotoninergic effects including nausea and agitation.

Electroconvulsive therapy (ECT) involves the passage of a small electric charge across the brain by e applied to the frontotemporal aspects of the scalp with inducing a tonic-clonic seizure. ECT requires the patien receiving a general anaesthetic. It may cause memory although this is generally transient. ECT is usually reserved for psychiatric illness where pharmacotherapy has been unsuccessful for instance the severely depressed patient who has stopped eating drinking. Modern-day ECT is a safe and effective alte to pharmacotherapy and remains a first-line option in cl circumstances where rapid, response is desired, when be life-saving.

Mood stabilizers In bipolar affective disorder patients suffer episodes of mania, hypomania and depression, classically with periods of normal mood in between. Manic episodes involve greatly elevated mood, often interspersed with periods of irritability or undue excitement, accompanied by biological symptoms (increased energy, restlessness, decreased need for sleep, increased sex drive), loss of social inhibitions, irresponsible behaviour and grandiosity. Psychotic features may be present, particularly disordered thinking, manifested by grandiose delusions and “flight of ideas” with rapid speech.

Hypomania is a less dramatic and dangerous presentation but retains the features of elation or irritability and the biological symptoms, abnormalities in speech and in social conduct to overfamiliarity and mild recklessness. Depressive episodes include depressive symptoms described before and may include psychotic features. Lithium salts are ineffective for prophylaxis of bipolar affective disorder in around 35% of patients and cause severe unwanted effects. The search for alternatives has produced drugs that are more famous as anticonvulsants (carbamazepine and sodium valproate, and possibly lamotrigine).

The main effect of lithium is probably to inh hydrolysis of inositol phosphate, so reducing recycling of free inositol for synthesis of phosphatidylinositides. These intracellular mole are part of the transmembrane signaling system is important in regulating intracellullar calcium io concentration, which subsequently affects neurotransmitter release. Other putative mecha involve the cyclic AMP “second messenger” sys and monoaminergic and cholinergic neurotrans

Action of lithium on the IP 3 and DAG second-messenger The schematic diagram shows the synaptic membrane of a n (PIP 2 – phosphatidylinositol-4, 5 -bisphosphate; PLC – phospholipa G – G-coupling protein). Result: activation of protein kinase C, m of intracellular Ca 2+, etc. Lithium, by inhibiting the recycling of substrates, may cause depletion of the second-messenger so and therefore reduce the release of IP 3 and DAG.

The therapeutic plasma concentration is close the toxic concentration (low therapeutic index). L is a small ion that, given orally, is rapidly absorbed throughout the gut. High peak plasma concentratio are avoided by using sustained-release formulation which deliver the peak plasma lithium concentratio With chronic use the plasma t 1/2 of lithium is 15– Lithium is usually given 12 -hourly to avoid unneces fluctuation (peak and trough concentrations) and to maintain a plasma concentration just below the tox level. A steady-state plasma concentration will attained after about 5– 6 days (i. e. 5 x t 1/2).

Lithium carbonate is effective treatment in 75% of episodes of acute mania or hypomania. Because its therapeutic action takes 2– 3 weeks to develop, lithium is generally used in combination with lorazepam or diazepam (or with a neuroleptics where there also psychotic features). For prophylaxis, lithium is indicated when there have been two episodes of mood disturbance in two years.

Lithium is also used to augment the action of antidepressants in treatment-resistant depressio The difference between therapeutic and toxic do is narrow and therapy must be guided by monito of the plasma concentration once a steady state is reached. Increments are made at weekly inter until the concentration lies within the range of 0. 4– 1 mmol/L (maintenance at the lower level is preferred for elderly patients). The plasma concentration should be checked every 3 month Thyroid function and renal function (plasma creatinine and electrolytes) should be measured before initiation and every 3 months during thera

Side-effects of Lithium CNS: ataxia, dysarthria, choreoathetoid disturbances, extrapyrimidal symptoms, confusion, tremor, epileptic seizures, 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 disorder often requires treatment with neuroleptics (chlorpromazine, haloperidol), though lithium or valproic acid supplemented with high-potency benzodiazepines (eg, lorazepam or clonazepam) may suffice in milder cases. Recent controlled trials support the efficacy of monotherapy with atypical antipsychotics (olanzapine) in the acute phase (up to 4 weeks) of mania.

Psychostimulants have predominant cortical action. The effects are more important than those on medullary vital c (1) Methylxanthines Three methylxanthines are pharmacologicall important: caffeine, theophylline, and theobro All of them occur naturally in certain plants. Only caffeine is used as a CNS stimulant. It is wid consumed in the form of beverages, including as infusions or decoctions, derived from these plants

Methylxanthines (purine alkaloids) Caffeine, Theophylline, Theobromine Coffea Theobroma Cola acuminata. Thea sinensis arabica (seeds)cacao (cocoa) (Guru nuts) (leaves) In an average In 330 ml bottle In an average cup of coffee: cup of cocoa: of cola drink: cup of tea: Caffeine 75 mg. Caffeine 4 mg Caffeine 50 mg Theobromine 200 mg Theophylline 1 mg

Actions of methylxanthines They block adenosine-1 -receptors. Adenosine acts mediators in CNS, CVS and other systems. Adenosine co bronchial muscles, dilates cerebral blood vessels, depres cardiac pacemaker and inhibits gastric secretions. Methylxanthines inhibit phosphodiesterase which degra intracelullarly c. AMP. Theophylline-containing preparations enhance c. AMP accumulation. It results in bronchodilation vasodilation and cardiac stimulation (including tachycardia Caffeine and theophylline are CNS stimulants, primarily a higher centres. Caffeine (150 to 250 mg) produces a sens wellbeing, alertness, beats boredom, alleviates fatigue; th becomes clear, improves performance and increases mot activity.

As a CNS stimulant caffeine is more active than theoph In higher doses caffeine causes nervousness, restlessn panic, insomnia, and excitement. Still higher doses pro tremor, arrhythmia, delirium, and convulsions. Methylxanthines, especially caffeine, also stimulate med vagal, respiratory and vasomotor centres (analeptic effe Vomiting in higher doses is due to both to gastric irritatio stimulation of chemoreceptor trigger zone (CTZ). Methylxanthines directly stimulate the heart and increas of myocardial contraction. They tend to increase heart r direct action, but also decrease it by vagal stimulation. N is variable. Tachycardia is more common with theop

Cardiac output is increased. This action is more marked in CHF patients. At high doses cardiac arrhythmias may be produced. Methylxanthines, especially theophylline, dilate system vessels, including coronaries. Cranial vessels are co by caffeine: this is one of the bases of its use in m Effect of blood pressure is variable and unpredictable. a rise in systolic and fall in diastolic BP is observe Antiasthmatic (bronchodilatation) effect of theoph more potent then those of caffeine.

Caffeine > 300 mg/d: 5– 6 coffee cups daily (– ) ATP AC c. AMP 3’, 5’-AMP Hypercholesterolemia (+) Lipolysis PD (+) Cholesterol synthesis

Methylxanthines are mild diuretics. They act by inhibitin reabsorption of Na+ and water. Theophylline and theob are more potent diuretics than caffeine. At high dose caffeine enhances the contractile power o muscle: it increases release of Ca 2+ from sarcoplasma reticulum by direct action. In addition, caffeine facilitate neuromuscular transmission by increasing ACh release central action relieves fatigue and increases muscula Methylxanthines enhance secretion of acid and pepsin stomach, even on parenteral application. They are gast irritants – theophylline more than caffeine.

Caffeine is an alkaloid with p. Kb 0. 8. It is rapidly absorbed oral administration. It is < 50% bound to plasma proteins. t 1/2 is 4 h. Caffeine is nearly completely metabolized in the demethylation and oxidation, and excreted in urine. Caffe to be avoided in peptic ulcer patients. It is not contra in gout because it is not converted in the body to uric aci Moderate coffee drinking does not contribute to development of hypertension. Uses of caffeine • In analgesic drug combinations: caffeine benefits heada probably by allaying fatigue and boredom. • Migraine attacks: in combination with ergotamine. • To counteract hypnotic overdose, but its value is do better not to be used.

Caffeine is an alkaloid with p. Kb 0. 8. It is rapidly absorbed oral administration. It is < 50% bound to plasma proteins. t 1/2 is 4 h. Caffeine is nearly completely metabolized in the demethylation and oxidation, and excreted in urine. Caffe to be avoided in peptic ulcer patients. It is not contra in gout because it is not converted in the body to uric aci Moderate coffee drinking does not contribute to development of hypertension. Uses of caffeine • In analgesic drug combinations: caffeine benefits heada probably by allaying fatigue and boredom. • Migraine attacks: in combination with ergotamine. • To counteract hypnotic overdose, but its value is do better not to be used.

(2) Amphetamines

Amphetamines are central indirect adrenomimetic central and peripheral activity ratio is exhibited by dextr amphetamine and methylamphetamine (methamphe Amphetamines stimulate mental than motor activity. Convulsive doses are much higher. Abuse potential of the amphetamines is very

Methylphenidate is chemically and pharmacologically to amphetamine. Both act by releasing NA and DA in th Both produce increase in mental activity at doses which little action on other central and peripheral functions. Methylphenidate is considered superior to amphetamin treatment of hyperkinetic children (attention deficit d because it causes less tachycardia and growth reta Behaviour and learning ability are improved in 75% Methylphenenidate can also be used for concentration attention defect in adults, and for narcolepsy. Side effects of methylphenidate are anorrhexia, insom abdominal discomfort, and bowel upset.

(3) Cocaine is an alkaloid from the leaves of Erythroxy a South American plant. The natives of Peru and Bolivia chew these leaves. Cocaine is used sometimes in ocular anaesthesia as eyes drops. It should be never be injected because it can causes tissue necrosis. After system absorption cocaine produces prominent CN stimulation with marked effect on mood and behaviour (a of wellbeing, delays fatigue and increases power of endu In susceptible individuals it produces strong psychologi but not physical dependence. Cocaine is unique amon abuse, because it is does not produce tolerance on rep use. It also stimulate vagal, vasomotor, vomiting and use thermoregulatory centres. In periphery it blocks reuptak and adrenaline and acts indirectly as a sympathomime

Nootropic drugs (cognition enhancers) Piracetam is a cyclic GABA derivative w GABA like activity. Piracetam selective improves efficiency of higher encephalic integrative activity by: • Enhancement of learning and memory • Facilitation of interhemisphere information transf • Increased tonic cortical control of subcortical are • Improves ATP/ADP ratio in encephalon • Stimulates synaptic transmission, etc.

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

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