Medical University of Sofia, Faculty of Medicine Department of Pharmacology and Toxicology

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

(Abstract)

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

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

(1) brief reactive or secondary depression

ordinary life events;

(3) manic-depressive depression

(most common), occurring in response to real stimuli such as

grief, illness (2) major depression (melancholic and recurrent depression) a genetically determined biochemical disorder

, etc; manifested by an inability to experience ordinary pleasure or to cope with (depression associated with

bipolar affective disorder

a continuing role for ) Pharmacologic treatment of depressions is very important, although

electroconvulsive therapy

for severe forms of life-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 with vague complaints that resist explanation as manifestations of somatic disorders and those who might be simplistically described 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 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 associated with 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 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, of 5-HT, NA, or both.

.

except bupropion are classified as having their primary actions on the metabolism, reuptake, or selective receptor antagonism

.

,

(NE) (5-HT) (DA)

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

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

c

yclic AMP

r

esponse-

e

lement

b

inding

( CREB ) protein

which in turn is involved in regulating the transcription of genes that influence survival of other proteins including

b

rain

d

erived

n

eurotrophic

f

actor (

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

is an

(

only deficieny of NA, 5-HT, and DA

)

of a complicated picture. include the

Other systems

are implicated in the etiology of depression (and which provide potential targets for drug therapy)

hypothalamo-pituitarythyroid axis and the hypothalamo-pituitary-adrenal axis

(HPA). that The finding that

50% of depressed patients have elevated plasma cortisol

concentrations constitutes evidence that

depression is associated with increased HPA drive

.

Structural relationships between various 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 plasma concentrations of TCAs show great individual variation but correlate with therapeutic effect.

Antidepressants in general are inactivated princi pally by metabolism by hepatic cytochrome P450 enzymes (2D6 and 3A4). Other cytochrome enzymes are CYP 1A2 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 meta bolic 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 2D6 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 number of

other uses

migraine

.

have been established by clinical experience.

Antidepressants may benefit most forms of SSRIs are effective in milder cases of the

anxiety disorder

(panic disorder, generalized anxiety disorder, post-traumatic stress, obsessive-compulsive disorder, and social phobia),

eating disorder

bulimia nervosa

, particularly fluoxetine (in higher doses than are required for depression).

Antidepressants appear to be

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 treatments

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 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, GI complaints, liver function disturbances, increased body weight.

TCAs – Interactions: Potential Results MAOIs

hyperthermia, palpitations, excitation

Adrenomimetics Alcohol Clonidine, Methyldopa T3, T4 Physostigmine Anticholinergics Neuroleptics Levodopa Lithium

hypertension, hyperthermia, tachycardia effect of alcohol may be increased decreased hypotensive effects enhanced potential for CV toxicity antagonism additional anticholinergic activity inhibition of metabolism of antidepressants overreaction of levodopa the therapeutic response is increased in some cases and suppressed in others

Precautions:

close supervision, especially in early phase of treatment (

suicide risk of TCAs

). The possibility of unmasking a latent psychosis should be considered. A switch into a manic or hypomanic condition may occur (

“switch process”

narrow-angle glaucoma, and thyroid disease. ).

Caution should be exercised in CVD, history of urinary retention,

Side-effects of SSRIs

(mainly during the 1 The st and 2

serotonin syndrome

nd weeks of treatment): CNS: head ache, restleness; CVS: bradycaria; GIT: nausea, diarrhoea is a rare but dangerous complication with features

restlessness, tremor, hуperthermia, convulsions

, coma and death. Risk is increased by co-administration with MAOIs, 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

pickled fish, meat extracts containing ” – high blood pressure), broad beans, smoked or 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 heavy sedation is required. Trazodone also has the advantages of

lacking antimuscarinic effects

of the possibility of

priapism

and being relatively safe in overdose. Males should be warned (painful penile erections), due to the

blockade of peripheral postsynaptic alpha-1-adrenoceptors

.

Mianserin has the advantages of

lacking antimuscarinic effects too

, but can cuases

aplastic anaemia

.

Agomelatine

(Valdoxan ® )

is a melatonergic agonist (MT

1

- and MT

2

-receptors) and 5-HT

2C 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 are aware of the benefits of the herbal remedy

St. John’s Wort.

The major active antidepressive constituents are thought to be

hyperforin and hypericin

. Some believe 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 are aware of the benefits of the herbal remedy St. John’s Wort.

The major active antidepressive constituents are thought to be

hyperfurin and hypericin

. Some believe That

hyperfurin

is the major constituent responsible for antidepressant activity. It receptors.

inhibits the reuptake of

5-HT, DA, and NA (NE).

Hyperfurin also has affinity for GABA and glutamate

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 1A2 and CYP 3A4 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) passage of a small electric charge across the brain by electrodes applied to the frontotemporal aspects of the scalp with the aim of inducing a tonic-clonic seizure. ECT requires the patient to be receiving a general anaesthetic. It may cause involves the

memory deficit

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 or drinking

.

Modern-day ECT is a safe and effective alternative

to pharmacotherapy and remains a first-line option in clinical circumstances where rapid, response is desired, when it can 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 inhibit hydrolysis of inositol phosphate

, so reducing the recycling of free inositol for synthesis of phosphatidylinositides. These intracellular molecules are part of the transmembrane signaling system that is important in regulating intracellullar calcium ion concentration, which subsequently affects neurotransmitter release. Other putative mechanisms involve the cyclic AMP “second messenger” system and monoaminergic and cholinergic neurotransmitters.

Action of lithium on the IP

The schematic diagram shows the synaptic membrane of a neuron.

(PIP

2

– phosphatidylinositol-4,5-bisphosphate; PLC – phospholipase-C; G – G-coupling protein).

3

Result:

and DAG second-messenger system.

activation of protein kinase C, mobilization of intracellular Ca 2+ , etc. Lithium, by inhibiting the recycling of inositol

substrates, may cause depletion of the second-messenger source PIP 2 and therefore reduce the release of IP 3 and DAG.

The therapeutic plasma concentration is close to the toxic concentration

(low therapeutic index). Lithium is a small ion that, given orally, is rapidly absorbed throughout the gut. High peak plasma concentrations are avoided by using sustained-release formulations which deliver the peak plasma lithium concentrations in 5 h.

With chronic use the level.

plasma t 1/2

of lithium is 15–30 h.

Lithium is usually given 12-hourly to avoid unnecessary fluctuation (peak and trough concentrations) and to maintain a plasma concentration just below the toxic

A steady-state plasma concentration will be 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 are 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 depression.

The difference between therapeutic and toxic doses is narrow and therapy must be guided by monitoring of the plasma concentration once a steady state is reached. Increments are made at weekly intervals 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 months

.

Thyroid function and renal function (plasma creatinine and electrolytes) should be measured before initiation and every 3 months during therapy.

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)

of mania.

in the acute phase (up to 4 weeks)

Psychostimulants

Psychostimulants have predominant cortical action. Their psychic effects are more important than those on medullary vital centres.

(1) Methylxanthines

Three methylxanthines are pharmacologically important: caffeine, theophylline, and theobromine.

All of them occur naturally in certain plants.

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

Methylxanthines (purine alkaloids)

Caffeine, Theophylline, Theobromine

Coffea

arabica (seeds) In an average cup of coffee:

Caffeine 75 mg

Theobroma

cacao (cocoa) In an average cup of cocoa: Caffeine 4 mg

Cola acuminata

(Guru nuts) In 330 ml bottle of cola drink:

Caffeine 50 mg

Theobromine 200 mg

Thea sinensis

(leaves) In an average cup of tea:

Caffeine 50 mg

Theophylline 1 mg

Actions of methylxanthines

They

block adenosine-1-receptors

. Adenosine acts as a local mediators in CNS, CVS and other systems. Adenosine contracts bronchial muscles, dilates cerebral blood vessels, depresses cardiac pacemaker and inhibits gastric secretions.

Methylxanthines inhibit phosphodiesterase which degrades intracelullarly cAMP. Theophylline-containing preparations enhance cAMP accumulation. It results in bronchodilation, vasodilation and cardiac stimulation (including tachycardia).

Caffeine and theophylline are CNS stimulants, primarily affect the higher centres. Caffeine (150 to 250 mg) produces a sense of wellbeing, alertness, beats boredom, alleviates fatigue; thinking becomes clear, improves performance and increases motor activity.

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 medullary vagal, 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 force of myocardial contraction. They tend to increase heart rate by direct action, but also decrease it by vagal stimulation. Net effect is variable. Tachycardia is more common with theophylline.

Cardiac output is increased. This action is more marked in CHF patients. At high doses cardiac arrhythmias may be produced.

Methylxanthines, especially theophylline, dilate systemic blood vessels, including coronaries. Cranial vessels are constricted by caffeine: this is one of the bases of its use in migraine.

Effect of blood pressure is variable and unpredictable.

Usually a rise in systolic and fall in diastolic BP is observed.

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

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

Methylxanthines are mild diuretics. They act by inhibiting tubular reabsorption of Na + and water. Theophylline and theobromine are more potent diuretics than caffeine.

At high dose caffeine

enhances the contractile power of skeletal muscle: it

increases release of Ca 2+ from sarcoplasmatic reticulum by direct action

. In addition, caffeine facilitates neuromuscular transmission by

increasing ACh release

.

Its central action relieves fatigue and increases muscular work .

Methylxanthines enhance secretion of acid and pepsin in the stomach, even on parenteral application. They are

gastric irritants – theophylline more than caffeine

.

Caffeine is an alkaloid with pK b 0.8. It is rapidly absorbed after oral administration. It is < 50% bound to plasma proteins. Its t 1/2 is 4 h. Caffeine is nearly completely metabolized in the liver by demethylation and oxidation, and excreted in urine. Caffeine is

to be avoided in peptic ulcer patients. It is not contraindicated

in gout because it is not converted in the body to uric acid.

Moderate coffee drinking does not contribute to development 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 pK b 0.8. It is rapidly absorbed after oral administration. It is < 50% bound to plasma proteins. Its t 1/2 is 4 h. Caffeine is nearly completely metabolized in the liver by demethylation and oxidation, and excreted in urine. Caffeine is

to be avoided in peptic ulcer patients. It is not contraindicated

in gout because it is not converted in the body to uric acid.

Moderate coffee drinking does not contribute to development 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. Higher central 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 similar to amphetamine. Both act by releasing NA and DA in the brain.

Both produce increase in mental activity at doses which have little action on other central and peripheral functions. Methylphenidate is considered superior to amphetamine for treatment 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 and attention defect in adults, and for

narcolepsy.

Side effects of methylphenidate are anorrhexia, insomnia, abdominal discomfort, and bowel upset.

(3) Cocaine

is an alkaloid from the leaves of Erythroxylon coca, a South American plant. The natives of Peru and Bolivia habitually 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 CNS stimulation with marked effect on mood and behaviour (a sense of wellbeing, delays fatigue and increases power of endurance).

In susceptible individuals it produces strong psychological,

but not physical dependence use.

thermoregulatory centres. . Cocaine is unique among drugs of abuse, because it is does not produce tolerance on repeuted It also stimulate vagal, vasomotor, vomiting and In periphery it blocks reuptake of NA

and adrenaline

and acts indirectly as a sympathomimetic.

Nootropic drugs (cognition enhancers)

Piracetam

is a cyclic GABA derivative without GABA 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.

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