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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

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slide1

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

slide2

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, although

a continuing role for electroconvulsive therapy for severe forms of

life-threatening depression is also noted.

slide4

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 afterthe 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.

slide7

Rauwolfia serpentina

    • (a small indian shrub)
      • Reserpine
      • Ajmaline
slide8

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 the
  • metabolism, reuptake, or selective receptor antagonism
  • of 5-HT, NA, or both.
slide9

(5-HT)

(NE)

(DA)

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

slide10

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.

slide12

The monoamine hypothesis of depression is an

oversimplification(only deficieny of NA, 5-HT, and

DA)of a complicated picture. Other systems that

are implicated in the etiology of depression (and

which provide potential targets for drug therapy)

include the hypothalamo-pituitarythyroid axis and

the hypothalamo-pituitary-adrenal axis (HPA).

The finding that 50% of depressed patients have

elevated plasma cortisol concentrations constitutes

evidence that depression is associated with

increased HPA drive.

slide14

Structural relationships between

various tricyclic antidepressants (TCAs).

Their structures are similar to phenothiazines.

slide16

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).

slide17

Several of these drugs produce active metabolites

which prolong their action (e.g. fluoxetine is

metabolized to norfluoxetine, t1/2 200 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.

slide18

Clinical indications

The 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-traumatic

stress, obsessive-compulsive disorder, and social phobia),

migraine.

SSRIs are effective in milder cases of the eating disorder

bulimia nervosa, particularly fluoxetine (in higher doses than

are required for depression). Antidepressants appear to be

ineffective in anorexia nervosa.

slide19

SSRIs (selective serotonin

  • reuptake inhibitors)
  • are used in:
  • panic disorders
  • chronic anxiety
  • depression
  • bulimia neurosa
  • (fluoxetine – in higher doses)
slide20

Schematic representation of the time course of panic treatments

Adapted from Bennett and Brown (2003)

slide21

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.

slide22

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.

slide23

Side effects of TCAs

Anticholinergic (atropine-like): dry mouth, blurred vision,

accommodation disturbances, increased ocularpressure, 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,

Haemolyticanaemia.

Other ADRs: impairedrespiration,libido changes,tinnitus, GI

complaints, liver functiondisturbances,increased body weight.

slide25

Precautions:close supervision, especially in early phaseof

treatment (suicide risk of TCAs). The possibility of unmasking

a latentpsychosis should be considered. A switch into amanic

or 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, diarrhoea

The serotonin syndrome 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.

slide27

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 or

pickled fish, meat extractscontaining

brewer's yeast, fermentedsausages (e.g. salami);

red wine, sherry, beer and excessive amounts of alcohol.

slide28

Trazodone acts by antagonism of central

presynaptic alpha-2-adrenoceptors.

It is an option for depressed patients where heavy

sedationis required. Trazodone also has the

advantages of lacking antimuscarinic effects and being

relatively safe in overdose. Males should be warned

of the possibility of priapism (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.

slide29

Agomelatine (Valdoxan®) is

a melatonergic agonist

(MT1- and MT2-receptors) and 5-HT2C

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.

slide30

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 behyperforin and hypericin. Some believe

thathyperforin is the

major constituent responsible

forantidepressant activity.

Itinhibits the reuptake

of 5-HT, DA, and NA.

Hyperforin also has affinity

for GABA and glutamate

receptors.

Hypericum perforatum L.

slide31

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 behyperfurin and hypericin. Some believe

Thathyperfurin is the major constituent responsible for

antidepressant activity.Itinhibits the reuptake of

5-HT, DA, and NA (NE).

Hyperfurin also has affinity for GABA and glutamate

receptors.

slide32

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.

slide33

Electroconvulsive therapy (ECT)involves the

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 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.

slide34

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.

slide35

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).

slide36

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.

slide37

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, mobilization

of intracellular Ca2+, etc. Lithium, by inhibiting the recycling of inositol

substrates, may cause depletion of the second-messenger source PIP2

and therefore reduce the release of IP3 and DAG.

slide38

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 plasma t1/2 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

level. A steady-state plasma concentration will be

attained after about 5–6 days (i.e. 5 x t1/2).

slide39

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.

slide40

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.

slide41

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.

slide42

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.

slide43

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.

slide44

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

Theobromine 200 mg

Cola acuminata

(Guru nuts)

In 330 ml bottle

of cola drink:

Caffeine 50 mg

Thea sinensis

(leaves)

In an average

cup of tea:

Caffeine 50 mg

Theophylline 1 mg

slide45

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.

slide46

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 ofchemoreceptor 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.

slide47

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.

slide48

Caffeine >300 mg/d:

5–6 coffee cups daily

(–)

AC

PD

cAMP

ATP

3’, 5’-AMP

Hypercholesterolemia

(+)

(+)

Cholesterol synthesis

Lipolysis

slide49

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 Ca2+ 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.

slide50

Caffeine is an alkaloid with pKb 0.8. It is rapidly absorbed after

  • oral administration. It is < 50% bound to plasma proteins. Its
  • t1/2 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.
slide51

Caffeine is an alkaloid with pKb 0.8. It is rapidly absorbed after

  • oral administration. It is < 50% bound to plasma proteins. Its
  • t1/2 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.
slide53

Amphetamines are central indirect adrenomimetics. Higher

central and peripheral activityratio 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!

slide54

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.

slide55

(3) Cocaineis 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. Cocaine is unique among drugs of

abuse, because it is does not produce tolerance on repeuted

use.It also stimulate vagal, vasomotor, vomiting and

thermoregulatory centres. In periphery it blocks reuptake of NA

and adrenaline and acts indirectly as a sympathomimetic.

slide56

Nootropic drugs (cognition enhancers)

Piracetamis 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.
slide57

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.
  • Pramiracetamhas similar properties and indications.
slide58

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