pharmacology of antipsychotic drug pharmacology of antipsychotic drugs

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Pharmacology of Pharmacology of Antipsychotic Antipsychotic drug drugs

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Page 1: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

Pharmacology of Pharmacology of Antipsychotic Antipsychotic

drugdrugs

Page 2: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

Antipsychotic drugs, neuroleptic or anti-

schizophrenic drugs are used mainly to manage

psychosis (including delusions or hallucinations and disordered thought )

particularly in schizophrenia and bipolar

depression

Page 3: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

Schizophrenia

Page 4: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

It is a chronic disabling disorder which affects people during late adolescence

or early adulthood Schizophrenia has a strong genetic

component and is probably due to biochemical abnormality (dysfunction

of D-ergic neurons) There is some evidence for involvement

of 5-HT

Page 5: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

Patients with schizophrenia have problems with seeing things, hearing voices, imagining things, having terrifying thoughts (positive symptoms)

Apathy , blunted emotions, anhedonia and reduced ability to react with people ‘social withdrawal’(Negative symptoms)

Page 6: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

Positive SymptomsPositive Symptoms•Hallucinations Delusions•Thought disturbances

Negative SymptomsNegative SymptomsBlunted emotionsSocial withdrawal Loss of motivationimpaired personal hygiene

Schizophrenia: Symptoms

Page 7: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

“Dopamine hypothesis”

Schizophrenia has a strong genetic component and

probably reflects too much dopamine activity in the

mesolimbic system which is the part of brain that controls

seeing, hearing, imaging etc…..

Page 8: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

“Dopamine hypothesis” - Evidences

Drugs that increase dopamine may produce positive psychotic

symptoms (e.g. Cocaine, amphetamine)

All known antipsychotics drugs capable of treating positive

psychotic symptoms block the dopamine receptors (D2)

Page 9: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

Antipsychotic

Drugs

Page 10: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

Antipsychotics are broadly divided into two groups: The typical = 1st generation and the atypical = 2nd generation antipsychotics

Atypical drugs are preferred as a first line treatment because they:1- have fewer side effects 2- have additional benefits for the

“ -ve symptoms”of schizophrenia

Page 11: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

Mechanism of Action

Page 12: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

All antipsychotic drugs block D2

receptors in the brain & peripheryAtypical antipsychotics exert part of their action through blocking of 5-HT2A receptors Antipsychotics take days or weeks to work, suggesting that secondary effects (e.g. increase in number of D2-receptors in limbic structure) may be more important than direct effect of D2-receptor block.

Page 13: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

Many antipsychotics block

other receptors e.g. acetylcholine (M),

noradrenaline (α ) and histamine (H1) receptors

Page 14: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

Typical antipsychotic Drugs

1- Phenothiazine derivatives: Chlorpromazine, promethazine, Fluphenazine2- Butyrophenone derivatives: Haloperidol, droperidol

Atypical antipsychotic drugs Risperidone , Clozapine , Olanzapine Aripiprazole

Page 15: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

Pharmacological Actions

Page 16: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

1- Antipsychotic effects Though blocking D2 receptors in the mesolimbic system, antipsychotic drugs relieve hallucination, improve thoughts. The additional blocking effects of atypical antipsychotics on 5-HT2 receptors can treat the negative symptoms of schizophrenia2- Autonomic effects: Anticholinergic effects , dry mouth, constipation and blurred visionBlocking of α–adrenergic receptors hypotension

Page 17: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

3- Exrapyramidal effects Blocking of D2 receptors in the nigrostriatal

pathway causes unwanted parkinsonian-like symptoms; rigidity and tremors. Clozapine and risperidone exhibit a low incidence of these symptoms ( block D4)

4- Antiemetic effect Blocking D2 receptors both centrally in the

CTZ in the medulla and peripherally in the stomach

Page 18: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

5- Endocrine effects: Amenorrhea-galactorrhea, false–positive pregnancy tests in women and decreased libido and gynecomastia in men (due to blockade of D2 in the pituitary leading to an increase in prolactin release)

6-Antipsychotics block H1 receptors causing sedation and confusion

7- Antipsychotic depress the hypothalamus affecting thermo-regulation (hypothermia)

Page 19: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

Therapeutic Uses

Page 20: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

1- Treatment of schizophrenia

Typical antipsychotics are most effective in treating positive symptoms

Atypical antipsychotics with serotonin blocking activity are effective in many patients resistant to the traditional agents, especially in treating negative symptoms

Page 21: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

2- Treatment of other psychotic disorders e.g. mania and mood (bipolar) disorders

3- Prevention of severe nausea and vomiting (drug-induced nausea)

4- Droperidol is used in combination with fentanyl in neuroleptanalgesia

Page 22: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

5- Due to its antihistaminic effects, promethazine is used in cases of pruritus and as a preoperative sedative

6- To induce hypothermia in certain major operations (Chlorpromazine)

7- Chlorpromazine is used to treat intractable hicough حازوقه

Page 23: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

Adverse Effects

Page 24: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

Extrapyramidal Symptoms (EPS)Dopamine Vs Acetylcholine

Dopamine (inhibitory) and ACh (excitatory) have a reciprocal relationship in the Nigrostriatal pathway A delicate balance allows for normal movementDopamine blockade by antipsychotic drugs results in relative increase in cholinergic activity causing EPS

When high potency antipsychotics are chosen, we often prescribe anticholinergic medication like benztropine

Page 25: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

Antipsychotics have a wide range of side effects1- Sedation (drowsiness) is a common side effect of antipsychotics (?) This can be dealt with by taking medication at night just before going to bed2- Movement disorders; Extrapyramidal side effects are common with the typical antipsychotics ; include dystonia, akathisia parkinsonian- like syndrome Treatment: anticholinergic drugs (benztropine)

Page 26: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

It is the most important adverse effect of long-treatment with typical antipsychotic drugs and is characterized by excessive movement of the lips, tongue and jaw, limbs Tardive dyskinesia may be irreversible and is postulated to result from increased number of dopamine receptors that are synthesized in response to long-term dopamine receptor blockade, which leads to neuronal supersensitivity to dopamine

Tardive dyskinesia

Page 27: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

Atypical drugs have lower incidence of EPS & tardive dyskinesia as they block 5-HT2A receptors and have less D2 receptor

blocking effect

Page 28: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

3-Autonomic effects:Orthostatic hypotension !!!!, (α-adrenoceptor blockade) and anticholinergic adverse effects (urinary retention, constipation, ppt of glaucoma,…..)

4- Endocrine and metabolic effects: hyperprolactinemia in the form of galactorrhea, amenorrhea in women, gynecomastia and changes in libido & impotence in men

Page 29: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

5- Allergic reactions: Agranulocytosis (common with clozapine), cholestatic jaundice and skin eruptions

6-Occular complications: may cause retinal pigmentation, corneal and lens opacities (Chlorpromazine)

7- Clozapine and chlorpromazine tend to lower an individual’s seizure threshold

Page 30: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

Neuroleptic Malignant Syndrome

An idiosyncratic, life-threatening neurological disorder associated with antipsychotic therapy

Idiosyncracy: An unusual or unexpected sensitivity exhibited by an individual to a particular food or drug. Idiosyncrasy is usually determined genetically and it may be due to a biological deficiency (e.g. an inability to metabolize a drug).

Page 31: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

Neuroleptic Malignant Syndrome

Clinical manifestations include:

Encephalopathy, Hyperpyrexia, delirium

Autonomic instability (BP)

Rigidity of muscles

Elevated creatine phosphokinse (CPK) due to increased muscular activity and rhabdomyolysis (destruction of muscle tissue)

Page 32: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

PathophysiologyThe mechanism is thought to depend on dopamine activity due to:

Dopamine receptor blockadeGenetically reduced function of dopamine

receptor There is an increased calcium release

from the sarcoplasmic reticulum of muscle cells which can result in rigidity and cell breakdown

Page 33: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

Treatment involves:Immediate discontinuation of antipsychotic drugTreat hyperthermia Hydration, maintain vital functions

Dantrolene sodium: a muscle relaxant that acts by abolishing excitation contraction coupling in muscle cell

Page 34: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

Typical antipsychotics

Page 35: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

ChlorpromazinePhenothiazine classIncreased prolactin (gynaecomastia)Hypothermia Anticholinergic effectsHypersensitivity reactionsObstructive jaundiceOcular complications EPS

Page 36: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

Fluphenazine

Phenothiazine class but: does not cause jaundice causes less hypotension causes more EPS

Page 37: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

Halopirodol

Butyrophenone classAs chlorpromazine but does

not cause jaundice Fewer anticholinergic side

effectsStrong EPS tendency

Page 38: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

Atypical Drugs

Page 39: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

Differences between typical and atypical

groupsreceptor profile Serotonin receptors (5-HT2A) are involvedincidence of extrapyramidal side effects (less in atypical group) efficacy (specifically of Clozapine in treatment of resistant group of patients efficacy against negative symptoms

Page 40: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

Dibenzodiazepine class

Potent antagonist at D4-receptors

Selectively blocks 5-HT2A receptors

Sedation

Extrapyramidal side effects are minimal

Low incidence of Tardive dyskinesia

Increased risk for seizures (2-3%)

Clozapine

Page 41: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

Agranulocytosis in 1% (regular granulocyte counts weekly is required)

Agranulocytosis risks increase when co-administered with carbamazepine

Anticholinergic side effects

Weigh gain

Shows efficacy in 'treatment-resistant' patients

Effective against negative and positive symptoms

Clozapine

Page 42: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

Largely replacing clozapine. No risk of agranulocytosis

Low incidence of EPS and minimal sedation

Weight gain

Resperidone is approved for the treatment of autism and bipolar depression

Risperidone

Page 43: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

Recently approved drug

Long acting (plasma half-life ∼3 days)

No effect on prolactin secretion

No weight gain

Less incidence of dystonias and Tardive dyskinesia

D2 partial agonist profile may account for paucity of side effects

Aripiprazole

Page 44: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

Advantages & disadvantages of

ClozapineAdvantages Effective in the treatment of negative and positive symptoms of schizophrenia More effective than classical agents for resistant cases

DisadvantagesClozapine has the

risk of inducing agranulocytosis

Clozapine tends to lower an

individual seizure

threshold

Page 45: Pharmacology of Antipsychotic drug Pharmacology of Antipsychotic drugs

Advantages

Incidence of extrapyramidal symptoms is lowestTardive dyskinesia is extremely rare with clozapine

Disadvantages

Atypical drugs cause weigh gainAtypical drugs may exacerbate DM & hyperlipidemiaAre more expensive than typical antipsychotics