Post on 14-Dec-2015
Pharmacology of Pharmacology of Antipsychotic Antipsychotic
drugdrugs
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
Schizophrenia
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
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)
Positive SymptomsPositive Symptoms•Hallucinations Delusions•Thought disturbances
Negative SymptomsNegative SymptomsBlunted emotionsSocial withdrawal Loss of motivationimpaired personal hygiene
Schizophrenia: Symptoms
“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…..
“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)
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
Mechanism of Action
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.
Many antipsychotics block
other receptors e.g. acetylcholine (M),
noradrenaline (α ) and histamine (H1) receptors
Typical antipsychotic Drugs
1- Phenothiazine derivatives: Chlorpromazine, promethazine, Fluphenazine2- Butyrophenone derivatives: Haloperidol, droperidol
Atypical antipsychotic drugs Risperidone , Clozapine , Olanzapine Aripiprazole
Pharmacological Actions
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
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
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)
Therapeutic Uses
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
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
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
Adverse Effects
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
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)
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
Atypical drugs have lower incidence of EPS & tardive dyskinesia as they block 5-HT2A receptors and have less D2 receptor
blocking effect
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
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
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).
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)
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
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
Typical antipsychotics
ChlorpromazinePhenothiazine classIncreased prolactin (gynaecomastia)Hypothermia Anticholinergic effectsHypersensitivity reactionsObstructive jaundiceOcular complications EPS
Fluphenazine
Phenothiazine class but: does not cause jaundice causes less hypotension causes more EPS
Halopirodol
Butyrophenone classAs chlorpromazine but does
not cause jaundice Fewer anticholinergic side
effectsStrong EPS tendency
Atypical 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
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
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
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
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
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
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