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ANTIPSYCHOTICS - Coggle Diagram
ANTIPSYCHOTICS
PSYCHOSIS
Serious distortion of thought, behaviour & perception
Organic
- Toxic/ pathological basis associated with delirium, dementia, confusion
Functional
- No underlying pathology
- Not associated with delirium/ dementia
○ Schizophrenia→ split mind
○ Paranoid states→fixed delusions or beliefs
○ Affective disorders- Mania/depression
NEUROSIS
Insight present
- Anxiety
○ Unpleasant emotional state
○ uneasiness/ worry/ tension for future
- Phobic states
○ Fear of unknown/ or some specific object, persons, or situations
- Obsessive-compulsive disorder
○ Recurrent intrusive thoughts
○ Ritual like behaviours
○ Not able to overcome even on voluntary effort
- Reactive depression
○ D/t physical illness/ loss / blow to self esteem/ bereavement
- Hysterical
○ Dramatic symptoms resembling serious physical illness, but situational
○ in the presence of others
○ Patient does not feign(actually undergoes the symptoms)
○ Psychic basis only
- Post traumatic stress disorder
MOA
Typical antipsychotics :check:
- Potent D₂ antagonist in mesolimbic & mesocortical dopaminergic projections
- Also block D₁,D₃,D₄ ®
Atypical antipsychotics :check:
- Weak D₂ blocking action
- Clozapine selectively blocks D₄ ®
- Blocks 5HT₂ ®
ADVERSE EFFECTS
CNS
- Sedation
- Lethargy/ drowsiness
○ low potency typical APs & atypical-quetiapine& clozapine
- ↑ Appetite & weight gain
- Aggravation of seizures in epileptics
○ Non-epileptics also develop in presence of high dose of clozapine/olanzapine
CVS
- Postural hypotension/ palpitation/ inhibition of ejaculation(Thioridazine) → α adr. blockade
- QT prolongation & cardiac arrhythmia
○ Thioridazine/ pimozide/ziprasidone overdose
Anticholinergic
- Dry mouth/ blurring of vision/ urinary hesitancy
(thioridazine)
- Hypersalivation- clozapine
- Dry mouth, constipation→ olanzapine
Endocrine
- Galactorrhea
- Gynecomastia
- Amenorrhea/ infertility
○ Typical antipsychotics & risperidone
Metabolic effects
- Elevation of blood sugars & TGs
○ CPZ/ thioridazine/ clozapine
- Diabetes pptd by CPZ/ thioridazine/ olanzapine/ clozapine
Miscellaneous
- Corneal & lenticular opacities
- Retinal degeneration( thioridazine)
- Agranulocytosis( clozapine)
- Urticaria/ rash/ photosensitivity (CPZ)
- Blue pigmentation of exposed skin(CPZ)
- Weight gain, cholestatic jaundice
- Myocarditis(clozapine)
Tolerance
- Sedative/hypotensive action
EXTRAPYRAMIDAL DISTURBANCES
- most imp. dose related S/E
1.A/c muscular dystonia
- Muscle spasm involving jaw, facial & neck muscles
- Develops within hours to days of therapy
- Central anticholinergics, promethazine
2.Akathisia
- Restlessness, feeling of discomfort, agitation
- Compelling desire to move about
- 1-8 weeks
- Central anticholinergics, diazepam/ clonazepam, propranolol
3. Parkinsonism
- Rigidity/ tremor/ hypokinesia (1-4 wks)
- Perioral tremors/ rabbit syndrome( years)
- Central anticholinergics
4. Tardive dyskinesia
- Involuntary facial & limb movements(long years)
- Supersensitivity of DA ®
- Difficult to treat
○ New drugs- Deutetrabenazine, Valbenazine
○ VMAT2 inhibitors→ depress synaptic stores of DA
5. Malignant neuroleptic syndrome
- Rarely with high doses of potent agents
- Rigidity, tremor, fever , high BP
- Stop the drug. Give IV dantrolene,bromocriptine
TYPICAL ANTIPSYCHOTICS
ACTIONS
1. CNS
In non- psychotic
- Indifference to surroundings/ paucity of thought/ psychomotor slowing/ emotional quietening
- Tendency to go to sleep(from which easily arousable)
- Neuroleptic syndrome
In psychotics
- ↓ irrational behavior, agitation, aggressiveness
- ↓ hyperactivity, hallucinations, delusions
- Sedation
- Chlorpromazine- ↓ seizure threshold→ fits in untreated epileptics
- Temp. control lost at relatively high doses→ individual becomes poikilothermic
- CPZ, triflupromazine, thioridazine → low potency, more sedation, cause greater potentiation of hypnotics, opioids, etc.
- Phenothiazines & butyrophenones except thioridazine have potent antiemetic action→ through CTZ
2. ANS
- Varying degrees of α adr. blocking activity
○ CPZ= triflupromazine= thioridazine> fluphenazine> haloperidol> trifluoperazine> pimozide
More potent compounds→ less α blocking action
- Weak anticholinergic activity
○ Thioridazine> CPZ> triflupromazine> trifluoperazine = haloperidol
- Phenothiazines→ weak H₁- antihistaminic & anti 5-HT actions as well
3. Local Anaesthetic
+ Potent as procaine
- Not used d/t irritant action
4. CVS
- Postural hypotension→ central & peripheral action on sympathetic tone
○ More after parenteral admn. & parallels with α blocking potency
○ Not prominent in psychotic patients but accentuated by hypovolemia
○ Partial tolerance→ c/c use
- Reflex tachycardia
- High dose CPZ→ depress heart, ECG changes ( QT prolongation & suppression of T wave)
- CPZ→ some antiarrhythmic action
- Thioridazine overdose→ arrhythmia
5. Endocrine
- ↑ PRL release → block inhibition of pituitary lactotropes
○ Result in galactorrhea/gynecomastia
- CPZ→ ↓ GH,↓ gonadotropins( amenorrhea/infertilty) , ↓ ADH
- CPZ& few others→ impair glucose tolerance, ↑ s. triglycerides→ aggravate diabetes/ cause weight gain
PHARMACOKINETICS :check:
- IM/IV admn better
- Highly bound to plasma as well as tissue proteins, brain conc.> plasma conc.
- Vd ~20L/kg
- Metabolised in liver by CYP2D6
- Cumulates on repeated admn→ possible to give total maintenance dose OD
- Duration of clinical benefit> elmn T½ → tight binding to D₂ ®
- Metabolites→ excr. for months in urine/bile after discontinuation
DRUGS
1. Triflupromazine
- Aliphatic phenothiazine
- More potent than CPZ
- Use: antiemetic
- Inj. produce a/c muscle dystonias in children
2. Thioridazine
- Low potency
- Marked central anticholinergic action
- Extrapyramidal S/E low
- Cardiac arrhythmias & interference with male sexual fn→ more common
- Long term use→ risk of eye damage
3. Trifluoperazine, fluphenazine
- High potency
- Piperazine phenothiazines
- Min. autonomic actions
- Marked extrapyramidal S/E & tardive dyskinesia
- Hypotension, sedation, lowering of seizure threshold not significant
- Less likely→ impair glc tolerance, cause jaundice/HS
- Fluphenazine decanoate depot IM inj→ every 2-4 weeks in uncooperative psychotics
4. Haloperidol
- Most commonly used
- High potency
- Use : A/c schizophrenia, Huntington's disease, Giles de la Tourette's syndrome
- Few autonomic s/e, less epileptogenic, no weight gain, jaundice rare
- Metabolised by CYP3A4 & 2D6
5. Trifluperidol
- Slightly similar to haloperidol
6. Penfluridol
- Exceptionally long acting neuroleptic
- Use: C/c schizophrenia, affective withdrawal, social maladjustment
7. Flupenthixol
- Less sedating than CPZ
- Use: Schizophrenia, other psychoses( in withdrawn & apathetic patients
- Infrequently used now
8. Pimozide
- Selective D₂ antagonist with little α adr. / cholinergic blocking activity
- Long duration of action after single oral dose→ good for maintenance therapy(not when psychomotor agitation is present)
- Tends to prolong myocardial APD & carries risk of arrhythmias
- Use Gilles de la Tourette's syndrome & ticks
9. Loxapine
- Dibenzoxazepine with CPZ like DA blocking & antipsychotic activity
- Quick, short lasting
10. Levosulpiride
- Substituted benzamide
- Related to prokinetic cisapride
- Selective D₂ ® blocking action
- Antipsychotic with prokinetic activity
- Use: Schizophrenia, anxiety, GERD, IBS , peptic ulcer
CLASSIFICATION
Phenothiazines
Aliphatic side chain
- Chlorpromazine
- Triflupromazine
Piperidine side chain
Piperazine side chain
- Trifluoperazine
- Fluphenazine
Butyrophenones
- Haloperidol
- Trifluperidol
- Penfluridol
-
-
ATYPICAL ANTIPSYCHOTICS
1. CLOZAPINE
- 1st atypical AP
- D₄ action, weak D₂ blocking, additional 5HT₂ & α-adr. blockade.
- Significant H₁ blocking property present
Advantage :check:
Few/no EPS, tardive dyskinesias rare, PRL does not rise
Metabolism :check:
○ CYP1A2, CYP2C19, CYP3A4
○ Avg T½=12hrs
Use :check:
- Most effective drug in refractory schizophrenia(reserve)
Adverse effects :check:
- Higher incidence→ agranulocytosis
- Paradoxical hypersalivation
- Sedation
- Met. complications→ wt. gain, hyperlipidemia, precipitation of diabetes
- Seizures
- Unstable BP, tachycardia
- Urinary incontinence
- Myocarditis which may progress to death
2. OLANZAPINE
- D₂ blocking, 5HT₂ , α₁, α₂ as well as muscarinic & H₁ ® blockade
Metabolism
- CYP1A2 & glucuronyl transferase
- T½= 24-30hrs
Use :check:
- Broader spectrum
+ Approved for use in mania
- Schizo-affective disorders
Adverse effects :check:
- Dry mouth, constipation
- More epileptiogenic
- Weight gain, ↑ plasmaTG
- Worsening of diabetes
- Stroke in elderly↑ risk
3. RISPERIDONE
- D₂ + 5HT₂ ® blockade
- α₁, α₂ & H₁ ® blockade also
- More potent than clozapine
- Less epileptogenic
- Wt gain/ new onset diabetes less
Use :check: First line drug for schizophrenia Adverse Effects :check:
- EPS less only at low doses
- ↑ PRL levels
- Stroke risk in elderly
Paliperidone :check: active metabolite of risperidone
4. ZIPRASIDONE
- D₂ + 5HT₂ᴀ/₂ᴄ + H₁ + α₁ blockade
- Antagonistic action at 5HT₁ᴅ + agonistic action at 5HT₁ᴀ ® + mod. inhibition of NA/ 5-HT reuptake → some anxiolytic & antidepressant property
- Low propensity for EPS/ hyperprolactinemia
- Wt. gain/ blood sugar elevation less likely
Uses :check:
Adverse effects :check:
- Nausea/ vomiting- most common
- Dose related QT prolongation→ potential for cardiac arrhythmias
- Mild sedation
- Modest hypotension
5. ARIPIPRAZOLE
- Partial agonist at D₂ + 5HT₁ᴀ ; 5HT₂ antagonist
+ Long acting T½= 3 days
- HA but LI activity for D₂ ®
- Not sedating
- No EPS/ hyper PRLemia/ hypotension
Metabolism :check:
- CYP3A4 & CYP2D6
- Dose halved in patients taking ketoconazole/ quinidine & doubled in those taking carabamazepine
Use :check:
- Schizophrenia with +/- symptoms
- Resistant depression as augmenting agent
- Maintenance drug in bipolar disorder
Adverse effects :check:
- Nausea/ dyspepsia/ constipation, light headedness- common
- Mod. prolongation of Q-Tc at higher dose
- Little tendency for wt gain& ↑ blood sugar
6. QUETIAPINE
- New, short acting→ twice daily dosing
- T½= 6hrs
- Blocks D₂ , 5HT₁ᴀ , 5HT₂ , α₁, α₂ & H₁ ®
- D₂ blockade is low→ less EPS/ hyperprolactinemia
- Metabolism :check: CYP3A4
Interactions :check:
- Macrolides, antifungals, anticonvulsants, etc
Use :check:
- Acute mania
- Bipolar depression
ADR :check:
- Sedation (MC)
- Postural hypotension
- Urinary retention in some
- Some degree of QT prolongation
- Mod wt. gain/ rise in blood sugar
7. AMISULPIRIDE
- Congener of sulpiride
- HA for D₂ & D₃® & LA for 5HT₂ ®
- Few EPS
- Improves negative symptoms of schizophrenia
- No sedation
- Antidepressant property noted
- Oral absorption
- Excr. unchanged in urine , T½=12 hrs
Use :check:
- Schizophrenia with negative symptoms
- Acute psychosis
Adverse effects
- Insomnia, anxiety, agitation- common
- Hyperprolactinemia
- QT prolongation in elderly
8. ZOTEPINE
- D2 + D1, 5HT₂, α₁ & H₁ ® blockade, inhibits NA reuptake
- Benefits both +/- symptoms of schizophrenia
- Less effect than clozapine
- Oral absorption good but extensive FPM present
Use :check:- approved for schizophreniaAdverse effects :check:
- Common- weakness/ headache/ postural hypotension
- weight gain, hyperglycemia, dyslipidemia
- EPS
- Seizure risk ↑ at high doses
9. ASENAPINE
10. ILOPERIDONE
TYPICAL
- EPS- dose limiting s/e, Hyperprolactinemia
- Effective only against + symptoms
- No improvement in -/cognitive symptoms. May even exaggerate/ worsen
ATYPICAL
- Weaker D2 blocking, 5HT ® modulation, D4 action
- EPS less, less chances of hyperprolactinemia, Metabolic symptoms more
- Controls both +/- symptoms
- Improvement in -/cognitive symptoms
USES
1. Psychoses
Schizophrenia
- Wide range of symptom relief in functional psychoses
- Positive symptoms(both typical & atypical APs used)
○ hallucinations, delusions, disorganised thought
○ restlessness, insomnia, anxiety
○ fighting, aggression
- Negative symptoms- atypical APs effective
○ apathy, loss of insight & volition
○ emotional blunting, affective flattening
○ poverty of speech, social withdrawal
- Atypical APs better tolerated & commonly used now.
- Drug selection→
○ Agitated, violent→ haloperidol, quetiapine, CPZ
○ Withdrawn & apathetic→ trifluoperazine, fluphenazine, aripiprazole, ziprasidone
○ Neg. symptoms & resistant→ Clozapine, olanzapine, risperidone
○ Mood elevation, hypomania→ haloperidol, fluphenazine, quetiapine, olanzapine
○ To avoid EPS/ risk of tardive dyskinesia→ thioridazine, clozapine
○ Elderly patients→ high potency phenothiazine, haloperidol, aripiprazole
Gilles de la Tourette Syndrome
- Characterised by multiple motor/ phonic tics
- Mostly among kids
- Risperidone, aripiprazole
Acute Mania
- APs in high doses for rapid control
- Lithium/ valproate started simultaneously or after the a/c phase
- Haloperidol/ olanzapine IM
- Combination therapy is more effective
Bipolar Disorder
- Olanzapine/ aripiprazole, quetiapine alone or in combination with lithium/ valproate
- Maintenance therapy
Organic brain syndromes
- Haloperidol/ risperidone/ aripiprazole/ ziprasidone
Depressed psychotic
- Tricyclic/ SSRI + lower dose of atypical antipsychotic
- Quetiapine
- Relapsing cases→ low dose maintenance/ intermittent regimens of APs
- Depot inj. eg. fluphenazine/ haloperidol decanoate at 2-4 weeks
2. Anxiety
- Low dose of quetiapine, risperidone / olanzapine useful as adjuvants to SSRIs in general anxiety disorder
- BZDs are primary drugs in anxiety
3. Antiemetic
- Drug/ disease induced vomiting
- Not useful for motion sickness
4. Other Uses
- Potentiate hypnotics, analgesics, anaesthetics- rarely used now
- Intractable hiccough→ parenteral CPZ
- Tetanus→alt. drug to relieve skeletal muscle spasm
- Alcoholic halucinosis/ Huntington's
INTERACTIONS
- Potentiate all CNS depressants→ overdose symptoms may occur
- Block actions of levodopa & direct DA agonists in Parkinsonism
- Antihypertensive action of clonidine/ methyldopa ↓ → d/t central α2 blockade
- Phenothiazines & others are poor enzyme inducers
- Enzyme inducers( barbiturates, anticonvulsants) ↓ blood levels of neuroleptics