Week 19 Pharmacology

Antipsychotic agents:

  • Dopamine hypothesis
    • Excessive limbic dopamine is hypothesised to cause psychosis
    • Many antipsychotics inhibit dopamine 2 receptors in mesolimbic and striatal frontal system in CNS
    • Drugs that increase dopamine eg amphetamines, levodopa, bromocriptine –> aggravate schizophrenia psychosis.
    • Diminished dopamine activity in cortex and hippocampus
    • Cognitive impairment and negative symtoms of Schizophrenia eg emothional blunting, social withdrawal, lack of motivation.
    • Dopamine hypothesis doesn’t explain all aspects of psychosis.
  • Basis of action
    • Typical antipsychotics – dopamine blockade
    • Atypical antipsychotics eg clozapine, quetiapine are 5HT 2a receptor blockers (inverse agonists)
    • Most are readily but incompletely absorbed
    • Significant first pass metabolism
    • Bioavail 25-35%(chlorpromazine), 65% (haloperidol)
    • Highly lipid soluble and protein bound 92-99% –> large volume of distribution
    • Long duration of action
    • 6mo for average relapse post ceasing meds, clozapine is the exception – relapse is rapid and severe.
  • Neuroleptic malignant syndrome – life threatening disorder due to excessive rapid blockade of Dopamine receptors. Sx – muscle rigidity, fever, altered BP and HR. Needs supportive treatment with cooling, muscle relaxants and anti-parkinsons drugs. Switch to atypical after recovery.
  • OD – rarely fatal, Sx – hypotension, hypothermia, drowsiness, coma, convulsions, miosis.

 

Phenothiazines (Learn Chlorpromazine)

  • D2 block >>> 5HT2a – low clinical potency
  • Alpha adrenoceptor blockade – hypotension, impotence
  • Anti muscarinic – urinary retention, constipation, vasodilation, dilated pupils
  • H1 receptor blockade
  • SE – sedation, wt gain, decreased seizure threshold, QT prolongation, EPS (akathisia, dystonia, parkinsons sx, tardive dyskinesia, hyperprolactinemia – due to nigrostriatal dopamine pathways), hypotension.  Deposits in cornea and lens.
  • Long half lives
  • Metabolism dependent elimination. Almost completely metabolised by p450 system in liver

 

 

Butyrophenones (Learn Haloperidol)

  • Typical antipsychotic
  • Commonly used
  • D2>5HT
  • Highly potent with less autonomic SE but more EPS than phenothiazines
  • Sedation and hypotension is low

 

Thioxanthenes

  • (Don’t learn much in detail, just know the name of one Typical antipsychotic i.e. Thiothixene)
  • Typical antipsychotic

 

Atypical antipsychotics

  • Olanzapine, Risperidone, clozapine, quetiapine, aripiprazole
  • Risperidone is rapidly converted into its active metabolite paliperidone except in 10% who are poor metabolisers
  • Primary action is 5HT blockade, some minor dopamine blockade.
  • Clozapine should never be abruptly stopped unless myocarditis or agranulocytosis. (rapid relapse rate)
  • Olanzapine – effective against negative as well as positive sx

 

 

Lithium

  • Uses – manic bipolar disorder, prev of recurrent manic or depressive bi polar disease
  • PD
    • Not clearly understood
    • Supresses inositol signaling and inhibits GSK -3
  • PK
    • Virtually complete absorption in 6-8hrs, peak plasma levels in 0.5-2hrs
    • Distribution – total body water, no protein binding, vD 0.7-0.9L/kg
    • No metabolism
    • Excreted in urine
    • T 1/2 20 hrs
    • Renal clearance reduced by 25% by diuretics/NSAIDS
  • SE
    • Tremor, ataxia, dysarthria, confusion, decreased thyroid function(reversible), nephrogenic diabetes insipidus, oedema, wt gain, bradycardia(Sinus node depression), acni
  • OD
    • Can be dialysed

 

Antidepressants:

  • Basis of action (biogenic amine hypothesis).
    • Depression is thought to be due to dysfunction or deficiency of monoamines in the CNS as well as deficiencies in neurotrophic and endocrine factors.
    • The aim of antidepressants are to increase monoamines such as seretonin, NA and dopamine in CNS.
  • TCAs:
    • Act at seretonin, histamine, acetylcholine, and alpha adrenoceptors
    • Amitriptyline, imipramine
    • SE – anticholinergic (dry mouth, urinary retention, constipation, mydriasis, impotence), sedation(5HT/histamine), orthostatic hypotension ( adrenoceptor blockade), wt gain
    • Well absorbed, long half life, extensive hepatic metabolism. 5% excreted unchanged in urine. Can induce or inhibit CytP450
    • Amitriptyline – 45% bio avail, 90% protein bound, t 1/2 31-46hr, active metabolite, Vd 5-10L,
    • Overdose – can be lethal – arrhythmias and seizures–> need cardiac monitoring, airway support and gastric lavage.
  • Heterocyclics: Superficial knowledge.
    • Mirtazepine – tetracyclic, has SE similar to TCA- sedation, wt gain, inhibit Cyt P450
  • SSRIs:
    • Inihibit seretonin transporter (SERT)
    • Commonest antidepressant in use
    • Use- generalised anxiety, PTSD, OCD, panic disorder, bulimia
    • Fluoxetine, sertraline, paroxetine, citalopram, escitalopram
    • Fluoxetine
      • PK – 70% bioavail, 95% protein bound, highly lipiphilic, Vd 12-97L, metabolised into active norfluoxetine(t1/2 180hr). Long half life(48-72). Inhibits Cytochrome p450.
    • Safe in OD
    • SE – sexual dysfunction, nausea, GI upset, diarrhoea, seretonin syndrome
  • MAO inhibitors:
    • Moclobemide – reversible MOA-A inhibitor.
    • Inhibit Monoamine breakdown
    • SE – toxicity, potentially lethal food(tyramine breakdown prevented in gut –> high serum NA –> hypertension) and drug interactions, orthostatic hypotension, insomnia, sexual dysfunction
    • PK – extensive 1st pass metabolism,
    • OD – autonomic instability, psychotic sx, confusion, delerium, fever, seizures.
    • Need to avoid cheese, tap beer, soy, dried sausages.

 

Serotonin syndrome.

  • Over stimulation of 5HT receptors in medulla and central grey nuclei
  • Cognitive
  • Delerium, coma
  • Autonomic
  • Hypertension, tachycardia, diaphoresis
  • Somatic
  • Myoclonus, hyper-reflexia, tremor\

 

Viva questions:

  • How do antipsychotics work ?
  • Tell me about Chlorpromazine.
  • Tell me about Haloperidol.
  • Tell me about Lithium and Lithium overdose.
  • Tell me about TCAs and TCA overdose.
  • Tell me about Fluoxetine / Fluoxetine overdose.
  • Tell me about Serotonin syndrome.
  • Tell me about MAOs.
  • Tell me about Benztropine
    • Benzatropine is an anticholinergic drug used in patients to reduce the side effects of antipsychotic treatment, such as parkinsonism and dystonia.
    • Muscarinic antagonist