Neuronal regulation

  • Neurotransmitters
    • GABA
    • Glutamate
  • Neurohormones
    • oxytocin
    • ADH
  • Neuromodulators
    • CO2
    • ammonia
    • steroids
    • adenosine
    • prostaglandins
  • Neuromediators
    • cAMP
    • cGMP
    • inositol phosphates
  • Neurotrophic factors
    • brain derived neurotrophic factors

When drugs for major depressive disorder (MDD)/ psychoses are administered

  • There is
    • prompt binding of drugs to receptor
    • but clinical effect is delayed & slow to develop
  • Actual drug effect may be mediated by long term adaptation
    • intracellular signalling pathways
    • neuronal gene expression

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Revision

Hypothesis for these disorders

  • Schizophrenia
    • dopamine overactivity in limbic system
  • Mania
    • catecholamine excess in CNS
  • Depression
    • deficiency of NE/5-HT activity
      • prolonged use of reserpine
      • depletes NE
  • Hallucinations
    • taking LSD
      • stimulate 5-HT2A
  • Major depressive disorder
    • Monoamine hypothesis
      • deficiency in serotonin, NE, dopamine
        • in cortical and limbic system
    • Neurotrophic hypothesis
      • drop in BDNF (brain dervied neurotrophic factor)
    • Neuroendocrine factors
      • abnormal HPA axis
      • elevated cortisol level
      • hypothyroidism
      • deficient sex steroids

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Antidepressants

  • Selective Serotonin Reuptake Inhibitors (SSRI)
    • Examples
      • Fluoxetine
      • Paroxetine
      • Sertraline
      • Citalopram
    • MOA
      • act by selective inhibition of serotonin reuptake transporter (SERT)
      • Concentration of 5HT in synaptic cleft rises and leads to antidepressant effect
    • Pharmacological actions
      • effective in treatment of endogenous depression
      • preferred drug
        • free of troubling side effect of  TCA
          • time course & efficacy the same
        • less sedation
        • few anti-muscarinic effects
        • low cardiotoxicity
        • no weight gain
        • no food reaction
    • Side effects
      • GI
        • nausea
        • vomiting
        • anorexia
        • diarrhea
      • CNS
        • headache
        • anxiety
        • restlessness
        • aggressiveness
        • insomnia
        • tremors
        • weight loss
        • seizures with high dose
        • extrapyramidal effects
          • with paroxetine
    • Overdose
      • cause serotonin syndrome
    • Clinical uses
      • MDD
      • Bulimia
      • Obsessive-compulsive disorder (OCD)
      • Anorexia
      • Pain asso. with diabetic neuropathy
      • Premenstrual syndrome
  • Sernotonin-norepinephrine reuptake inhibitors (SNRI)
    • Examples
      • Venlafaxine
      • Duloxetine
    • MOA
      • inhibit the active reuptake of serotonin & NE into presynaptic nerve terminals in CNS
        • same as SSRI
        • but slow to develop (weeks)
    • Pharmacological actions (SNRI,NRI, TCA)
      • CNS
        • elevation of mood
        • improved mental alertness
        • increased physical activity
      • ANS
        • anticholinergic effects
          • cardiac arrhythmia in overdose
      • CVS
        • alpha-adrenergic block
          • orthostatic hypotension
          • reflex tachycardia
        • AV block
        • ventricular flutter
        • sudden death
    • Pharmacokinetics (SNRI,NRI,TCA)
      • well absorbed
        • variable biovailability
          • due to 1st pass effect
      • lipid soluble
        • widely distributed including CNS
      • long half life
        • high protein binding
      • metabolized by hepatic microsomal system
        • conjugated with glucoronic acid
        • excreted as inactive metabolites in urine
      • high volumes of distribution
        • extracorporeal dialysis ineffective in acute poisoning
    • Adverse effects (SNRI,NRI,TCA)
      • CNS & ANS
        • fine tremor
        • sedation
        • paraesthesia
        • ataxia
        • convulsion
      • CVS
        • arrhythmia
        • heart block
        • dizziness, syncope
          • orthostatic hypotension in elderly
      • Respi
        • respiratory depression
          • overdose
      • Allergy
        • intrahepatic cholestatic jaundice
        • skin reactions
      • Hyponatraemia
        • usually in elderly
          • due to SIADH
        • consider this when
          • drowsiness, confusion / convulsion develop in patient
      • Weight gain
    • Clinical uses (SNRI,NRI,TCA)
      • MDD
      • Panic attacks
      • Noctural anuresis
        • in children over 6 y/o
        • amitriptyline
        • imipramine
      • Phobic anxiety syndromes
      • OCD
      • Adjunctive drug in
        • psychosis
        • chronic pain
        • neuralgia
        • migraine
      • ADHD
        • alternative choice
          • after methylphenidate (ritalin)
  • Tricyclic antidepressants (TCA)
    • Monoamine reuptake inhibitors
    • Examples
      • Sedative
        • amitriptyline
        • clomipramine
        • doxepin

        < li>Less sedative

        • imipramine
        • nortriptyline
        • desipramine
      • Stimulant
        • protriptyline
    • MOA
      • also block serotonergic, alpha-adrenergic, histamine, muscarinic receptors
  • N.B. Dopamine blockers
    • MOA
      • cause stimulation
      • not antidepressants
      • however, blockade of 5HT & NE reuptake
        • associated with mood elevation
  • 5HT2 Antagonists
    • Examples
      • Nefazodone
      • Trazodone
    • MOA
      • block 5HTs receptors
  • Monoamine oxidase-A inhibitors (MAOI)
    • Examples
      • Phenelzine
      • Tranylcypromine
      • Reversible MAOI (short acting)
        • moclobemide
    • MOA
      • Irreversibly inhibit MAO
        • produce long lasting actions (weeks)
        • increased stores of 5HT, NE, DA in the neuron
        • diffusion of excess neurotransmitter into the synaptic cleft
      • Inhibit other oxidases involved in metabolism of drugs & tyramine
        • normal constituent of some food
    • Pharmacological actions
      • elevates mood in normal & depressed patient
      • normal patient
        • immediate increase in motor activity
        • euphoria
        • excitement
    • Pharmacokinetics
      • well absorbed orally
        • but antidepresant effect require 2-4 weeks
      • when switching drugs
        • minimum of 2 weeks delay must be allowed, so that new enzyme sysnthesis can take up fully
    • Adverse effects
      • postural hypotension
        • sympathetic block
        • dizziness
        • drowsiness
      • atropine-like effects
      • CNS stimulator
        • tremor
        • restlessness
        • insomnia
        • convulsion in acute overdose
      • Weight gain
        • inappropriate appetite
      • Liver damage
        • jaundice
        • hepatocellular necrosis
      • Paraesthesia
      • peripheral neuropathy
      • hyponatremia
    • Uses
      • Depression
        • when TCA not satisfactory & electroconvulsion not appropriate
      • Phobic anxiety states
        • clautrophobia
        • agoraphobia
      • Narcolepsy
      • Bulimia
      • Post-traumatic reactions
  • MAO-B inhibitor
    • Example
      • Selegiline
        • used for parkinsonism

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Anti-psychotics (Neuroleptics)

  • 2 types of neuroleptics
    • Typical neuroleptics (1st generation)
      • Phenothiazines
        • marked sedative effect
          • chlorpromazine
          • promazine
        • marked atropine-like effect
          • thiaridazine
        • increased extrapyramidal effect
          • fluphenazine
          • prochlorperazine
      • Butyphenones
        • extrapyramidal effect
          • haloperidol
    • Atypical neuroleptics (2nd generation) [major difference: less extrapyramidal effects]
      • Clozapine
        • block D4 receptor
        • 5HT2A inverse agonist
      • Olanzapine
      • Risperidone
        • block D2 receptors
        • block serotonin S2 receptors
      • Quetiapine
      • Ziprasidone
  • MOA
    • Dopamine receptor blockade in brain
      • all neuroleptics block D2 receptors in CNS
        • in limbic system
        • most also block other monoamine receptors
      • takes days – weeks to modify abnormal behaviour
        • control hyperactive & hypomanic states in schizophrenia
    • Serotonin receptor blockade in brain
      • newer atypical agents
        • exert action through inhibition of serotonin receptors
  • CNS effects
    • Inhibition of dopaminergic system
      • neuroleptic/behavioural effects
      • anti-emetic activity
      • increased prolactin secretion
      • tardive dyskinesia
      • extrapyramidal effects
    • Anti-pruritic effect
      • block histamine H1 receptors
      • used for intractable pruritus
    • Lowering of convulsive threshold
    • Reflexes
      • depression of vasomotor centre
      • orthostatic hypotension
    • No respiratory depression
    • Poikilothermic effect
  • ANS effects
    • Anti-muscarinic effects
      • dry mouth
      • blurred vision
      • sedation
      • confusion
      • inhibiton of GI & urinary smooth muscle
        • constipation
        • urinary retention
    • Anti-adrenergic effects
      • orthostatic hypotension
      • light headedness
      • failure of ejaculation
      • miosis
  • Other effects
    • CVS
      • postural hypotension
      • quinidin –like effect
        • arrhythmia
        • prolong QT & PR interval
        • blunt T wave
    • Endocrine
      • increased prolaction
        • galactorrhea
        • painful breast
        • gynaecomastia
      • reduced pituitary gonadotrophin
        • inhibit ovulation
        • amenorrhea
        • infertility
        • impotence
      • decreased growth hormone
        • growth retardation
    • Kidney
      • weak diuretic effect
        • inhibit ADH
  • Adverse effect
    • neurological
      • acute dystonia
      • akathisia
      • parkinsonian effects
      • late appearing syndromes
        • perioral tremor (rabbit syndrome)
        • tardive dyskinesia
    • Sedation
    • Idiosyncratic & hypersensitivity reactions
    • Postural hypotension
    • Opa
      cities in cornea & lens of eye
      • epithelial keratopathy
    • weight gain
    • Fits
      • precipitated in epilepsy and alcoholics
  • Clinical uses
    • Mental disorders
      • schizophrenia
      • mania
      • manic depressive illness
    • Alcoholism
    • Withdrawal from drugs
    • Severe anxiety
      • panic states
    • painful terminal illness
    • intractable hiccup
    • persistent pruritus
    • nausea & vomiting
      • due to radiation, narcotics, uraemia, anticancer drugs

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Treatment guidelines

1st psychotic episode

  • Start with 2nd generation antipsychotic
    • observe for 6-8 weeks
    • If unresponsive
      • change to another 2nd generation drug/clozapine
        • monitor for agranulocytosis weekly (then fortnightly)
      • change to 1st generation drug
        • monitor yearly for tardive dyskinesia

Maintenance therapy

  • Continue treatment for 1 year
    • reevaluate
    • advise weight-loss program

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Lithium salts

  • General
    • lightest alkali metal
    • no psychotropic action
    • not a sedative
      • not a depressant
      • not a euphoriant
  • MOA
    • not clearly understood
  • Adverse effects
    • Hypothyroidism
      • rarely hyperthyroidism
    • Nausea
      • vomiting
      • diarrhea
    • Tremor
    • Weight gain
    • Renal effects
      • polyuria
      • thirst
        • interfere with stimulation of cAMP by ADH
    • Loss of bone calcium
      • interference with parathyroid hormone
    • Fetal
      • fetal cardiac abnormality
      • Fetal goitre
  • Acute toxicity
    • confusion
    • motor impairment
      • spasticity
      • ataxia
    • dehydration
    • convulsion
    • coma
    • death
  • Treatment
    • sodium chloride & water diuresis
      • sodium bicarbonate IV
      • osmotic diuretics
    • dialysis if severe
  • Uses
    • prophylaxis
      • in manic depressive disorder
      • able to prevent mood swings

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