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
- 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
Less sedative
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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