Lecture 3: Antidepressants Flashcards
How was depression treated pre 1950?
Sedatives
What is the most effective antidepressant?
Electroconvuslive therapy
Why are monoamine oxidase inhibitors used as antidepressants?
Monoamine oxidase degrades serotonin & noradrenaline - so inhibiting it means more serotonin & NA is available in synapse
What is the monoamine hypothesis of depression?
The notion that depression is caused by a lack of NA, da and 5-ht in the cns
What are limitations to the mahod?
• Does not explain Ad latency
• illicit uppers such as cocaine & meth go against this hypothesis
What are tricyclic antidepressants?
• Work on NA
• Block reuptake of NA into presynaptic cell
• some also have this effect on 5-ht
Give examples of tca’s
• Dibenzazepines → imipramine
• Dibenzcycloheptmes → amitriptyline
What are some off-target effects of TcA?
• Antihistamine → H1 receptor antagonist → drowsiness, weight gain
• Anticholinergic → M1 receptor antagonist
• Antiadrenergic → alpha adrenergic antagonist
Tca & overdose
• Cardiotoxic
• signs: hypoxia, seizure, tachycardia
An example of a safe Tca
Lofepramine → structure does not lend itself to the off-target effects
Tca pharmacokinetics
• Orally bioavailabe → lots of 1st pass metabolism
• Sticky with proteins → large distribution volume
• long half life → be careful with elderly due to hepatic & renal insufficiency
• metabolism in liver → demethylation & hydroxylation
• metabolites excreted in urine
Tca drug interactions
• Aspirin → competition for Plasma protein binding
• Steroids → cytochrome p450
• Alcohol → potentiates sedative effects
What do maoi do?
• Prevent degradation of monoamines such as 5-ht, NA, & da
What are the 2 types of maoi?
• type A → metabolise NA & 5-HT
• type B → metabolise Da
Main metabolite of maoi?
Dihydroxyphenylglycol
Selectivity & reversibility status of maoi?
 non Selective & irreversible (generally), aside from meclobemide which is a-specific & reversible
What are some features of Mao that lead to maoi limitations?
• Monoamines are intaken in diet → not good as maoi are irreversible & non-selective, which could lead to hypertension → increased stroke risk
• the cheese effect is a clinical liability → tyramine → headache
Side effects of maoi?
• Hypertension
• insomnia
• convulsions
• coma
Maoi pharmacokinetics
• Orally bioavailable
• persistence long after activity @ active site
→ can’t measure activity from bloods
Maoi drug interactions
• Anaesthetic, sedatives, depressants → potentate
• TCA → potentate → need a washout period of 2 weeks (5 for fluoxetine)
Major problems of maoi
• Compliance
• tolerance
• side effects
What do ssri do?
Inhibit 5-ht reuptake transporter specifically to increase 5-ht conc. In synapse
Examples of ssri
Sertraline, fluoxetine
What varies from ssri to ssri
• Potency
• selectivity
• pharmacokinetics
Ssri pharmacokinetics
• Hepatic metabolism
• fluoxetine has an active metabolite (nor-fluoxetine) → prevent withdrawal
• in general → no active metabolites
• physiological dependence → must discontinue in intervals
What are the most potent / selective ssri?
• Most potent → paroxetine
• most selective → citalopram
Side effects of ssri
• Neurological → sexual dysfunction, insomnia, akithesia, anxiety
• Vascular → headache, migraine
• GI → nausea, vomiting, diarrhoea
