Lecture 3: Antidepressants

Question 1

How was depression treated pre 1950?

Answer 1

Sedatives

Question 2

What is the most effective antidepressant?

Answer 2

Electroconvuslive therapy

Question 3

Why are monoamine oxidase inhibitors used as antidepressants?

Answer 3

Monoamine oxidase degrades serotonin & noradrenaline - so inhibiting it means more serotonin & NA is available in synapse

Question 4

What is the monoamine hypothesis of depression?

Answer 4

The notion that depression is caused by a lack of NA, da and 5-ht in the cns

Question 5

What are limitations to the mahod?

Answer 5

• Does not explain Ad latency
• illicit uppers such as cocaine & meth go against this hypothesis

Question 6

What are tricyclic antidepressants?

Answer 6

• Work on NA
• Block reuptake of NA into presynaptic cell
• some also have this effect on 5-ht

Question 7

Give examples of tca’s

Answer 7

• Dibenzazepines → imipramine
• Dibenzcycloheptmes → amitriptyline

Question 8

What are some off-target effects of TcA?

Answer 8

• Antihistamine → H1 receptor antagonist → drowsiness, weight gain
• Anticholinergic → M1 receptor antagonist
• Antiadrenergic → alpha adrenergic antagonist

Question 9

Tca & overdose

Answer 9

• Cardiotoxic
• signs: hypoxia, seizure, tachycardia

Question 10

An example of a safe Tca

Answer 10

Lofepramine → structure does not lend itself to the off-target effects

Question 11

Tca pharmacokinetics

Answer 11

• 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

Question 12

Tca drug interactions

Answer 12

• Aspirin → competition for Plasma protein binding
• Steroids → cytochrome p450
• Alcohol → potentiates sedative effects

Question 13

What do maoi do?

Answer 13

• Prevent degradation of monoamines such as 5-ht, NA, & da

Question 14

What are the 2 types of maoi?

Answer 14

• type A → metabolise NA & 5-HT
• type B → metabolise Da

Question 15

Main metabolite of maoi?

Answer 15

Dihydroxyphenylglycol

Question 16

Selectivity & reversibility status of maoi?

Answer 16

 non Selective & irreversible (generally), aside from meclobemide which is a-specific & reversible

Question 17

What are some features of Mao that lead to maoi limitations?

Answer 17

• 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

Question 18

Side effects of maoi?

Answer 18

• Hypertension
• insomnia
• convulsions
• coma

Question 19

Maoi pharmacokinetics

Answer 19

• Orally bioavailable
• persistence long after activity @ active site
→ can’t measure activity from bloods

Question 20

Maoi drug interactions

Answer 20

• Anaesthetic, sedatives, depressants → potentate
• TCA → potentate → need a washout period of 2 weeks (5 for fluoxetine)

Question 21

Major problems of maoi

Answer 21

• Compliance
• tolerance
• side effects

Question 22

What do ssri do?

Answer 22

Inhibit 5-ht reuptake transporter specifically to increase 5-ht conc. In synapse

Question 23

Examples of ssri

Answer 23

Sertraline, fluoxetine

Question 24

What varies from ssri to ssri

Answer 24

• Potency
• selectivity
• pharmacokinetics

Question 25

Ssri pharmacokinetics

Answer 25

• Hepatic metabolism • fluoxetine has an active metabolite (nor-fluoxetine) → prevent withdrawal • in general → no active metabolites • physiological dependence → must discontinue in intervals

Question 26

What are the most potent / selective ssri?

Answer 26

• Most potent → paroxetine • most selective → citalopram

Question 27

Side effects of ssri

Answer 27

• Neurological → sexual dysfunction, insomnia, akithesia, anxiety • Vascular → headache, migraine • GI → nausea, vomiting, diarrhoea