Pharm Part 1 Flashcards
(11 cards)
How phases of drug trails are there?
4 phases
Pre-clinical trials Phase 1 (human) → Aim in safety and pharmacology of drug. Given to small amount of subjects to ascertain safety,tolerability and pharmacokinetics
Phase 2 (Human) → Aim is to trial drug to a comparator. Here the aim is to establish effective dose, method of dosing and dosing interval.
Phase 3 (Human) → Aim drug undergoes double-blind RCT to further evaluate safety and effective dose. This is usually the final step before seeking regulatory approval.
Phase 4(Human) → Aim Post marketing surviallence. In this phase less common side effects can be identified and drugs in a specific population, as at this point the drug is given on a larger scale.
The Four CYP enzymes
CYP 2D6
CYP 1A2
CYP 3A4
CYP 2C19
Tell me about CYP 2D6 & CYP 1A2
CYP 2D6 → ultra-rapid metabolizers. 30% of east Africans e.g. Ethiopians. (7% of white people, 25% of East Asians). SSRI are potent inhibitors of this enzyme. Risperidone is metabolised uding this enzyme. Codeine is metabolised through this enzyme.
CYP 1A2→ Metabolism of olanzapine and clozapine. Caffeine increase lvls of clozapine through competitive inhibition of this enzyme. Smoking on the other hand reduced lvls of clozapine through enzyme induction. Ciprofloxacin also increase the enzyme and can cause increase in clozapine lvls.
tell me about CYP 3A4 & CYP 2C19
CYP 3A4 → Metabolism of quetiapine and ziprasidone. 35% of clozapine metabolism. Induced by carbamazepine, phenytoin, barbiturates and rifampicin
CYP 2C19 → Some people are poor metabolizers . 20% of Orientals are deficient in this enzyme. Fluoxetine are inhibitors of this enzyme but there are no major clinical interactions
SSRI MOA
Inhibit SERT ( serotoin transporters). Increase levels in the synaptic cleft to act of synaptic neurons.
The reduction of side effects is due to the desensitzation of the post-synaptic neuron.
MOst SSRI’s has a half-life of 24 hours, however fluoxetine has a half-life of 5-7 days.
Most SSRI’s are highly protein bound.
Tricyclic Antidepressants
MOA
Act to inhibit Serotonin, Noradrenaline and dopamine.
Clomipramine is the most serotonin specific
Imipramine, most noradrenergic effect
Amitriptyline, active metabolite of nortriptyline great nor adrenergic effect
TCA’s high propensity to cause QT prolongation
Most TCA’s have a long half life of about 24 hours → hence daily dosing.
MOA-I MOA
Act to inhibit MAO- A enzyme which metabolises noradrenaline and serotonin.
Most MOA-I are irreversible, except moclobemide, which is reversible
Advisable to wait two weeks before ceasing MAO-I before starting another antidepressant to allow synthesis of new
enzymes usually takes 5-7 days for this to happen
SNRI’s
Venlafaxine and duloxetine fall into this category
Duloxetine can be used for stress incontinence and chronic neuropathic pain
Venlafaxine has a short half life of 3.5-5 hours, hence XR for daily dosing
Duloxetine has a half-life of 12 hours
Sweating is more common than SSRI’s
Serotonin Antagonist & Reuptake inhibitors
MOA
Trazodone and nefazodone are part of this category
Trazodone is also a weak inhibitor of serotonin uptake and a 5HT2A & 5HT2C antagonist. Its active metabolite mCPP can lead to anxiety, weight loss & migraine.
Trazodone is associated with priapism
Nefazodone is not commonly used due to its inhibition of CYP 3A4 & hepatotoxicity
Noradrenaline and Serotonergic Specific Antagonist (NASSA)
Mianserin & Mirtazapine. The main mechanism is through alpha 2 inhibition which which increases nor adrenaline and dopaminergic transmission
Additional mechanisms of mirtazapine include antagonism to 5HT2A (anti-anxiety), 5HT2C (treatment of sexual side effects) and 5HT3 ( reduction is nausea)
Both these drugs can lead to agranulocytosis
Buspirone
5HT1A partial agonist
Short half life of 2-11 hours
