Pharmacology

Question 1

What drugs alter Digoxin clearance, and what is the mechanism?

Answer 1

Clearance decreased due to increased MDR1 transporter activity

Drugs that cause this: amiodarone, dronedarone, quinidine, ritonavir, ranolazine

Question 2

St John’s Wort acts on which CYP, and in which way?

Answer 2

Induce 3A4

Ciclosporin is key drug that is metabolised more

Question 3

Celecoxib and Warfarin

Answer 3

Celecoxib inhibits CYP2C9, leading to raised s-Warfarin and thus increased warfarin effect. Can double INR

Question 4

What transporter variant is associated with Imatinib resistance?

Answer 4

ABCG2

Question 5

Furosemide and Lithium

Answer 5

Furosemide will increase serum lithium levels

As will HCT

Question 6

Valproate and Lamotrigone

Answer 6

If used together, Lamotrigine needs dose adjustment

Question 7

Ciclosporin metabolism

Answer 7

CYP3A4 in liver
Metabolism also occurs in small intestine via same CYP3A4

Question 8

Pharmacokinetics

Answer 8

What the body does to a given drug (absorption, distribution, metabolism, elimination)

Question 9

Pharmacodynamics

Answer 9

What the drug does to the body

Question 10

Best measure of overall exposure to a drug

Answer 10

Area under the curve

Question 11

For what drugs is Cmax most important?

Answer 11

Those with low therapeutic index - i.e. toxicity develops easily above therapeutic range

Question 12

Bioavailability and hepatic extraction ratio

Answer 12

Hepatic extraction ratio = 1 - bioavailability

Question 13

Volume of Distribution

Answer 13

Conceptual not actual volume. Would be the volume of fluid required to contain all of the drug in the body at the concentration it exists in plasma. More in the cells = bigger volume of distribution

Volume of distribution = total amount of drug in body/plasma drug concentration

Question 14

How to determine a loading dose

Answer 14

Volume of distribution multiplied by target plasma concentration

Question 15

What binds with highest affinity to albumin?

Answer 15

Acidic drugs

Salicyclic acid, warfarin, phenylbutazone, penicillins, sulphonamides

Has lower affinity for basic and neutral drugs, but high capacity for these which can cause displacement. Digitoxin, bilirubin and fatty acids can all bind.

Question 16

Bioavailability versus clearance for drug metabolism

Answer 16

Drug with low bioavailability will be more affected by changes in metabolism or transporters in bowel than changes in clearance.

Question 17

Calculation for half life

Answer 17

half life = 0.693 x Volume of distribution/clearance

Question 18

First order versus zero order kinetics

Answer 18

First order: constant proportion of drug eliminated per unit time
Zero order: constant amount of drug eliminated per unit time

Question 19

What is the therapeutic index?

Answer 19

Difference between dose at which adverse effect and therapeutic effects occur

Therapeutic index = adverse effect EC50/Therapeutic effect EC50

(EC50 = concentration of drug required to give half maximal response)

Question 20

Tachyphylaxis

Answer 20

Rapid tolerance to drug - response to same plasma concentration decreases rapidly

Results in hysteresis loop.

Question 21

Reverse Hysteresis Loop

Answer 21

Delay in onset and duration of effect due to:
- Prodrug/active metabolite
- Secondary messengers
- Redistribution phase

Question 22

Potency

Answer 22

Measure of dose required to produce a response

NOT a measure of maximum response

So the lower the dose required, trhe higher the potency. Usually based on dose required to produce 50% of maximal effect/dose required to produce response in 50% of population

Question 23

Dosing aims for Vancomycin

Answer 23

Measure with 24h AUC/MIC
Essentially give as much antibiotic as possible without causing toxicity

Question 24

Aminoglycoside dosing aims

Answer 24

Target peak level >10x MIC
Measure Cmax/MIC
Concentration dependent and some post antibiotic effect

Question 25

Fluoroquinolone dosing aims

Answer 25

Aim AUC >125 Measure with AUC/MIC Concentration dependent and post antibiotic effect

Question 26

Dosing aims for beta lactams

Answer 26

Time ? MIC Aiming to be above MIC 40-70% of the time

Question 27

Type 1 Error

Answer 27

False outcome by chance

Question 28

Type 2 Error

Answer 28

Rejecting a true outcome by chance (sample size key)

Question 29

Phase 1 drug trial:

Answer 29

Assessing safety, bioavailability, maximum tolerated dose, side effects

Question 30

Phase 2 drug trial

Answer 30

Dose selection Effect

Question 31

Phase 3 drug trial

Answer 31

Efficacy in target population Survival benefit

Question 32

Common CYP Inducers

Answer 32

Rifampicin (1A2, 2B6, 2C8, 2C9, 2C19, 3A4/5) - so all but 2D6 Phenytoin ( 1A2, 2B6, 3A4/5)

Question 33

Do -azoles typically inhibit or induce CYP enzymes?

Answer 33

Typically inhibit

Question 34

Clopidogrel and CYP Enzymes

Answer 34

Inhibits: 2B6, 2C8 Substrate for 2B6, 2C19

Question 35

Antibiotics and CYP enzymes

Answer 35

Mostly inhibitors other than Rifampicin Cipro: 1A2 inhibitor Clarithromycin: 2C19 inhibitor, 3A4/5 inhibitor Erythromycin: 3A4/5 inhibitor

Question 36

Inhibition or Induction of which CYP enzymes will influence Warfarin levels?

Answer 36

1A2, 2C9, 2C19, 3A4/5

Question 37

Bioavailability Calculation

Answer 37

Two key calculations: AUC of oral / AUC of IV Also Bioavailability = 1 - hepatic extraction ratio When using AUC, need to ensure have considered the doses in the question

Question 38

Key clinical features of Serotonin Syndrome

Answer 38

Rapid onset within 24hr of commencing causative drug (i.e. whichever drug tips patient over into SS) Autonomic dysfunction: diaphoresis, tachycardia Neuromuscular excitability: hyperreflexia, clonus, increased tone Altered mental state Nausea, vomiting, diarrhoea MAOI can cause hypotension (whereas hypertension overall more typical)

Question 39

Acute management of Serotonin Syndrome

Answer 39

Discontinue all serotonergic drugs Benzodiazepines for agitation/excessive muscle activity Active cooling for hyperthermia Antihypertensives Cardiac monitoring Consider need for intubation/sedation

Question 40

Temperature indication for sedation/intubation in Serotonin Syndrome

Answer 40

>41.1 degrees Use non depolarising agent for paralysis, e.g. rocuronium. So don't use Sux

Question 41

Mechanism and key causes of Neuroleptic Malignant Syndrome

Answer 41

Dopamine blockade is key. Central C2 receptor blockade in nigrostriatal pathway and hypothalamus -> movement disorders, impaired thermoregulation, increases sympathetic tone, disrupted autonomic regulation, calcium release from muscle First generation antipsychotics, second generation antipsychotics, metoclopramide, promethazine

Question 42

Presentation of NMS

Answer 42

Insidious onset, can take 2-4 weeks Cognitive changes early Catatonia Parkinsonism Hyperthermia Autonomic instability Raised CK No clonus or hyperreflexia

Question 43

Management of NMS

Answer 43

Discontinue cause Supportive Dantrolene if severe Dopamine agonists ECT for refractory disease