L4 - Introduction to Clinical Pharmacology

Question 1

Theraputic Ration (or Index) =

Answer 1

TR = MTC / MEC

MTC = maximum tolerated concentration
MEC = minimum effective concentration

High TR indicated safe drugs, low is unsafe - TR essentially gives a numerical value to the ‘Theraputic Window’

Question 2

Quantal Dose-response Graph

Answer 2

Plots yes or no answers essentialy

Depicts frequency of distribution of the dosage at which patients responded theraputically

Generalised effect of a drug to a population as not all individuals the same

Question 3

EC50

Answer 3

Effective concentration in 50% of the population

Question 4

TD50

Answer 4

Toxic dose in 50% of the population

Question 5

LD50

Answer 5

Lethal Dose in 50% of the population

Question 6

Drug Interaction:

Answer 6

Pharmacodynamic - a drug modifies pharmacological effect of another drug, eg alcohol is PAM of GABAaRs, so are benzodiazepines
- usually predictable from knowledge of drug pharmacology

Phamacokinetic - a drug modifies the concentration of another drug, eg warfarin and cimetidine, both metabolised by same CYP enzyme
- less predictable and affect ADME

Question 7

Drug Distribution Changes

Answer 7

• drug that alter rate of GI motility
• Enterohepatic recirculation (liver shunting drug into bile, goes into duodenum, and can be reabsorbed), of oral contraceptives , especially low-dose ones, can be altered by antibiotics. eg oestrogen is administered as a prodrug and in converted into active form from conjugated form by gut bacteria, antibiotics can kill these bacteria.

Question 8

Drug Metabolism Changes

Answer 8

Drugs can cause:
Enzyme induction - increases expression of enzymes, up Km, same Vmax
Enzyme inhibition - decreases expression of enzymes, same Km, lower Vmax

Can affect their own, and other drugs’ metabolism

Question 9

Drug Excretion Changes

Answer 9

Drugs can share common transporters, so can be competition for binding

Question 10

Variability of Drug Concentration:

Answer 10

Cp too high:
liver/renal problems
genetic hypometabolism
very young/very old

Cp too low:
poor absorption
genetic hypermetabolism (high first pass metabolism)
non-compliance

Question 11

fu

Answer 11

fraction of drug excreted by kidney in unchanged form

Question 12

Liver Disease

Answer 12

• impaired drug metabolism due to decreased enzyme capacity and blood flow
• High CL drugs affected by BF and enzyme capacity
• Low CL drugs affected by BF

General effects include:

• decreased synthesis of plasma proteins (hypoprotinaemia), and clotting factors
• Impaired bile excretion
• Hepatic encephalopathy ( liver disease-induced brain function decline)
• Ascities, accumulation of fluid in peritoneal cavity

Question 13

Renal Impairment

Answer 13

• Lower estimated glomerular filtration rate (eGFR), detected by creatinine clearance from skeletal muscle, then plotted on graph (CL and fu), and adjusted accordingly
• Drugs predominantly eliminated by kidney will need altered dosage to achieve non-toxic steady state concentration

Question 14

eGFM

Answer 14

Estimated Glomerular Filtration Rate

20-50ml/min = mild impairment
10-20ml/min = moderate impairment
<10ml/min = severe imapirment

Question 15

Dose Altering

Answer 15

Can be altered by:
Reducing tablet size
or
Increase time interval between doses

Question 16

Drugs and Children

Answer 16

• may find it difficult to take medicine
• parents likely have to help aid compliance
• consent
• dosing by body weight, or by body surface area
• in neonates (first 30 days), altered PK/PD eg inefficient filtration, enzyme deficiencies, delayed excretion

Question 17

Drugs and Elderly

Answer 17

• Impaired renal excretion, thus increased Cp and sensitivity
• Polypharmacy likely
• CL impaired
• Difficulty swallowing
• Non-compliance via forgetfulness and confusion more likely

Question 18

Drugs in Pregnancy

Answer 18

AVOID

• teratogenicity
• foestus most at risk before mother knows she is pregnant
• if drug can be absorbed, can likely cross placenta
• Benefits can outweigh risk, eg in epileptics
• PK handling changes, eg vomiting, decreased albumin, increased GFR