Sesh 7: Pharmacodynamics

Question 1

Name 3 enteral administration routes.

Answer 1

1. Oral
2. Sublingual
3. Rectal

Question 2

What is the ‘most addictive’ method of administration, and why?

Answer 2

Intranasal, as drug can enter the brain rapidly.

Question 3

Why is the oral drug administration route the most common?

Answer 3

It is the safest and most convenient.

Question 4

Where does most drug absorption take place?

Answer 4

Jejunum

Question 5

What is the typical small intestine transit time and pH?

Answer 5

About 3-5 hrs, with pH 6-7.

Question 6

What physicochemical factors can affect drug absorption?

Answer 6

• GIT surface area
• Drug lipophilicity/ pKa
• Density of GI SLC expression

Question 7

Where does first pass metabolism mainly occur?

Answer 7

Liver

Question 8

What are the 2 major metabolising enzyme groups in the liver?

Answer 8

1. Phase 1-CYP450s

2. Phase II- Conjugating enzymes

Question 9

Define bioavailability.

Answer 9

The fraction of a defined dose of a drug that reaches a specific body compartment (usually the circulation).

Question 10

How is oral bioavailability calculated?

Answer 10

Amount reaching systemic circulation (area under curve via oral route) / total drug given IV (area under curve IV route).

Question 11

What are the 3 types of capillary endothelium, and what can they affect?

Answer 11

1. Continuous
2. Fenestrated
3. Sinusoidal-incomplete basement membrane
   Can affect drug distribution if hydrophilic.

Question 12

What is the volume of distribution (Vd)?

Answer 12

A model summarising the movement of a drug from the plasma, to interstitial fluid, to intracellular compartments. Units= L or L/kg

Question 13

What effect will increasing drug penetration into interstitial and intracellular compartments have on:
A) plasma concentration of the drug
B) volume of distribution of the drug

Answer 13

A) reduced

B) increased

Question 14

What is the action of hepatic phase I enzymes on a drug?

Answer 14

CYP450s increase the ionic charge on a drug via modifying its existing functional groups, e.g. Via redox reactions, to increase their renal elimination.
Can also convert pro-drugs into their active form e.g. Codeine to morphine.

Question 15

What action do phase II enzymes have on drugs?

Answer 15

Conjugating enzymes further increase the ionic charge of drugs by adding new functional groups on to the drug, to increase their renal elimination.

Question 16

By what 3 mechanisms can CYP450 enzymes be induced?

Answer 16

1. Increased transcription
2. Increased translation
3. Reduced degradation

Question 17

What effect will it have if a drug is metabolised by a CYP450 that is induced?

Answer 17

Will reduce the plasma levels of the drug, and reduce its therapeutic efficacy.

Question 18

By what mechanisms can CYP450 inhibition occur?

Answer 18

Competitive/non-competitive inhibition.

Question 19

If a drug is metabolised by a CYP450 that is inhibited, what may happen?

Answer 19

Drug plasma levels will increase, potentially leading to side effects/ toxicity.

Question 20

What are the 3 main stages of renal elimination?

Answer 20

1. Glomerular filtration
2. Proximal tubular secretion-ACTIVE
3. Distal tubular reabsorption-PASSIVE

Question 21

The glomerulus receives __% of renal bloodflow, whilst the peritubular capillaries receive __%.

Answer 21

1. 20

2. 80

Question 22

What type of transporters are highly expressed in the kidney, and transport ionised molecules across the membrane?

Answer 22

OATs and OCTs (solute-linked carriers).

Question 23

What is clearance?

Answer 23

The volume of plasma completely cleared of drug per unit time (mL.min-1) i.e. Rate of elimination of drug from body.

Question 24

Which 2 values can, together, provide an estimate of drug half life (t 1/2)?

Answer 24

Volume of distribution and clearance.

T0.5=0.7 X Vd / CL

Question 25

What are linear/first order elimination kinetics?

Answer 25

The rate of drug elimination is proportional to the concentration of drug. Needs plenty of phase I/II enzymes and OATs/OCTs, therefore rate of elimination will be proportional to the no. Of molecules occupying a catalytic/carrier site per unit time.

Question 26

What are zero order elimination kinetics?

Answer 26

Occur when elimination processes are saturated/ rate-limited…often at high doses.

Question 27

What are the clinical implications of a drug with zero order kinetics?

Answer 27

• likely ADRs/SADRs, as small change in dose can cause large change in plasma conc
• t 0.5 not calculable so can’t easily predict dosing regimes
• increased risk of drug-drug interactions
• more of a prob in children/adults/ill with less or immature metabolic capacity.