Brief overview - PD, PK & ADME

Question 1

What is pharmacodynamics (2)

Answer 1

1. Study of the effects of drugs and their mechanisms of actions
2. What does the drug do to the body?

Question 2

What is pharmacokinetics (2)

Answer 2

1. What the body does to the drug
2. Absorption, Distribution, Metabolism, Excretion, (Toxicity) (ADME(T))

Question 3

What is the two-state model receptor theory (6)

Answer 3

1. The receptor is shown in two confrontation states, Resting (R) and Activated (R*), which exist in equilibrium.
2. No ligand = the equilibrium to left, more R.
3. Agonists = affinity for R*, equilibrium to right.
4. The greater the affinity for R* (activated), the greater the efficacy of the agonist
5. Antagonist = higher affinity for R, equilibrium to the left.
6. Neutral antagonist = equal affinity to R and R*, does affect, equilibrium, reduces by competition the binding of other ligands.

Question 4

Why are there spare receptors (4)

Answer 4

1. Allow maximal response without total receptor occupancy
2. Increasing the sensitivity of the system.
3. bind (and internalise) extra ligands, preventing an exaggerated response if too much ligand is present.
4. At half-maximal effect, ED50=KD. Sometimes, the full effect is see

Question 5

What are other mechanisms of antagonism (4)

Answer 5

1. Chemical antagonism: Substances combine in solution
2. Pharmacokinetic antagonism: ‘Antagonist’ reduces the concentration of the active drug at its site of action
3. Block of receptor-effector linkage
4. Physiological antagonism: opposing actions of two drugs cancel each other

Question 6

What is dimerisation/oligomerisation (3)

Answer 6

1. Two or more receptors of the same receptor (homodimerisation)
   or
2. Different receptors (heterodimerisation) functioning together as if they were a single receptor
3. The pharmacology of dimer is distinct from that of each of the protomers.

Question 7

What are the mechanisms underlying desensitisation and tolerance (6)

Answer 7

1. Change in receptors
2. Translocation of receptors
3. Exhaustion of mediators
4. Increased metabolic degradation
5. Physiological adaptation
6. Active extrusion of drug from cells

Question 8

What is the paracellular route (2)

Answer 8

1. Passive diffusion between cells; hydrophilic compounds e.g. Levothyroxine
2. Experimental agents to modify pore diameter to absorption

Question 9

What is the transcellular route: passive diffusion (5)

Answer 9

1. The most common mechanism for the oral route
2. Compound moves from high to low concentration (Fick’s law)
3. requires an appropriate balance of lipid & aqueous solubility
4. Driven by the concentration gradient and lipid solubility
5. (Most drugs have adequate aqueous solubility.)

Question 10

What are the 3 transporters and their locations (3)

Answer 10

1. Large Neutral Amino Acid Transporter (LAT1) - Blood-Brain Barrier
2. Organic Anion Transporter (OAT) - Brain; kidneys; placenta etc
3. Organic Cation Transporter (OCT) - Liver; small intestine

Question 11

What are the locations and functions of P-gP (5)

Answer 11

1. Intestine - Prevents chemical uptake into the system
2. Liver - Excretion to bile / re-presents chemical to metabolising enzymes
3. Kidney - Excretion into urine
4. Brain - Prevents uptake into the brain
5. Tumours- Prevents uptake of chemotherapeutic agents – drug-resistant tumours