Week 1 Pharmacology - Pharmacodynamics and Kinetics

Question 1

What is potency?

Answer 1

Concentration (EC50) or dose (ED 50) of a drug required to produce 50% of drugs maximal effect

Question 2

What does potency depend upon?

Answer 2

Affinity for receptor
Efficiency of drug-receptor interaction coupled to response

Question 3

What is maximal efficacy?

Answer 3

Limit of dose-response relationship (i.e. increasing dose fails to exert greater effect)

Question 4

What is an agonist?

Answer 4

Drug that binds and ACTIVATES receptor, directly or indirectly bringing about an effect

Question 5

What is a full agonist?

Answer 5

Drug that causes shift of almost all receptors within a pool to active state (i.e. when binding, producing high response when all receptors occupied)

Question 6

What is a partial agonist?

Answer 6

Drugs that produce small/low response at full receptor occupancy

Question 7

What is an inverse agonist?

Answer 7

Drugs which bind in the same way as agonist, but reduce levels of activity below basal levels observed in absence of drug

Question 8

What is an antagonist?

Answer 8

Drug that binds to and inhibits receptors and downstream pharmacological effect

Question 9

What is a competitive antagonist, and give example?

Answer 9

In presence of fixed concentration of agonist, increasing concentration of competitive antagonist progressively inhibit agonist response (and vice versa)

Noradrenaline and propranolol

Question 10

What happens to the Emax of an agonist if adding a competitive antagonist?

Answer 10

Emax remains the same, but the dose response curve is shifted to the right. (I.e. you can ‘outcompete’ the antagonist if you increase the dose of the agonist, and eventually you will reach the maximal effect)

Question 11

What is a non-competitive antagonist?

Answer 11

Often binds in covalent way, preventing future occupation by an agonist and reducing total number of receptors available for binding

Question 12

What happens to Emax in setting of a non-competitive antagonist?

Answer 12

Bind receptors and prevents agonist from activating, no matter the concentration of the agonist (i.e. you cannot outcompete this antagonist by increasing dose)

Therefore, Emax is reduced (i.e. you cannot reach the same maximal effect as before, unless you have enough spare receptors or antagonist concentration is low enough)

Question 13

What is a chemical antagonist?

Answer 13

When one drug ionically binds another, making agonist unable to interact with receptor

Question 14

What are the respective axises on a dose/response curve?

Answer 14

Y axis = ‘percentage of maximum’ and x axis = ‘agonist dose’

Question 15

How does a partial agonist effect the dose response curve?

Answer 15

Will effectively reduce total drug response by occupying potential receptors sites of the agonist, and eliciting a partial activation/response when compared to a full agonist. i.e. doesn’t shift curve per se, but does reduce the Emax

Question 16

What types of receptors are located intracellularly? What properties allow the agonists/molecules to reach them?

Answer 16

Steroid, lipid soluble molecules allow passage across plasma cell membrane

Question 17

What is the usual effect of binding an intracellular receptor?

Answer 17

Change in regulation of gene transcription, i.e. up or down regulating protein synthesis to bring about a particular action (i.e. thyroid hormone causing increased synthesis of thyroglobulin)

Question 18

What is a ligand-regulated transmembrane receptor, and common example?

Answer 18

Polypeptide with extracellular hormone binding domain, and cytoplasmic enzyme domain, connected by hydrophobic component that spans lipid bilayer.

Insulin = common example, (tyrosine kinase)

Question 19

What are examples of ligand gated ion channels?

Answer 19

Nicotinic/Muscarinic receptors
GABA receptors

Question 20

What is the underlying mechanism by which G-protein-coupled receptors exert their effect?

Answer 20

Up-regulate intracellular concentrations of 2nd messengers - i.e. cAMP, Ca2+, IP3)

Question 21

What are the steps involved in activation of GPCR?

Answer 21

1. Activation by binding extracellular component of receptor
2. This causes activation of G-protein on cytoplasmic side of GPCR
3. G protein then changes activity of effector element, usually enzyme or ion channel

Question 22

What is the mechanism of cAMP?

Answer 22

Binding of extracellular component of GPCR causes activation of Adenylyl cyclase (enzyme) –> formation of cAMP from ATP, and main enzymatic target is protein kinase A –> downstream effects

Question 23

What are some common examples of cAMP mediated activity?

Answer 23

Effects of catecholamines
Glycogenolysis
Vision

Question 24

What is the mechanism of phospholipase C?

Answer 24

GPCR binding that causes activation of phospholipase C enzyme, which splits PIP2 (component of plasma membrane) into 2 second messengers (IP3 and DAG). DAG activates PKC and IP3 diffuses through cytosol to bind to ligand gated calcium channels to cause release from intracellular vesicles –> downstream effects

Question 25

What cell type is the prototypical example of cyclic GMP activity?

Answer 25

Vascular smooth muscle cells

Question 26

How does cGMP cause relaxation of smooth muscle?

Answer 26

Ligands such as NO or ANP bind to GPCR, causing guanylyl cyclase to form cGMP, which stimulate protein kinase to dephosphorylate myosin light chains and prevent contraction. (Mechanism used by nitrates and hydralazine)

Question 27

What is volume of distribution?

Answer 27

Volume of distribution (Vd) is the apparent volume into which a drug disperses in order to produce the observed plasma concentration. i.e. if you give 1g of a drug, but measure only 1mg/L, the Vd would be 1000L (even though only 5L plasma)

Question 28

How can Vd be expressed in terms of formula?

Answer 28

Vd = amount of drug in body / concentration of drug in plasma

Question 29

What is 'half life'? What factors influence it?

Answer 29

Time required to to change the amount of drug in body by one-half during elimination. Factors = volume of distribution and the clearance

Question 30

When dose drug accumulation occur in terms of dosing and half life?

Answer 30

Dosing interval being shorter than four half-lives

Question 31

What is bioavailability? What factors influence it?

Answer 31

Fraction of unchanged drug that reaches systemic circulation following administration by any route. Influenced by absorption, and first pass metabolism.

Question 32

How is a loading dose calculated?

Answer 32

Volume of distribution x target concentration (is divided by bioavailability if not IV) i.e. Loading dose of phenytoin, 10mg/L target concentration in 70kg male. Loading dose = VD of phenytoin (35L) x 50 (10mg/L x 5 to get to plasma volume) = 350mg

Question 33

What factors affect volume of distribution, in terms of drug factors and patient factors?

Answer 33

Drug factors = protein binding, molecular size, pKa, charge, lipid solubility Patient factors = age, gender, body fat/muscle proportion, water distribution (ascites, effusions, pregnancy)

Question 34

What does a very high Vd suggest about a drug?

Answer 34

Very high concentration in extravascular tissues, i.e. not homogeneously distributed.

Question 35

What is zero order kinetics?

Answer 35

a constant amount (eg. so many milligrams) of drug is eliminated per unit time, i.e. independent of concentration of drug --> linear process

Question 36

What is first order kinetics?

Answer 36

First order elimination kinetics: a constant proportion (eg. a percentage) of drug is eliminated per unit time, i.e. dependent on concentration, if higher, there will be higher rate of elimination

Question 37

What is therapeutic index?

Answer 37

Relationship of dose required to produced desired effect to that which produces toxic effects i.e. Therapeutic index = (Td50) Median toxic dose/ (Ed50) median effective dose The higher the Ti, the safer, the lower, the more dangerous.