Pharmacodynamics

Question 1

Molecular targets for drug action?

Answer 1

TIRE

Transporters: Inhibitors or false substrates

Ion channels: Blockers or false substrates

Receptors: Agonist or antagosist action

Enzymes: Inhibitors or false substrates

Question 2

Drug receptor concepts

Answer 2

• Represent the quantitative relationship between drug dose and phamalogical effect (Dose repsonse curve)
• Selective to differenct receptors/action is selective

Question 3

Graded dose response relates what?

Answer 3

Drug dose to the size of the response in a single individual (also reflects maximal efficacy of a drug)

Question 4

Quantal dose response relates what?

Answer 4

Drug dose to the proportion of individuals displaying a desired pharmacological response (also reflects variability of responsiveness among individuals)

Question 5

What can both quantal and graded dose response curves tell you?

Answer 5

Potency and selectivity of drug action

Question 6

What is the Quantal Dose response?

Answer 6

Frequency (y axis) with a given drug dose (x axis) produces a fixed (all-or-none) response

Distribution of minimum doses that can produce a given effect (quantal) in a population of subjects

Question 7

What are therapeutic indices (ratios)?

Answer 7

TI = LD₅₀/ED₅₀

Want drugs to have a large TI

Question 8

Potency?

Answer 8

Amount of drug required to produce a given effect, relative term - different drugs can have different potencies but achieve the same effect

Question 9

Efficacy?`

Answer 9

The intrinsic ability of a drug to exert an effect and frequently is used to describe the maximum effect a drug can produce

Question 11

What does tolerance do to the dose response curve?

Answer 11

Shifts it to the right

Question 12

Full agonists

Answer 12

Bind to a receptor and produce a molecular response with a subsequent cellular response

Question 13

Partial agonists

Answer 13

Bind to a receptor BUT even the highest drug concentration is incapable of producing a sufficient molecular response to generate the cellular response seen following administration of a full agonist

Can displace a full agonist (antagonizing it)

Lowers maximum efficacy, regardless of concentration

Question 14

Inverse agonist

Answer 14

Have higher binding affinity for a receptor in the resting state than in the active state, produce negative efficacy

Question 15

Antagonist

Answer 15

Compounds that diminish or prevent an agonist (either endogenous or exogenous) compound from exerting its effect

1. Chemical (nonreceptor)
2. Physiologic (nonreceptor)
3. Reversible/Irreversible (active site receptor)
4. Reversible/Irreversible (allosteric binding)

Question 16

Reversible Competitive antagonist

Answer 16

Binds to the active site and inhibits an agonist/substrate from binding thus blocking the effects fo the drug. Dependent upon endogenous/exogenous agonist present

“Reversible”

Dose response curve = shifts right

ED₅₀ (K_m) = increases

E_max (V_max) = unchanged

Potency = decreases

Question 17

Irreversible competitive antagonist

Answer 17

Bind to the active site but they disassociate very slowly (covalent bond) and cannot be reversed by adding more agonist.

“Remove receptors from the system”

Dose response curve = lower, possible right if enough spare receptors available

E_max (V_max) = decreases

ED₅₀ (K_m) = unchanged

Efficacy = decreases

Question 18

Noncompetitive antagonist

Answer 18

Blocks at a location remote (allosteric) from the receptor site and reduces the affinity of the receptor for the agonist

Question 19

Drug biotransformation?

Locations in body?

Answer 19

Takes an exogenous drug and makes it more soluble in water

Location = Liver, gut, lungs, kidneys and skin

Question 20

What is the difference between phase I and Phase II hepatic metabolism?

Answer 20

Phase I - Nonsynthetic, preparatory

Phase II - Synthetic

Question 21

Prodrugs?

Answer 21

Inactive precursors that are metabolized to active metabolites

Ex. Levadopa, famciclovir

Question 22

Stereoisomers

Answer 22

Drugs with the same molecular formula but different structural formulas

Question 23

Enantiomers

Answer 23

Optical isomerism (mirror images)

2 or more chiral carbons

Racemic mixtures have each + and -, usually only one is the active metabolite

Question 24

Diastereoisomers

Answer 24

Geometric isomers (Cis/trans)

Question 25

What are the human P450 enzymes?

Answer 25

Many different enzymes that acto on endogenous/exogenous compounds by metabolism or detoxification, respectively

Each is encoded by a seperate gene

Question 26

CYP2D6

Answer 26

CYP - abbreviation for the cytochrome (location)

2 (family) - enzymes with >40% AA in common

D (subfamily) - enzymes with >55% AA in common

6 (isozyme) - enzymes with >97% AA in common

Question 27

Half-life

Answer 27

Half-life = 0.693/K_e

Half-life = 0.693 x V_d/Cl

Question 28

Ke

Answer 28

Elimination rate constant

Slope of the log curve

Question 29

How does an inducer affect half-life?

Answer 29

Decreases the half-life or increases the elimination rate constant (K_e)

Stimulates the enzyme

Question 30

How does an inhibitor affect the half-life?

Answer 30

Rapid onset, short duration

Decrease in the elimination rate constant and increases half life

Question 31

Clearance

Answer 31

Clearance = V_d x K_d

Clearance = rate of elimination (K_e) / C_p

Remember: Systemic clearance is additive of kidney, liver, and other

Question 32

First-order reactions

Answer 32

Concentration independent clearance

The amount of drug eliminated in a set amount of time, is proportional to the amount present in the body

dC/dt = -K_e x C

Question 33

Zero-order reactions

Answer 33

A constant amount of drug is eliminated per unit time regardless of the amount of drug in the body

INdependent of drug concentration

dC/dt = -K_e

Question 34

Drug accumulation

Answer 34

Drugs accumulate if they are re-administered at a dosing interval which is < 5 x half-life

Question 35

Maintenance Dose

Answer 35

Maintenance Dose = [Cp_ss x clearance] / F x S

Question 36

What three factors influence the renal clearance of a drug?

Answer 36

1. Glomerular filtration in the Bowmans capsule (f [GFR])
2. Proximal tubular secretion for protein bound weak acids and some bases (fixed capacity)
3. Distal tubular reabsorption possible for lipid soluble unionized drugs (pH effect)

(Cl)_r = d (GFR) + [Rate of TS - rate of TR] / C_p

Question 37

What does a renal clearance ratio of < 1 mean?

Answer 37

Either the substance is not filtered, or it is filtered and reabsorbed. The drug is partially reabsorbed in addition to being filtered by GFR.

Question 38

What does a renal clearance of = 1 mean?

Answer 38

The substance must be a glomerular marker (filtered, but neither reabsorbed nor secreted)

Drug is filtered by GFR only

Question 39

What does a renal clearance of > 1 mean?

Answer 39

The drug is actively secreted in addition to being filtered by GFR. Concurrent administration of probenecid will reduce renal clearance for drugs which involve active tubular secretion.