Pharmacodynamics Flashcards
Lecture 2 (Cuddy)
Molecular targets for drug action?
TIRE
Transporters: Inhibitors or false substrates
Ion channels: Blockers or false substrates
Receptors: Agonist or antagosist action
Enzymes: Inhibitors or false substrates
Drug receptor concepts
- Represent the quantitative relationship between drug dose and phamalogical effect (Dose repsonse curve)
- Selective to differenct receptors/action is selective
Graded dose response relates what?
Drug dose to the size of the response in a single individual (also reflects maximal efficacy of a drug)
Quantal dose response relates what?
Drug dose to the proportion of individuals displaying a desired pharmacological response (also reflects variability of responsiveness among individuals)
What can both quantal and graded dose response curves tell you?
Potency and selectivity of drug action
What is the Quantal Dose response?
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
What are therapeutic indices (ratios)?
TI = LD50/ED50
Want drugs to have a large TI
Potency?
Amount of drug required to produce a given effect, relative term - different drugs can have different potencies but achieve the same effect
Efficacy?`
The intrinsic ability of a drug to exert an effect and frequently is used to describe the maximum effect a drug can produce
What does tolerance do to the dose response curve?
Shifts it to the right
Full agonists
Bind to a receptor and produce a molecular response with a subsequent cellular response
Partial agonists
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
Inverse agonist
Have higher binding affinity for a receptor in the resting state than in the active state, produce negative efficacy
Antagonist
Compounds that diminish or prevent an agonist (either endogenous or exogenous) compound from exerting its effect
- Chemical (nonreceptor)
- Physiologic (nonreceptor)
- Reversible/Irreversible (active site receptor)
- Reversible/Irreversible (allosteric binding)
Reversible Competitive antagonist
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 (Km) = increases
Emax (Vmax) = unchanged
Potency = decreases
Irreversible competitive antagonist
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
Emax (Vmax) = decreases
ED50 (Km) = unchanged
Efficacy = decreases
Noncompetitive antagonist
Blocks at a location remote (allosteric) from the receptor site and reduces the affinity of the receptor for the agonist
Drug biotransformation?
Locations in body?
Takes an exogenous drug and makes it more soluble in water
Location = Liver, gut, lungs, kidneys and skin
What is the difference between phase I and Phase II hepatic metabolism?
Phase I - Nonsynthetic, preparatory
Phase II - Synthetic
Prodrugs?
Inactive precursors that are metabolized to active metabolites
Ex. Levadopa, famciclovir
Stereoisomers
Drugs with the same molecular formula but different structural formulas
Enantiomers
Optical isomerism (mirror images)
2 or more chiral carbons
Racemic mixtures have each + and -, usually only one is the active metabolite
Diastereoisomers
Geometric isomers (Cis/trans)
What are the human P450 enzymes?
Many different enzymes that acto on endogenous/exogenous compounds by metabolism or detoxification, respectively
Each is encoded by a seperate gene
CYP2D6
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
Half-life
Half-life = 0.693/Ke
Half-life = 0.693 x Vd/Cl
Ke
Elimination rate constant
Slope of the log curve
How does an inducer affect half-life?
Decreases the half-life or increases the elimination rate constant (Ke)
Stimulates the enzyme
How does an inhibitor affect the half-life?
Rapid onset, short duration
Decrease in the elimination rate constant and increases half life
Clearance
Clearance = Vd x Kd
Clearance = rate of elimination (Ke) / Cp
Remember: Systemic clearance is additive of kidney, liver, and other
First-order reactions
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 = -Ke x C
Zero-order reactions
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 = -Ke
Drug accumulation
Drugs accumulate if they are re-administered at a dosing interval which is < 5 x half-life
Maintenance Dose
Maintenance Dose = [Cpss x clearance] / F x S
What three factors influence the renal clearance of a drug?
- Glomerular filtration in the Bowmans capsule (f [GFR])
- Proximal tubular secretion for protein bound weak acids and some bases (fixed capacity)
- Distal tubular reabsorption possible for lipid soluble unionized drugs (pH effect)
(Cl)r = d (GFR) + [Rate of TS - rate of TR] / Cp
What does a renal clearance ratio of < 1 mean?
Either the substance is not filtered, or it is filtered and reabsorbed. The drug is partially reabsorbed in addition to being filtered by GFR.
What does a renal clearance of = 1 mean?
The substance must be a glomerular marker (filtered, but neither reabsorbed nor secreted)
Drug is filtered by GFR only
What does a renal clearance of > 1 mean?
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.
