Pharmacodynamics: Healthy Animals Block 7 Exam

pharmacodynamics

how drugs produce effects in body

• drug binds to target molecule

• change in physical property of cell

• chemical or metabolic changes

• do not create new cell effects/actions

drug receptors

• proteins on or within cell surface/cytoplasm

• ex: other drug targets, enzymes, DNA/RNA

ligand

• something that binds a receptor

• ex: acetylcholine, norepinephrine, insulin

ionotropic receptor

• forms ion channel

• ions can flow

• fast-acting

• ex: ligand-gated ion channels (GABA receptor)

metabotropic channel

• no pore/channel

• linked to other enzymes/2nd messengers

• slower onset of action

• indirectly linked to ion channels

• ex: G-protein coupled receptors

4 major types of receptors

• ion channel

• GPCRs

• Enzyme-linke

• intracellular

ion channels

• ionotropic receptor

• pores formed in cell membrane

• voltage gated or ligand gated

G-protein coupled receptors

• metabotropic channel

• 7 transmembrane receptor

• 3 families/alpha subtypes (each have alpha, beta, gamma)

  • G_s

  • G_i

  • G_q

• these receptors are targets for 50% of drugs

• binding of receptor activates G protein which activates or inhibits enzyme, ion channel, or other target

GPCR subtype G_s

• activate ADENYLYL CYCLASE

• increase cAMP

  • activates protein kinase A

• generates response

GPCR subtype G_i

• decrease AC and cAMP

• inhibits ion channels

GPCR subtype G_q

• activate PLC

  • create IP3

  • create DAG

Enzyme-linked receptors

• metabotropic

• transmembrane receptor

  • extracellular binding site, forms heterodimer

  • activated receptor autophosphorylates, ultimately generating cell signaling

• ex: insulin receptor, growth factors

Intracellular receptors

• metabotropic

• interior of cell

• alter DNA for protein synthesis

activity

ability of drug to have response

affinity

• force of attraction between drug and receptor

• tendency to bind to receptor

selectivity

• drug’s ability to affect particular receptor population in preference to others

• multiple receptors can be involved but highly selective drug for one receptor is preferred

• ex: epinephrine binds to all alpha and beta receptors but is selective for alpha one and beta one

agonist

• binds to receptor and causes response

• mimics activity of endogenous substance

partial agonist

• binds to receptor

• activates receptor

• only results in partial response

antagonist

• binds to receptor and does not cause a response

• blocker

• can still have affinity of receptor

• usually reversible

inverse agonist

binds to receptor and has opposite effect of normal effect

competitive antagonist

• looks like drugs - binds at same site

  • high enough concentrations can overcome interaction

  • usually reversible

non-competitive antagonist

• binds anywhere else

• changes conformation and agonist can’t bind

dose response relationships

as you give more drug you get more response

maximum response

intrinsic activity/efficacy

potency

amount of rug needed to produce effect (dose)

high efficacy on graph

taller curve

increasing potency on graph

curve has same steepness but shifted left

therapeutic drug concentration

range of plasma or blood concentrations which is normally required to achieve a therapeutic effect in absence of toxicity

TD50

dose at which toxicity occurs in 50% of patients

LD50

lethal dose in 50% of patients

LD95

lethal dose in 95% of patients

therapeutic or safety index

• measure of safety of a drug compared to toxicity of drug

• LD50/ED50

• higher number = safer drug

efficacy

drug’s ability to produce maximum effect under ideal conditions

effectiveness

drug’s ability to produce clinically relevant effect

potency

amount of drug to produce a specific effect, all about dose

ED50

dose of medication that produces specific effect in 50% of patients

ED95

dose of medication that produces a specific effect in 95% of patients

apparent volume of distribution

• Vd

• hypothetical volume

• fluid volume that drug would have to be dissolved in to achieve concentration observed in plasma

• functional volume that can be a volume that is bigger than animal

What is Vd affected by

• distribution

  • what tissues can drug diffuse into

• protein binding

  • binding to plasma protein = Vd small

  • binding to tissue protein = Vd large

• size of body water compartments

Calculation of Vd

Vd = dose/C

clearance

volume of biological fluid that would have to be completely free of drug to account for amount of drug lost

total body clearance is

sum of clearance by all organs in body

first order kinetics

• constant fraction of drug is eliminated per unit of time (10% a day)

• most common

zero order kinetics

• constant amount of drug is eliminated per unit of time (10mg/day)

• clearance of drug is independent on drug concentration

clearance equation

Clearance = rate of elimination/Clearance at steady state

area under curve

total load of drug

bioavailability

• proportion of drug that is available within body to exert its pharmacologic effect

bioavailability equation

bioavailability = AUC oral/AUC IV

half life

time it takes for plasma concentration or amount of drug in body to be reduced by 50%

half life equation

t ½ = 0.693 x (Vd/Cl)