Lecture 2: Pharmacokinetics and Pharmacodynamics II

bioavailability

rate and extent active drug enters systemic circulation

affects absorption

essential for determining dosage amounts

helps predict onset of effect

absolute bioavailability

extravascular route vs IV bioavailability (considered 100%, straight into bloodstream)

when determining absorption, think about…

• bioavailability

• crossing membrane barriers

• drug specific properties

• physiologic factors

• patient factors

crossing membrane barriers

diffusion → most common

transport → needs specific mechanism, often drug specific

absorption drug specific properties

lipid solubility

ionization

protein binding

formulation and dissolution rate

particle size

physiologic factors that affect absorption

blood flow

surface area for absorption

characteristics of the organ (skin vs GI)

patient factors that affect absorption

age

disease status

diet (fatty meal vs grass)

distribution

pharmacokinetics

how a drug spreads through the body to the effect site

protein binding in plasma and tissues (distribution)

only “free” drug is active

tissue protein binding may allow to act as a reservoir

lipid solubility and ionization (distribution)

helps to reach the site of action

volume of distribution (theoretical)

volume in which the drug would dissolve to create the measured plasma concentrations

useful for determining an initial dose of drug needed to achieve a specific plasma concentration (loading dose)

metabolism

PK

liver

first pass effect

metabolism - liver

cytochrome P450

Phase II

may be needed to create active form of some drugs

cytochrome P450 - liver metabolism

70-80% of current drugs

Phase I oxidation primarily

Phase II - liver metabolism

create water soluble forms for excretion

first pass effect - metabolism

GI delivered drugs are metabolized before reaching circulation

markedly decreases oral effect of some drugs

changes dose needed and route chosen

excretion

PK

renal excretion

hepatic/bilary excretion

renal excretion

water soluble drugs and. metabolites

• glomerular filtration

• tubular reabsorption

• tubular secretion

glomerular filtration - renal excretion

protein binding

GFR

tubular reabsorption - renal excretion

ionization

urine pH

tubular secretion - renal excretion

mostly active transport and bypasses glomerulus

hepatic/ biliary excretion

larger particles are transported directly into bile

enterohepatic recirculation can continue to form more water soluble metabolites

clearance

overall efficacy with which the drug is eliminated from the body

volume of plasma from ehich drug is completely removed per unit time (L/hr)

total body clearance is the sum of all clearance pathways (renal + hepatic + other)

T1/2 (half life)

key PK term

time required for the plasma concentration of a drug to decrease by 50%

independent of dose for most drugs

plasma concentration vs time curve

guides dosing interval and frequency

determines time to reach steady state (~4-5 half-lives)

determines time for drug elimination after stopping therapy

short T1/2

frequent dosing needed

long T1/2

risk of accumulation and toxicity if dosed too often

area under the curve (AUC)

key PK term

area under the plasma concentration vs time curve

represents the total drug exposure over time

reflects the extent of drug absorption and overall bioavailability

used to compare bioavailability of different formulations (drug design)

helps in dose optimization and therapeutic drug monitoring

avoiding potential toxicity

High AUC

greater systemic drug exposure

drug administration → drug absorption → drug distribution to receptor sites

pharmacokinetics

drug in receptor microenvironment → drug binds to receptor → receptor activation of cell signaling → physiologic response

pharmacodynamics

drug binding to a receptor is mediated by…

the chemical structure of the drug that allows it to interact with complementary surfaces on the receptor

dextrorotatory

when the plane of polarized light is rotated in a clockwise direction when viewed through a polarimeter

+ or d

levorotatory

when the plane fo polarized light is rotated in a counter-clockwise direction when viewed through a polarimeter

(-) or l

receptor specificity

when a drug acts on only a single target, it is termed ‘specific’

rare property in drugs, may occur if concentrations are low

dependent on drug-receptor interaction

receptor selectivity

most drugs display activity at a variety of receptors

often this is concentration dependent

common receptor types

(PD)

g-protein coupled receptors

receptor gated ion channels

enzyme receptor: tyrosine kinase

soluble or intracellular receptors

affinity (k₁ and k_-1)

describes the strength of binding to receptors

k₁ describes the rate at which a drug associates with the receptor, while k_-1 describes the ease at which a drug dissociates from its receptor

factors governing drug action

affinity

potency

efficacy

intrinsic acitivity

potency

concentration of a drug required to produce a given physiologic effect

drugs with a higher receptor affinity will exhibit greater potency than those with lower affinity

efficacy

describes the maximal level of response a drug can produce

intrinsic activity

measure of the ability of a drug that is bound to the receptor to generate an activating stimulus and produce a change in cellular activity

• agonist, partial agonist, antagonist

non-receptor drug targets

enzymes

voltage-gated ion channels

transporters

neurotransmitters

microtubules

DNA

physical interaction

non-receptor drug target - enzymes

inhibitors:

• reversible (ibuprofen) vs irreversible (aspirin)

• enzyme isoforms (robenacoxib)

recombinant enzymes

non-receptor drug target - voltage-gated ion channels

Na+ and Ca2+ blockers

K+ openers

non-receptor drug target - transporters

inhibitors

non-receptor drug target - neurotransmitters

precursors and releasers (indirect agonists)

synaptic vesicle protein 2A (SV2A)

non-receptor drug target - microtubules

inhibitors

non-receptor drug target - DNA

cancer and anti-inflammation drugs

non-receptor drug target - physical interaction

antacids

local anesthetics MOA

diffusion of drug across the membrane

penetration and block of Na channel from inside membrane (stereospecific)

nerve block of motor and sensory fibers

receptor desensitization

tachyphylaxis

tolerance

tolerance

a higher dose of drug is required to produce the same response over time

• receptor down-regulation

• depletion of second messengers