Lecture 1: Pharmacokinetics and Pharmacodynamics 1

pharmacokinetics

what the body does to the substance

study of drug absorption, distribution, metabolism, and excretion (ADME)

determined drug concentration in blood and tissues and how this changes after exposure

pharmacodynamics

what the substance does to the body

study of substance (drug) effects on the body

involves receptor/site binding, does-response, and mechanisms of action

What is the importance of the distinction between pharmacokinetics and pharmacodynamics?

guides route, dosage, effect, and safety

What term determines drug concentration in blood and tissue and how this changes after exposure?

pharmacokinetics

ADME

Absorption: how drugs enter the body

Distribution: how drugs spread to tissues

Metabolism: how drugs are broken down (mainly liver)

Excretion: how drugs leave the body (urine)

absorption

process by which a drug moves from the site of exposure into the bloodstream

critical step in determining the onset and intensity of drug action

influenced by species differences, drug properties, and route of administration

routes of administration

oral (PO)

intramuscular (IM)

subcutaneous (SC)

intravenous (IV)

oral (PO)

routes of administration

variable absorption due to pH, food, gut flora

intramuscular (IM)

route of administration

depends on blood flow and muscle mass

subcutaneous (SC)

route of administration

slower absorption

influenced by hydration and fat

intravenous (IV)

route of administration

direct systemic circulation

What are some of the drug properties that affect absorption?

solubility

ionization

molecular size

What are some of the physiological factors that affect absorption?

GI motility, pH, enzyme activity, age

What are some of the species differences that affect absorption?

ruminants vs monogastrics, birds vs mammals

What are some of the pathological states that affect absorption?

dehydration

hypotension

GI disease

What factors affect absorption?

drug properties

physiological factors

species differences

pathological states

distribution

reversible transfer of a drug between the bloodstream and tissues

determines how a drug spreads through the body after absorption

What factors affect distribution?

blood flow to tissues (brain vs bone, skin)

plasma binding protein

tissue permeability, binding, and reservoirs

membrane permeability (blood-brain barrier, placenta)

properties of the drug (lipid solubility, ionization)

What are the two most common drug binding proteins in mammals?

albumin and alpha-1-acid glycoprotein

albumin

drug binding protein

• many sedative/anesthetics

• many NSAIDs

• seizure meds

• some antibiotics

alpha-1-acid glycoprotein

drug binding protein

• local anesthetics

• anti-arrhythmics

• anti-depressants

• beta-blockers

volume of distribution (Vd)

theoretical volume that relates the amount of drug in the body to plasma (blood) concentration

important for determining doses

A drug that is extensively distributed into tissues has a [high/low] Vd.

high

A drug that remains mostly in plasma has a [high/low] Vd.

low

metabolism

biotransformation of substances in the body

convert lipophilic drugs into hydrophilic metabolites for excretion

primarily occurs in the liver, but also in the lungs, kidneys, and intestines

Phase I (drug metabolism)

oxidation, reduction, hydrolysis

introduces or unmasks functional groups

cytochrome enzyme systems are key players

Phase II (drug metabolism)

glucuronidation, sulfation, acetylation

increases water solubility

facilitates excretion

factors that affect metabolism

species differences

age

genetics

disease states (hepatic dysfunction)

drug interactions (enzyme induction or inhibition)

Excretion

process of eliminating drugs or their metabolites from the body

crucial for determining drug duration and intensity of action

factors that influence excretion

species, age, and health status

kidney and liver function

drug properties (polarity, molecular size, tissue binding)

How do drug properties affect excretion?

polarity, molecular size, tissue binding

What is the primary route of excretion for most drugs?

renal (urine)

How does the body mainly excrete large molecules and conjugates?

biliary (feces)

How does the body excrete volatile anesthetics?

pulmonary system

What are some of the more uncommon routes of excretion?

saliva, milk, sweat, tears

renal excretion

glomerular excretion

tubular secretion

tubular reabsorption

influenced by urine pH and flow rate

glomerular filtration

part of renal excretion

passive filtration of small, unbound drugs

tubular secretion

part of renal excretion

active transport into renal tubules

tubular reabsorption

part of renal excretion

lipid-soluble drugs may be reabsorbed

biliary excretion

drugs excreted into bile and eliminated via feces

enterohepatic recycling prolongs drug action

species differences: dogs and ruminants have more active biliary excretion

What two species have more active biliary excretion?

dogs and ruminants

clinical relevance of ADME

determines drug dosing and frequency

explains species and breed specific drug sensitivities

prevents drug toxicity or therapeutic failure

guides drug selection for safe and effective therapy

dose-response relationship

relationship between drug dose and effect

ED50, LD50, therapeutic index, etc.

ED50

dose producing 50% of maximal effect

LD50

dose lethal to 50% of subjects

therapeutic index

safety margin (LD50/ED50)

[PK/PD] determines how much drug reaches the site of action and how. quickly it leaves.

PK

[PK/PD] determines the effect at the site of action.

PD

[PK/PD] guides dosage regimens in animals.

both

What is the goal of prescribing a drug?

maximize therapeutic effect and minimize toxicity

clinical relevance in vet-med

species-specific differences in ADME and response

importance in food animals: drug residues, withdrawal times

informs safe and effective drug use