Basic Biopharmaceutics, Pharmacokinetics, and

Pharmacodynamics

Learning Outcomes

• Define biopharmaceutics

• Describe 4 processes of pharmacokinetics

• Describe factors that affect medication absorption

• Describe process & factors of distribution phase

• Describe 2 most common types of drug interactions

• Define pharmacodynamics

• Describe process & factors of elimination phase

Learning Outcomes

• Describe steps for medication to exert effect

• Describe potential problems that can occur when

– product formulation is disrupted

– absorption, distribution, metabolism, or elimination is altered

• how these alterations can affect pharmacodynamics of medication

Key Terms

• Absorption

• Bioavailability

• Biopharmaceutics

• Clearance

• Cytochrome P450

• Dissolution

• Drug interaction

• Elimination

• Excretion

• First-pass metabolism

• Half-life

• Loading dose

• Metabolism

• Metabolite

• Pharmacodynamics

• Pharmacokinetics

• Therapeutic level

• Volume of distribution

Biopharmaceutics

• Study of manufacture of medications

• Common formulations

• Choice of routes

• Precursor steps of absorption

– Disintegration

– Dissolution

Pharmacokinetics

• ADME

– Absorption

– Distribution

– Metabolism

– Elimination

Absorption

• Amount of medication that enters bloodstream

– only absorbed medication has pharmacologic effect

– bioavailability is percentage of dose that reaches bloodstream

• Factors

– amount of drug dissolved

– dosage form

– route of administration

First-pass Metabolism

• Following oral ingestion

– med metabolized before reaching main bloodstream

• through either intestine wall or liver

– result-lower percentage reaches main systemic circulation

Routes of Administration

• Rectal, inhalation, sublingual

– avoid first-pass metabolism

• Medications given intravenously

– 100% bioavailability

Distribution Phase

• Follows absorption

• Medication may

– leave bloodstream & enter tissues

– remain in the blood, bound to protein

• Medication bound to blood proteins (albumin) is inactive

– does not exert any pharmacologic effect

– reversible-drug may be released from protein & distributed into tissues

Therapeutic Level

• Desired effect with minimal side effects

• Concentration of drug in blood

– measured to help guide appropriate therapy

– determines whether a change in therapy is needed

• Examples of medications whose levels are measured

– phenytoin, carbamazepine, valproic acid, phenobarbital

– digoxin

– gentamicin, tobramycin, vancomycin

Volume of Distribution

• Extent drug distributes to various body tissues/spaces

• Medications with large volume of distribution

– have lower blood concentration

• Medications with small volume of distribution

– have a higher blood concentration

• Factors that affect extent of distribution

– highly protein bound

– high affinity to body fat

• Loading dose is used when medications have large volume of distribution

Metabolism • Breakdown of drugs (not all drugs susceptible)

– drug molecule is changed or altered metabolite

• Drugs may travel directly to kidneys excreted

• Liver is major organ in which drug metabolism occurs

• Small intestine-significant metabolism occurs

• Other organs-limited metabolism

– kidneys

– lungs

Enzyzmes

• Protein substances (enzymes) metabolize drugs

• Cytochrome P450 (CYP) family of enzymes

• Drug metabolites

• Metabolites may

– or may not be pharmacologically active

– be used as active form of pro-drugs

– be toxic

Excretion

• Removal of drug or metabolite from body fluid

• Kidneys

– filtering process –drug eliminated into urine without being metabolized

– metabolites - water soluble-susceptible to excretion by kidneys

• Bloodstream liver cellbile ductsmall intestine

• Drug clearance=elimination rate

• Half-life (T1/2,) is time for 50% of drug to be eliminated

Drug Interactions

• Impact of drug/food product on amount or activity of another drug

• Altered drug metabolism in liver

– Inhibition of enzyme activity

– Induction of enzyme activity

• Common drug-food interaction

– grapefruit juice (CYP enzyme inhibitor)

• injested with nifedipine (metabolized by CYP)

• results in hypotensive episodes

Variables in Pharmacokinetics

• Speed of gastrointestinal tract

– constipation or diarrhea

• Diseases of kidney and liver

– cirrhosis

• Reduced elimination prolonged half-life

• Changes in cardiac output

– changes in delivery of drugs via bloodstream

– low cardiac outputdecreased blood flow to kidneys & liver

– decreased clearance of medications

Kidney Disease • Renal failure

– hemodialysis

– kidney transplant

• Causes of kidney damage

– blood pressure

– high blood cholesterol

– diabetes

• Detection: blood levels of creatinine

• Doses adjusted based on degree of renal impairment

Liver Disease

• Cirrhosis

– decreased ability to metabolize certain medications

• Detected by measuring

– aspartate aminotransferase (AST)

– alanine aminotransferase (ALT)

– bilirubin

– albumin

• Reduced elimination & clearance of some drugs

• Albumin reduced reduced protein binding

Advanced Age

• Medications must be used cautiously in elderly

• Reduced kidney function

• Estimate patient’s creatinine clearance

– dose reduction may be needed for some drugs

– avoid drug accumulation & toxicity

• Reduced liver function

– watch for toxicity

• Topical medications

– less drug is absorbed

Pregnancy

• Increased blood volume? … hypothesized

• Drugs may be cleared through kidneys more quickly

• May need higher doses of some medications

• Some over-the-counter (OTC) drugs are unsafe

– avoid aspirin in last 3 months of pregnancy

– safety of herbal, botanical, & dietary supplements?

Pediatrics

• Medications are often dosed based on body weight

– accurate weight important

• Higher relative volume of distribution for some drugs

• Refer to pediatric references/manufacturer’s guidelines

• Pharmacist evaluates drug doses

– adjusted based on weight & other factors

Pharmacodynamics

• What drug does to body

• Pharmacodynamic responses

– increase in bone mass with bisphosphonates

– decrease in BP with antihypertensive agents

• Pharmacologic effect sequence of events

– absorption

– distribution

– bind to targeted receptor causing cascade of events that leads to drug’s response