Pharmacokinetics Lecture notes
Four basic pharmacokinetic processes are
¬Drug movement throughout the body
¬Absorption – movement of drug from its site of administration into blood
¬Dissolve – must dissolve before being absorbed
¬Surface area – the larger the faster
¬Blood flow – most rapid where blood flow is high
¬Lipid solubility - the higher the faster
¬pH partitioning
Absorption - Routes
IV – no barriers to absorption
Intramuscular – good for poorly soluble drugs, "time released"
Subcutaneous – again no significant barriers
Oral – must pass through cells of epithelium, enteric coating
Safer but highly variable absorption – enteric, sustained-release, tablets
Factors Affecting Drug Absorption
Rate of dissolution
Surface area
Blood flow
Lipid solubility
pH partitioning
Distribution
Blood flow to tissues
Exiting the vascular system once it has been delivered – pass through pores in capillary wall
Protein - binding
Drugs can bind with proteins
Parts of drugs will be bound during any given time period
Impedes drug’s ability to reach sites of action, metabolism, or excretion
Drug Distribution
Factors influencing distribution are
Blood flow to tissue
– Exiting the vascular system
– The blood-brain barrier
– Placental drug transfer
Metabolism
LIVER
Enzymatic alteration of drug structure
Consequences of metabolism
Accelerated renal excretion – kidney cannot excrete highly lipid soluable
Drug inactivation
Increased therapeutic action
Activation of prodrugs
Increased or decreased toxicity
Drug Metabolism
Biotransformation
Liver—primary site of drug metabolism
P450 system (cytochrome P450)
Drug Metabolism—Implications
Therapeutic consequences are
Accelerated drug excretion
Drug inactivation
Increased therapeutic action
Activation of prodrugs
Toxicity variations
Routes of Administration
Two major groups
Enteral
Via gastrointestinal tract
Parenteral
Outside the gastrointestinal tract
Usually referred to as "by injection"
Common routes—intravenous, subcutaneous, intramuscular
Special Considerations in Drug Metabolism
Age
Induction of drug-metabolizing enzymes
First-pass effect
Nutritional status
Competition between drugs
Drug Excretion
Removal of drug from the body
Kidney—via three processes
Glomerular filtration
Passive tubular reabsorption
Active tubular secretion
Time Course of Drug Responses
Plasma drug levels
Minimum effective concentration (MEC)
Toxic concentration
Therapeutic range
Drug half-life
Loading dose
Maintenance dose
Achieving and Maintaining Therapeutic Concentrations
•Repeated dose scheduling
•Drug accumulates in blood stream
•Plateau reached
•Amount administered = amount excreted
Differentiate between Loading Dose and Maintenance Dose
•Loading Dose
–Higher amount of given drug
•Maintenance Dose
–Doses administered at intermittent (scheduled) times
Drug Half-life
The time for the amount of drug in the body to decrease by 50%
Excretion
KIDNEY
Glomerular filtration – blood to tubular urine
Tubular reabsorption
Active tubular secretion – pumps for organic acids and organic bases – to urine
Monitoring drug levels
Plasma drug levels
Therapeutic range
Drug Half-life
Time requires for the amount of drug in the body to decrease by 50%
Will determine dosing requirements
Goal - plateau
Dosing
Loading doses – when plateau must be achieved quickly
Routine smaller doses – maintenance doses
Peak and trough levels
Maximal efficacy – largest effect a drug can produce
Potency – one that produces its effects at lower dosages
Receptors
Drugs bind to receptors to produce effects
Reversible
All that drugs can do is mimic the physiological activity of the body’s own molecules
Block the physiological activity of the body’s own molecules
Agonists
Mimic the body’s own regulatory molecules
Antagonists
Drugs that block the actions of endogenous regulators
Partial agonists
Mimic the actions but with reduced intensity
Drug Interactions
Can have varying effects
Direct chemical or physical – IV preparation
Drug – Food Interactions
Frequently decreased rate of absorption
Grapefruit juice can inhibit metabolism
"with food" – with or shortly after meal
"empty stomach" – one hour prior to meal or two hours after
