Week 4-5 content

Pharmacokinetics

processes of absorption, distribution, metabolism, and excretion of drug; what body does to drug; where and how long drug has effect

pharmacodynamics

processes of drug action at receptors; what drug does to body

pH and drug absorption

of drug

• ionization slows absorption and distribution

of body compartment where drug is distributed

• pKa interacts with local pH environment

common routes of administration

enteral (absorption via GI tract), parenteral (absorption outside of GI tract)

Enteral routes

oral, rectal, in mouth (buccal administration or sublingual)

Parenteral routes

• by needle and syringe = intravenous (IV), intramuscular (IM), intraperitoneal (IP — common in research but danger of peritonitis for humans), subcutaneous (SC), intradermal (ID), epidural (outside dura mater surrounding spinal cord), intrathecal (into CSF inside the subarachnoid space)

• topical routes = transdermal, nasal, inhalation, vaginal

• ocular

• other = intracerebroventricular (ICV) & intracerebral

factors influencing route choice

characteristics of drug, route that gets drug to site at effective concentration for long enough, fastest route, easiest/most desired, solubility

Oral route (p.o.)

drug must resist degradation by stomach acids and enzymes

absorption via

• capillaries surrounding stomach wall

• passage into small intestine lined with capillaries

  • blood flow through liver and general circulation (liver = primary site of metabolism)

Speed of absorption

IP > IM > SC > ID

parts of body of highest drug concentration

liver, kidney, heart, lungs, and brain

Placenta

not an effective barrier to drug distribution

drug depots

areas of body that can accumulate and temporarily sequester drug

• muscle, fat, and plasma protein binding

• no significant bio effect of drug occurs with depot binding

• drugs vary in susceptibility to depot binding

• reversible as blood levels fall

Blood brain barrier (BBB)

favors absorption of fat-soluble substances

• surrounds brain vasculature and blocks most chemicals from entering

• selectively permeable

What gets through BBB

• substances that are highly lipid soluble

• substances carries across by active transport

• incomplete at several brain regions (area postrema = mechanism for removal of toxic substances via vomiting reflex)

• median eminence, pineal gland, pituitary (mechanism for hormones entering blood)

Biotransformation

process by which body accepts drug, alters it chemically, and prepares it for excretion

Hepatocytes

functional cells of liver where most biotransformation occurs thanks to

• cytochrome P450 (CYP) enzyme family

• transferase enzyme family

Cytochrome P450 (CYP) enzymes

found in hepatocytes and GI tract & brain, relatively low specificity

Two main families for drugs:

• CYP3A₄ and CYPA₅ (account for 50% of drug biotransformations)

Result of metabolism

making drug more ionized and less lipid soluble (becomes more water soluble

routes that drugs leave body

kidney (urine), digestive system (feces), lungs (breath), skin (sweat), saliva, breast milk

First-order kinetics

fixed fraction biotransformation — amount cleared per unit time is dependent on total concentration (half-life)

zero-order kinetics of drug clearance

fixed amount biotransformation — amount cleared per unit time is independent of total concentration (greater the amount injested, longer it takes to clear)

first-pass metabolism

PO route highly susceptible

• blood levels rise relatively slowly

• can be irregular and unpredictable

• bioavailability of drugs taken PO is relatively low

enzyme induction

expression and/or function of enzyme is increased (results in decreased drug effectiveness)

enzyme depression

expression and/or function of anzyme is decreased (increased effectiveness or toxicity)

Causes for enzyme induction/depression

• previous exposure to same drug

• previous exposure to another drug metabolized by same enzyme

• nutrition/dietary influences

grapefruit juice effect

inhibits CYP3A₄ via furanocoumarins —> results in enzyme depression and increased effect of buspirone

drug competition

metabolism of one drug interferes with metabolism of another

Causes for individual differences in metabolism

genetics, body composition, age

receptor

molecule (protein) present on cell membrane or inside cell

ligand

molecule that binds to receptor with some selectivity

ion channel receptors

ligand-gated (ionotropic), voltage-gated, second messenger-gated

carrier proteins

Na⁺/K⁺ pump, reuptake transporters, vesicular transporters

drug action at receptors

Na⁺ channel blockers, K⁺ channel blockers, Na⁺/K⁺ ATPase inhibitors (Cardiac glycosides)

Agonist

ligand that binds to receptor and produces effect at receptor (endogenous and exogenous)

antagonist

ligand that binds to a receptor, has no effect on receptor but prevents it from being activated by an agonist

Competitive antagonist

blocks effects of endogenous chemical by preventing it from binding at its orthosteric site

noncompetitive antagonist

blocks effects of endogenous chemical by preventing it from having its typical effect by binding at an allosteric site

affinity

how well ligand binds to receptor

efficacy

how well ligand activates the receptor

potency

amount of ligand required to produce effect of given intensity (depends on affinity and efficacy)

E_max

maximum drug effect

ED₅₀

half-maximal effect, decribes potency

LD₅₀

lethal dose

therapeutic index (TI)

LD₅₀/ED₅₀

Margin of safety

TD₁/ED₉₉