PHARMACOLOGY

Pharmacokinetics
• Absorption, distribution, metabolism, and excretion
• What body does to drug
• Drug ionization
○ Nonionized active, lipid-soluble
○ Ionized inactive, water soluble
• When pKa = pH, half of drug exists in ionized form
• Acidic drugs ionized at highly ionized at high pH  inactive
• Drug absorption
○ Rate at which a drug leaves site of administration
○ Factors: large tablet size, high lipid solubility  easier passage, higher concentration, liquids >solids, higher area of absorption,
heat/vasodilation, ** degree of ionization (acidic drugs better absorbed in stomach)
○ First pass effect: pass thru liver before entering systemic circulation for delivery; propranolol, lidocaine
○ First pass pulmonary effect: lidocaine, propranolol, fentanyl  lungs act as a reservoir to release drug back to circ
• Drug distribution
○ Factors:
 pH/pKa
 degree of ionization
 protein binding
• albumin binds acidic drugs
• alpha1-acid glycoprotein binds basic drugs
• influenced by increasing age, hepatic and renal dz, trauma, surgery
 mol wt
 lipid solubility
 ion trapping
• lower pH of fetal blood allows local anesthetics and opioids cross placenta and become ionized  cannot
cross placenta  accumulation
• Redistribution/storage
○ Highly perfused tissues receive a larger amt of total dose
○ Drugs leave tissues when plasma drug concentration decrease (ie, redistribution)
○ Saturation of inactive tissues lead to delayed awakening
• Drug metabolism
○ Increased water solubility decreases the Vd of drug and enhances its renal excretion
○ Lipid soluble drug  reabsorbed from renal tubules into pericap fluid  minimal renal excretion
○ Microsomal fraction of smooth ER contains cytochrome P 450
○ Enzyme induction (phenobarb) results in accelerated metabolism of drugs
○ Phase I: oxidation, reduction, hydrolysis
○ Phase II: conjugation
• Drug excretion
○ Unchanged or metabolites
○ Sites: kidneys, lungs, skin, bile, intestines, breast milke, saliva, sweat
• Volatile anesthetics excreted by lungs
• Bile excretion  enterohepatic circulation (vec, erythromycin)
Pharmacokinetics
• Clearance- volume of plasma creaded of drug by renal excretion or metabolism or both, or liver; affected by blood flow to specific organ
○ Water-soluble drugs that are not bound are excreted more efficiently
• Volume of distribution- dose of drug given IV divided by plasma concentration
○ NMBD’s low Vd
• Elimination half-time
○ 5 elimination half times required for almost complete elimination of drug
○ Useful only in a one-compartment model
• Context-sensitive half-time
○ Time necessary for drug concentration to decrease to a predetermined % after d/c of IV infusion of a specific duration
• Additive effect: 2 or more drugs together is = to sum of each drug effect
• Synergistic effect: effect of 2 or more drugs is more than the sum of individual drug effect
• Time synergism: prolongation of action of one drug (lido + epi)
Competitive/noncompetitive antagonism
• Competitive:
○ Can be displaced by high doses
○ Shifts dose-response curve to right
○ Reversible
• Noncompetitive:
○ Conformational change  ↓ response even at high dose
○ Dose-response curve shifts to right, slope ↓ and max pharm dose ↓
○ Reversible or Irreversible
Drug stereospecificity
• Racemic (dextro and levo present equally)
• One isomer is therapeutically active and the other may contribute to side effects
• Example: d-bupivacaine remains in Na ion channels longer  cardiotoxic effects
• Ex: Ropivacaine and levobupivacaine  not as likely to produce cardiotoxicity
• Ex: D-ketamine hypnotic and analgesic while L-ketamine produces unwanted side effects
Drug tolerance
• Large dose of drug is required to eleicit an effect that is usually produced with smaller dose
• Natural
• Acquired
○ Tissure tolerance: confined to certain pharm effects (morphine)
○ Cross-tolerance: tolerance to EtOH  tolerance to other drugs
• Tachyphylaxis: acute tolerance (ephedrine, amphetamine)
Drug dependence
• Psychic or physical
• Characterized by behavioral response
Drug interactions
• Simultaneously administered drugs alter each other effects
• Ex: ranitidine or raglan can alter aborption by changing pH
• Changes in blood flow of one drug may affect another
• Drugs also interact at receptor sites