Principles of Pharmacology Pharmacokinetics Pharmacodynamics Pharmacokinetics n n

Principles of Pharmacology Pharmacokinetics & Pharmacodynamics

Pharmacokinetics n n Movement of drugs in the body Four Processes n n n Absorption Distribution Metabolism Excretion Drug concentration at sites of action influenced by several factors, such as: n n n Route of administration Dose Characteristics of drug molecules (e. g. , lipid solubility)

Drug Absorption n Routes of Drug Administration n n Oral (per os, p. o. ) Inhalation n n Mucous membranes n n intranasal (sniffing) sublingual rectal suppositories Injection (parenteral) n n n vapors, gases, smoke intravenous (IV) intramuscular (IM) subcutaneous (SC) intraperitoneal (IP; nonhumans only) Transdermal

DRUG ABSORPTION Lipid solubility n p. Ka = p. H at which 50% of drug molecules are ionized (charged) n n Only uncharged molecules are lipid soluble. The p. Ka of a molecule influences its rate of absorption through tissues into the bloodstream. p. H varies among tissue sites n e. g. , stomach: 3 -4, intestines: 8 -9

p. Ka and Lipid Solubility Image from Mc. Kim, 2007, p. 14

Routes of Drug Administration n Oral Drug Administration n Advantages: n n relatively safe, economical, convenient, practical Disadvantages: Blood levels are difficult to predict due to multiple factors that limit absorption. n Some drugs are destroyed by stomach acids. n Some drugs irritate the GI system. n

Routes of Drug Administration n n Advantages of Injection Routes n Absorption is more rapid than with oral administration. n Rate of absorption depends on blood flow to particular tissue site (I. P. > I. M. > S. C. ). Advantages specific to I. V. injection n No absorption involved (inject directly into blood). n Rate of infusion can be controlled. n A more accurate prediction of dose is obtained.

Routes of Drug Administration n Disadvantages/Risks of Injection n A rapid onset of action can be dangerous in overdosing occurs. n If administered too fast, heart and respiratory function could collapse. n Drugs insoluble in water or dissolved in oily liquids can not be given I. V. n Sterile techniques are necessary to avoid the risk of infection.

Drug Distribution n n Cell Membranes Capillaries n Drug affinities for plasma proteins n n n Bound molecules can’t cross capillary walls Blood Brain Barrier n Tight junctions in capillaries n Less developed in infants n Weaker in certain areas, e. g. area postrema in brain stem n Cerebral trauma can decrease integrity Placenta n Not a barrier to lipid soluble substances.

Termination of Drug Action n Biotransformation (metabolism) Liver microsomal enzymes in hepatocytes transform drug molecules into less lipid soluble by-products. n Cytochrome P 450 enzyme family n

Termination of Drug Action n Elimination Two-stage kidney process (filter, absorption) n Metabolites that are poorly reabsorbed by kidney are excreted in urine. n Some drugs have active (lipid soluble) metabolites that are reabsorbed into circulation (e. g. , pro-drugs) n Other routes of elimination: lungs, bile, skin n

Termination of Drug Action n Kidney Actions excretes products of body metabolism n closely regulates body fluids and electrolytes n The human adult kidney filters approx. 1 liter of plasma per minute, 99. 9% of fluid is reabsorbed. n Lipid soluble drugs are reabsorbed with the water. n

Termination of Drug Action n Factors Influencing Biotransformation Genetic n Environmental (e. g. , diet, nutrition) n Physiological differences (e. g. , age, gender differences in microsomal enzyme systems) n n Drug Interactions n Some drugs increase or decrease enzyme activity e. g. , carbamazepine stimulates CYP-3 A 3/4 n e. g. , SSRIs inhibit CYP-1 A 2, CYP-2 C n

Drug Time Course n Time Course Studies important for n n predicting dosages/dosing intervals maintaining therapeutic levels determining time to elimination Elimination Half-Life n n n time required for drug blood levels to be reduced by 50% Approx. 6 half-lives to eliminate drug from body With repeated regular interval dosing, steady-state concentration reached in approx. 6 x half-life

Therapeutic Drug Monitoring n n n TDM important for clinical decisions Plasma levels rough approximation of tissue/receptor concentrations TDM goals assess medication compliance n avoid toxicity n enhance therapeutic response n

Tolerance & Dependence n Mechanisms of Tolerance Metabolic (Pharmacokinetic, Dispositional) n Cellular-Adaptive (Pharmacodynamic) n Behavioral Conditioning n n Dependence Abstinence Syndrome n Not all addictive drugs produce physical dependence. n Some nonaddictive therapeutic drugs (e. g. SSRIs) can produce physical dependence. n

Pharmacodynamics n Drug actions at receptor sites and the physiological/chemical/behavioral effects produced by these actions Studies of drug mechanisms of action at the molecular level n Provides basis for rational therapeutic uses and the design of new, superior therapeutic agents n

Drug-Receptor Interactions n Receptors found on membrane spanning proteins n n Ligands (neurotransmitters, drugs) attach inside spaces between coils, held by ionic attractions n n n Continuous series of amino acid loops Reversible ionic binding of ligand activates receptor by changing protein structure. Intensity of transmembrane signal is determined by percentage of receptors occupied. Drugs may influence transmembrane signal by binding to neurotransmitter receptor or to nearby site.

Drug-Receptor Interactions n Drug/Receptor Binding Mimic actions of neurotransmitter at same site (agonist) n Bind to nearby site and facilitate neurotransmitter binding (agonist) n Block actions of neurotransmitter at same site (antagonist) n

Receptor Structures n n Ion Channel Receptors Carrier Proteins G Protein-Coupled Receptors Enzymes

Drug-Receptor Specificity n Alterations to a drug’s chemical structure may influence potency n n e. g. , amphetamine vs. methamphetamine Many drugs have multiple sites of action Some sites of action are responsible for side effects n e. g. , tricyclic antidepressants: sedation, dry mouth, blurred vision n

Dose-Response Relationships n. Potency n. Efficacy

Dose-Response Functions Efficacy (ED 50 = median effective dose) n Lethality (LD 50 = median lethal dose) n Therapeutic Index = LD 50 /ED 50 n