Introduction §Pharmacology is the science of studying the effect of drugs on living organisms. l It attempts to describe the biological responses produced by drugs and define the underlying mechanisms by which the responses are generated.

Drug definition and classification §A drug is a chemical substances that can alter or influence the responsiveness of a biological system. §a chemical which is utilized for the diagnosis, prevention, cure or amelioration of an unwanted health condition (definition by FDA). §Drugs can be classified into 4 broad categories: l drugs that replace physiological inadequacies, l drugs that cure, l drugs that treat symptoms, l and drugs that alter mood or behavior.

Examples: Group 1. Insulin to treat Diabetes mellitus; l-dopa for parkinsonism. Group 2. Antibiotics e.g. penicillin; sulfa drugs. Group 3. Antihypertensives; diuretics; anticoagulants; analgesic; anticonvulsant; sedatives; birth control pills. Group 4. Tranquilizers, alcohol, cocaine, opiates, hallucinogens

Outline of the course content §Part I- Fundamentals of Pharmacokinetics §Part II- Fundamentals of Pharmacodynamics and Toxicodynamics §Part III - Drugs that Replace [or drugs that affect the endocrine system] §Part IV - Drugs that Cure [or the chemo-therapeutic agents] §Part V - Drugs that Treat Symptoms [or drugs that act on the central and autonomic nervous system] §Part VI - Miscellaneous drugs

Pharmacokinetics is the study of the movement of drugs into and out of the body, including uptake, distribution, bio- transformation, and elimination. [Pharmacokinetics is the mathematical description of the rate and extent of uptake, distribution, and elimination of drugs in the body.] ” Pharmacokinetics is the branch of pharmacology that is concerned with the rates with which drug uptake and elimination proceed and with those processes that influence the time course of drug movement between one biological compartment to another.”

Pharmacodynamics is a description of the properties of drug- receptor interactions.

Chapter 1. Absorption and Distribution §Drugs are usually Xenobiotics (substances chemically foreign to the body).

Membrane characteristics Fluid-mosaic model a phospholipid bilayer-polar moieties at both the external and internal surface, and proteins periodically traversing the phospholipid plane perpendicularly. Phospholipid bilayer proteins

How drugs across membranes 1. Drugs cross membrane by passive diffusion or active transport. 2. A drug tends to pass through membrane if it is uncharged.

The rate of diffusion is high if: 1. The unionized form of a drug has a high lipid solubility. 2. A large proportion of the drug is present in the unionized form. 3. The membrane is thin. 4. The membrane is porous. 5. The surface area of the membrane is large. 6. The difference in concentrations on the two sides of the membrane is large. 7. The diffusion constant, based on molecular size, molecular shape, and temperature, is large.

The influence of pH upon the ionization of weak acids and bases may be calculated by the Henderson-Hasselbalch eqn pH = pKa + log [base/acid].

Principle of LeChaterlier ( if the conditions of a system, originally in equilibrium, are changed, the new equilibrium shifts in such a direction as to restore the original conditions). For a weak acid AH  A - +H + if [H + ] increase (pH becomes lower) the reaction will be driven to the left by mass action, and the proportion of drug in the nonionized form will increase and, hence, the number of lipid soluble molecules. Q. if the pK a of a weak acid is 5.0 and is placed in a medium of pH 4.0, 90% will be in ionized or non-ionized form?

For a weak base, the dissociation equilibrium is BH +  B +H + if [H + ] increases the proportion of drug in the ionized form will increase. Q. a solution of the weak base dextromethorphan (a drug present in cough preparation with a pK a of 9.2) in the stomach (pH 1) will have approximately 1 of every 160,000,000 molecules in ionized or non-ionized form?

. For a weak acid, when the pH is < the pK, the protonated form (nonionized) predominates. When the pH is > the pK, the unprotonated (ionized) form predominates. B. For a weak base, when the pH is < the pK, the protonated form (ionized) predominates. When the pH is > the pK, the unprotonated (unionized) form predominates. C. In the stomach (pH 2.0), weak acids are uncharged and will be absorbed into the bloodstream, whereas weak base are charged and will remain in the GI tract.

D. Ion trapping occurs with weak acids and weak bases if there is a difference in pH on the two sides of a membrane. The ionized form of the drug will be trapped on one side. 1. The ionized form of a weak acid will be trapped on the side with (higher or lower) pH. 2. The ionized form of a weak base will be trapped on the side with (higher or lower) pH.

H + + A- HAHA H+ + A- pH 7.4 pH 5.4 (100)(10) (1) A weak acid with pK a 6.4

Strong bases and acids are totally dissociated or ionized in solution; thus, they are poorly absorbed at any physiological pH.

routes to introduce a drug into the body: oral, injection, topical, inhalation, rectal, sub-lingual, intra-vaginal, intra-nasal. Drug’s delivery

I. The oral route (PO) is usually preferred. A. advantages include (1) convenience; (2) a large surface area for absorption; (3) less abrupt change of serum drug concentrations than with parenteral administration. B. a major disadvantage is first pass metabolism by the liver. (1) all the blood flow from the intestinal tract goes initially to the liver through the portal vein; therefore, the drug may be metabolized before being distributed to the other tissues in the body. (2) First pass metabolism of a drug can be avoided by sublingual administration and partially avoided by rectal administration.

II. The parenteral routes of administration are technically more difficult and usually must be performed by a heath care professional. A. advantages include: (1) a faster onset (2) more reliable absorption (3) No first pass metabolism B. Disadvantages include: (1) More difficult administration. (2) pain or necrosis at the site of injection (3) possibility of infection (4) toxicity from a bolus intravenous injection (5) necessity of dissolving the drug if given intravenously.

The initial distribution of a drug to the tissue is determined by the relative blood flow to the tissue. Sites with high blood flow will receive more of the drug. The final distribution, also called the apparent volume of distribution (V d ), will be affected by: 1. The lipid solubility of a drug, which, if high, will result in good penetration into cells. 2. Plasma protein binding and tissue binding a. plasma protein binding, especially to albumin, will reduce the V d. b. tissue binding will increase the V d. c. both types of binding act as reservoirs for the drug, as only the unbound drug can activate pharmacological receptors. Thus binding will: (1) slow the onset of drug action (2) prolong the duration of drug action, if the drug is eliminate by glomerular filtration in the kidney.

Capillary walls are quite porous except those in the central nervous system (CNS) where blood brain barrier exists. The barrier prevents the water-soluble and ionized drugs from entering CNS. (cf. Introduction to Pharmacology p.33 by M.A. Hollinger). Placental transfer of drugs from the maternal circulation to that of fetus. In general, lipophilic, unionized, low-molecular weight drugs in their unbound form tend to cross the placenta. A number of drugs are known to have adverse or teragenic effects on the developing fetus. (cf. Introduction to Pharmacology p by M.A. Hollinger).