Introduction To Pharmacology

1. Introduction To Pharmacology Dr. Hayder B Sahib Ph. D., M.Sc., D.Sc. B.Sc. Pharm.

2. OBJECTIVES • Describe how the size, shape and chemical nature of a drug affects its pharmacodynamic and pharmacokinetic properties. • Compare and contrast the common routes of drug administration. • • Name and define the two major processes that allow a drug to travel from its site of administration to its site of action. • • Explain why a hydrophobic drug is more likely than a hydrophilic drug to rely upon metabolism for elimination.

3. GENERAL DEFINITIONS • A. Pharmacology is the study of the interaction of chemicals with living systems. • B. Drugs are chemicals that act on living systems at the chemical (molecular) level. • C. Medical pharmacology is the study of drugs used for the diagnosis, prevention, and treatment of disease. • D. Toxicology is the study of the unpleasant effects of chemical agents on living systems. It is usually considered an area of pharmacology.

4. E. Pharmacodynamic properties of a drug describe the action of the drug on the body, including receptor interactions, dose-response phenomena, and mechanisms of therapeutic and toxic action. • F. Pharmacokinetic properties describe the action of the body on the drug, including absorption, distribution, metabolism, and excretion. • Elimination of a drug may be achieved by metabolism or by excretion • Placebo a. A substance containing no medication and prescribed to reinforce a patient's expectation to get well. b. An inactive substance or preparation used as a control in an experiment or test to determine the effectiveness of a medicinal drug.

5. *Drug receptors:-The molecular components of the body with which a drug interact to bring about its action. • *Source and nature of the drugs • 1-Synthetic drugs :e.g. aspirin, paracetamol, antidiabetics. • 2-Natural drugs: • a-Plant source: e.g. morphine, quinine. • b-Animal source; e.g. heparin, gonadotrophins. • c-Micro-organisms: e.g. penicillin, streptomycin. • d-Minerals: e.g. Fe, Mg. • 3-Semi-synthetic drugs: e.g. ampicillin, amoxicillin. • 4-Bio-synthetic drugs: e.g insulin ( by inserting the human pro-insulin gene in E.coli).

6. *Drug nomenclature:- • Typically a drug has:- • 1-one or more proprietary (brand) names e.gAmoxil, Novamoxil • 2-a non-proprietary (generic)name e.gAmoxacillin • 3-pre-market manufactures code e.g BRL-2333 • 4-chemical name e.g 6-amino(4-hydroxyphenyl)acetyl amino 2-carboxylic acid.

7. The non-proprietary name is worth to be remembered because it provide:- • 1-Clarity:because it gives information of the class of the drug • 2-Economy:usually cheaper than proprietary drug • 3-Convenience:pharmacists supply whatever version they stock. • Drug Evaluation:-Includes; • 1-Pre clinical( animal) tests • 2-Clinical (human ) tests. • 1-Pre-clinical tests: includes: • a-Pharmacological profile test: • Description of all the pharmacological effects of a drugs (effects on BP, GIT, respiration, renal function, endocrine function, and CNS ) • b-Reproductive toxicity test: • Involves the study of the fertility effects of the drug and its teratogenic and mutagenic effects.

8. Teratogenesis: Induction of developmental defects in the somatic tissue of the fetus • Mutogenesis: Induction of changes in the genetic material of the animals of any age and therefore induction of heritable abnormalities • Carcinogenesis: Is the induction of malignant characteristic in cells. • c-Pharmacokinetic testing: • Including studies on absorption, metabolism, distribution and elimination of the drug on laboratory animals. • d-Chemical and pharmaceutical development • to study drug synthesis, purification, and stability.

9. 2-Clinical test( clinical trial ) • *Phase 1 (human pharmacology): • -Healthy volunteers (20-50 subjects) to study: • -Pharmacokinetic (absorption, distribution, metabolism excretion) • -Pharmacodynamics (biological effects) • -Tolerability , • -Safety , • - Efficacy • *Phase 2 ( therapeutic exploration) • -Patients (50-300 ) • -Pharmacokinetic and Pharmacodynamic , dose ranging in carefully controlled studies for efficacy and safety which may involve comparison with placebo.

10. *Phase 3( therapeutic confirmation) • -Patients(250-1000+) • -Randomized controlled trials. • -Efficacy on a substantial scale, safety, comparison with existing drugs. • *Phase 4 (therapeutic use) (post-licensing study) • -Patients(2000-10000+) • -Surveillance for safety and efficacy • -Further formal therapeutic trials.(comparison with other - drugs • -Marketing and pharmacoeconomic studies

11. THE NATURE OF DRUGS • A. Size. The great majority of drugs lie in the range from molecular weight 100 to 1,000. Drugs in this range are large enough to allow selectivity of action and small enough to allow adequate movement within the various compartments in the body. • B. Chemistry and reactivity. Drugs may be small, simple molecules (amino acids, simple amines, organic acids, alcohols, esters, ions, etc.), carbohydrates, lipids, or even proteins.

12. Binding of drugs to their receptors the specific molecules in a biologic system that mediate drug effects, is usually by noncovalent bonds (hydrogen bonds, van de Waals attractions, and ionic bonds) • less commonly by covalent bonds. • Weaker, non-covalent bonds require a better fit of the drug to the receptor binding site and, usually, a reversible type of action. • Very strong bonding, eg, covalent bonds, usually involves less selectivity and an irreversible interaction.

13. Shape. The overall shape of a drug molecule is important for the fit of the drug to its receptor. • Between a quarter and a half of all drugs in use exist as stereoisomers. In most cases the stereoisomers are chiral enantiomers. Enantiomers are mirrored image twin molecules that result from the presence of an asymmetric carbon, or in a few cases, other asymmetric atoms in their structures. • Chiral enantiomers often differ in their ability to bind to and alter the function of receptors. • They also can differ in their rates of elimination and in their toxicity. Most chiral drugs are still provided

14. Drug passage across cell membranes. • Is determined by the natural processes of the fallowing; • 1- Passive diffusion. • 2- Filtration. • 3- Carrier-mediated transport. • 1- Passive diffusion. • It refers simply to the natural tendency of any substances to move passively from an area of high concentration to one of low concentration. • This process characterized by:- • -cellular energy is not required • -process does not become saturated. • -it is not inhibited by other substances.

15. Effect of Ph on drug absorption: The extent to which drugs are soluble in water or lipid is central to their capacity to cross cell membrane. Water or lipid solubility is influenced by environmental pH and the structural properties of the molecule. It is useful to classify drugs in physicochemical sense into: A- variably ionized according to environmental Ph. B-incapable of becoming ionized whatever the environm.Ph. C-permanently ionized whatever the environmental Ph.

16. A-variably ionized according to environmental Ph. *Many drugs are weak electrolytes i.e. their structural groups ionize according to environmental Ph. The degree of ionization influences lipid solubility and hence diffusibility . *The degree to which molecule has tendency to ionize is given by dissociation constant (pKa). If the pKa of the drug and the pH Of the environment are known , the fraction of molecules in ionized form can be predicted

17. *In an acid environment, an acidic group(drug) tends to retained a H ion and remains unionized , while in basic environment it will loss H ion and become ionized . • The opposite is the case for a basic group(drug).

18. - In general:- • Acidic drugs become less ionized in acidic environment and basic drug becomes less ionized in a basic (alkaline) environment so it is: • - more unionized • -more lipid-soluble (well absorbed) • -more diffusible

19. *Acidic drug becomes more ionized in basic environment and basic drug becomes more ionized in acidic environment so it is: • -more ionized • -less lipid soluble (not absorbed) • -less diffusible • Ion-trapping phenomenon:- • At steady state- an acidic drug would accumulate on the more basic side of a membrane and a basic drug on the more acidic side.

20. Clinical significance of ion trapping:- • *Basic drugs taken by mother can accumulate in the fetal circulation and breast milk and can have harmful effects in the fetus and breast-milk fed baby. • *Acidification or alkalization of urine can accelerate the excretion of basic or acidic drugs that have reached toxic concentration in the body. Examples: • -To increase excretion of acidic drugs such as Phenobarbital and salicylate, I.V bicarbonate is given. • -To increase excretion of basic drugs such as amphetamine, ammonium chloride may be given.

21. B-Drugs incapable of becoming ionized: • These include digoxin and steroid hormones . They are always unionized (nonpolar) and they are unaffected by environmental pH • C-Permanently ionized drugs: • These drugs are always ionized and not absorbed orally(not cross membranes) and not given orally e.g. heparine, tubocurarine. • 2- Filtration: • Aqueous channels in the tight junction between epithelial cells allow the passage of some water-soluble substances (low mol. weight e.g. ethanol) • Filtration play minor role in drug transfer in the body except in glomerular filtration.

22. 3-Carrier-mediated transport: • Some drugs cross cell membrane against a concentration gradient i.e. by active transport and this process characterized by: • -involve endogenous molecules. • -expend cellular energy. • -highly specific. • -subjected to saturation • -can be inhibited.

23. Examples: • -absorption of iron by gut. • -levadopa cross blood-brain Barrier.

24. The order of reaction or process: • 1-First-order kinetic (process) • * The rate at which absorption, distribution, metabolism and excretion of drug occur are directly proportional to its concentration in the body (high at high concentration and low at low concentration ).

25. *In other word, a constant fraction of drug is(absorbed, distributed, metabolized and excreted) per-unit of time. • *Most drug are subjected to first-order kinetic. • *Blood concentration declines in linear fashion over time. • *In 1st order kinetic , half-life is constant regardless the amount of drug in the body.

26. 2-Zero-order kinetic (process)(saturation kinetic) • *The rate of process reaches maximum amount at which it stay constant, e.g. due to limited activity of an enzyme, and further increase in rate is impossible despite an increase in the dose. • *The metabolic process for most drugs will show zero-order kinetic only at very high concentration. • *The metabolic capacity for few drugs become saturated at concentration within therapeutic range (e.g. phenytoin, aspirin, carbamazepin, ethanol.) • *Passive diffusion does not show zero-order kinetic.