Dennis S. Flores, MD

1. REVIEW OF BASIC PHARMACOLOGY Dennis S. Flores, MD

2. OBJECTIVES • Describe the different branches of pharmacology • Discuss the important concepts and mechanisms of • Pharmacodynamics • Pharmacokinetics • Exercise on pediatric drug dosing

3. PHARMACOLOGY • Is the science that deals with the mechanism of action, uses, adverse effects, and fate of drugs in animals and humans • It provides the basis for the understanding of body function and the subsequent treatment of disease

4. BRANCHES OF PHARMACOLOGY • PHARMACODYNAMICS • The study of what the drug does to the body • PHARMACOKINETICS • The study of what the body does to the drug • Absorption, Distribution, Metabolism, Excretion • PHARMACOTHERAPEUTICS • The study of drugs in the treatment and prevention of disease • Pharmacodynamics + Pharmacokinetics

5. BRANCHES OF PHARMACOLOGY • CLINICAL PHARMACOLOGY • The study of the clinical pharmacological evaluation of drugs in human use • Concepts and principles underlying approach to rational therapeutics • PHARMACOGENETICS • The study of genetic variation in response to drug efffects

6. BRANCHES OF PHARMACOLOGY • PHARMACOVIGILANCE • All scientific and data gathering activities that relate to detection, assessment, understanding, and prevention of adverse events • PHARMACOECONOMICS • The study of economic use and management of disease • Cost effectivity of drugs • TOXICOLOGY • The study of adverse effects of drugs

7. PHARMACODYNAMICS • The action of a drug on the body • Includes receptor interactions, dose-response phenomena, and mechanisms of therapeutic and toxic action

8. PHARMACODYNAMICS • A drug will exert its activity through interactions at one or more molecular targets • The macromolecular species that control the functions of cells • May be surface-bound proteins like receptors and ion channels • Species internal to cells, such as enzymes or nucleic acids

9. PHARMACODYNAMICS • Other sites of drug binding: • Proteins (in patient or microbes) • Genome (cyclophosphamide) • Microtubules (vincristine)

10. PHARMACODYNAMICSMECHANISMS AND SPECIFICITY OF DRUG BINDING • Majority occurs through non-covalent interactions • These govern • The folding of proteins and DNA • The association of membranes • Molecular recognition • Interaction between an enzyme and its substrate or the binding of an antibody

11. PHARMACODYNAMICSMECHANISMS AND SPECIFICITY OF DRUG BINDING • They are generally weak and operate only over short distances • So for an effect to occur, you need: • Large numbers of interactions for stability • High degree of complementarity

12. PHARMACODYNAMICSEFFECTS OF BINDING • CONFORMATION EFFECTS • Binding also locks a mobile, flexible molecule into a restricted conformation • CONFIGURATION EFFECTS • Differences in configuration (e.g. stereochemistry) can lead to startling differences in the biological effect • E.g. the L-enantiomer of penicillamine is highly toxic and only the S-enantiomer of indomethacin acts as an anti-inflammatory agent • Wrong configuration  either no reaction or a toxic effect

13. PHARMACODYNAMICSNON-RECEPTOR MEDIATED INTERACTIONS • Acid base reaction • Outcome does not need a receptor, just a simple acid-base equilibrium • Ex. antacid • Counterfeit incorporation mechanism • A form of poisoning • Utilized in cancer chemotherapy • Mechanism: feed the patient/cell with false nucleotides to cheat the cancer cells • Colligative mechanism • This elicits effect by means of numbers • Ex. Acetylcysteine, Mannitol

14. PHARMACODYNAMICSDRUG RECEPTOR • A macromolecular component of a cell with which a drug interacts to produce a response • Usually a protein which requires translation to have an effect AGONIST A drug that triggers the same events in the receptor as the native ligand ANTAGONIST A drug that stops the binding of the native agent without eliciting a response

15. PHARMACODYNAMICSRECEPTOR TYPES • TYPE 1: ionotropic receptors • (ligand-gated channels) • TYPE 2: metabotropic receptors • (G-protein coupled) • TYPE 3: tyrosine kinase-linked receptors • Ex. Insulin and growth factor receptors • TYPE 4: steroid receptors

16. PHARMACODYNAMICSENZYMES • Proteins that catalyze the reactions required for cellular function • Control a number of metabolic processes

17. PHARMACODYNAMICSENZYMES • INHIBITORS • Molecules that restrict the action of enzyme on its substrate • REVERSIBLE (competitive or non-competitive) • A very common mode of action of many drugs • E.g. in the patient (ACE inhibitors) in microbes (sulfas, penicillins) in cancer cells (5-FU, 6-MP) • IRREVERSIBLE • Enzyme inhibitors might be seen to allow very fine control of cellular processes • E.g. 6-methylpurines  death of CA cells

18. PHARMACODYNAMICSNUCLEIC ACIDS • Potentially the most exciting and valuable of the available drug targets • May be used in gene therapy • BUT designing compounds that can distinguish target nucleic acid sequences is not yet achievable

19. PHARMACODYNAMICSNUCLEIC ACIDS • ACTION: generally inhibit the processes of DNA manipulation required for protein synthesis and cell division • Suitable as drugs for applications where cell death is the goal of therapy – such as treatment of cancer

20. PHARMACODYNAMICSDRUG-RECEPTOR INTERACTION • DOSE-RESPONSE RELATIONSHIP • Most important concept in pharmacodynamics • “Dose of a drug translates to an effective response”

21. PHARMACODYNAMICSDRUG-RECEPTOR • CONCEPT OF A RECEPTOR • For most drugs, the site of action is at a specific macromolecule, termed as RECEPTOR • Not all drug actions and effects are mediated through receptors. An average of 10% of them is not • For most drugs, the magnitude of pharmacological response increases as the drug concentration (dose) increases at the site

22. PHARMACODYNAMICSTHEORY AND ASSUMPTIONS OF DRUG-RECEPTOR INTERACTIONS • Combination or binding of drug to receptor leads to response • Response to a drug is graded or dose-dependent • Drug-receptor interaction follows simple mass-action relationships. Only one drug molecule occupies each receptor site and binding is reversible

23. PHARMACODYNAMICSTHEORY AND ASSUMPTIONS OF DRUG-RECEPTOR INTERACTIONS • For a given drug, the magnitude of response is directly proportional to the number of receptor sites occupied by drug molecules (occupancy assumption) • The number of drug molecules is assumed to be much greater than the number of receptor sites

24. PHARMACODYNAMICSSIGNIFICANCE OF KD (DISSOCIATION CONSTANT) • Represents the drug concentration at which half maximal binding occurs • The smaller the KD, the greater the affinity the drug has for the receptor • The smaller the KD for a reaction, the lower the concentration of drug required in order to produce half maximal binding

25. PHARMACODYNAMICSOTHER TERMS • SAFETY • No drug is 100% safe • QUALITY • Tests bioavailability • How much of the drug will enter the system • VARIABILITY • Changes from patient to patient, drug to drug, and time to time

26. LOG DOSE RESPONSE CURVE • EFFICACY • Maximal ceiling effect • Drug effect irrespective of the dose • POTENCY • Does not refer to the strength of the drug • Drug effect with respect to the dose • Location of the drug response curve along the horizontal axis • The nearer the dose to the y axis, the greater the potency • The farther the dose, the lesser potency

27. Log dose response curve

28. Log dose response curvecomparison of drugs

29. PHARMACODYNAMICSAGONISTS • AGONIST DURGS • Drugs that interact with and activate receptors • Possess both affinity and efficacy • 2 TYPES • FULL – an agonist with maximal efficacy • PARTIAL – an agonist with less than maximal efficacy

30. PHARMACODYNAMICSAGONISTS • PARTIAL AGONISTS • A partial agonist is one that produces less of a response when all receptors are occupied than does a full agonist • Can compete with and can displace a full agonist for binding sites  the maximal effect of the full agonist will be less

31. PHARMACODYNAMICSANTAGONISTS COMPETITIVE NON COMPETITIVE Irreversible Antagonist will prevent the agonist from producing a maximal effect, at any agonist concentration Maximal effect of the agonist drug will be decreased, and this cannot be overcome by increasing the concentration of the agonist drug Dose-effect curve flattened out • Reversible • Maximal effect of the agonist drug will not be affected, but larger concentrations of the agonist drug will be required to achieve maximal effect • Dose-effect curve is shifted to the right

32. PHARMACOKINETICS • Action of the body to the drug • COMPONENT PROCESSES • ABSORPTION • The transfer of a drug from its site of administration to the blood stream • DISTRIBUTION • The process by which drug reversibly leaves the blood stream and enters the interstitium and/or other tissues

33. PHARMACOKINETICS • COMPONENT PROCESSES • METABOLISM • Process by which drug structure is altered for removal from the body • Liver is the major site of drug metabolism • EXCRETION • Usually through feces, urine, or bile

34. PHARMACOKINETICSABSORPTION • PASSIVE DIFFUSION • Aqueous or Lipid diffusion • Most common • ACTIVE TRANSPORT • Important for some drugs, particularly larger molecules

35. PHARMACOKINETICSABSORPTION • AQUEOUS DIFFUSION • Within large aqueous compartments (e.g. interstitial space, cytosol) • Driving force: drug concentration gradient (described by Fick’s Law) …. Molecules will tend to move from a higher concentration to a lower concentration • Plasma protein bound drugs cannot permeate through aqueous pores

36. PHARMACOKINETICSABSORPTION • LIPID DIFFUSION • Most important barrier for drug permeation due to many lipid barriers separating body compartments • Lipid-soluble drugs readily move across biological membranes • Ionization state of the drug is an important factor: charged drugs diffuse through lipid environments with difficulty

37. PHARMACOKINETICSABSORPTION • SPECIAL CARRIERS • Peptides, amino acids, glucose • Active transport, facilitated diffusion • Saturable (unlike passive diffusion) because of limited number of carrier sites

38. PHARMACOKINETICSABSORPTION • ENDOCYTOSIS/EXOCYTOSIS • Entry into cells by very large substances • E.g. iron, vit B12

39. PHARMACOKINETICSABSORPTION • PHYSICAL FACTORS INFLUENCING ABSORPTION • Blood flow to the absorption site • Blood flow to intestine > blood flow to stomach • Absorption from the intestine is favored • Total surface area available for absorption • Intestines: rich in microvilli, surface area about 1000-fold that of the stomach • Absorption from the intestine is favored • Contact time at the absorption surface • E.g. Diarrhea – drug moves through the GI tract very quickly, thus it is not well absorbed

40. PHARMACOKINETICSBIOAVAILABILITY • The fraction of administered drug that reaches the systemic circulation • Example • 100 mg of a drug administered orally • If 70 mg of this drug is absorbed unchanged, bioavailability is 70%

41. PHARMACOKINETICSBIOAVAILABILITY • HOW TO TEST FOR BIOAVAILABILITY • Get plasma levels of a drug after a particular route of administration (e.g. oral administration) • Compare the plasma levels obtained with plasma levels achieved by IV injection • By plotting plasma concentrations of the drug versus time, one can measure the area under the curve (AUC) • AUC – reflects the extent of absorption of the drug

42. PHARMACOKINETICSBIOAVAILABILITY • FACTORS THAT INFLUENCE BIOAVAILABILITY • First pass hepatic metabolism • Solubility of the drug • Very hydrophilic drugs cannot cross cell membrane lipid component, thus, may not be well absorbed • Paradoxically, drugs that are extremely hydrophobic are also poorly absorbed because they are totally insoluble in aqueous body fluids, thus, cannot gain access to the surface of cells • FOR GOOD ABSORPTION: The drug must be largely hydrophobic yet have some solubility in aqueous solutions

43. PHARMACOKINETICSBIOAVAILABILITY • FACTORS THAT INFLUENCE BIOAVAILABILITY • Chemical instability • Ex. Penicillin G – unstable in the pH of gastric contents • Nature of the drug formulation • Unrelated to drug chemistry • Ex. Enteric coatings

44. PHARMACOKINETICSABSORPTION • ROUTES OF ADMINISTRATION • Enteral • Oral • Sublingual • Parenteral • IV, IM, SC

45. PHARMACOKINETICSABSORPTION • ORAL ADMINISTRATION • Simplest, most convenient, most economical • Disadvantages • Emesis (drug irritation of GI mucosa) • Digestive enzymes/gastric acidity destroy the drug • Enteric coating of the drug protects it from the acidic environment • Unreliable or inconsistent absorption due to food or other drug effects • Metabolism of drug by GI flora

46. PHARMACOKINETICSABSORPTION • ORAL ADMINISTRATION • First-Pass Effect • Drugs absorbed from the GI tract passes through the portal venous system  LIVER and  systemic circulation • IMPORTANCE: Extensive hepatic metabolism/extraction results in minimal drug delivery to the systemic circulation

47. PHARMACOKINETICSABSORPTION • ORAL ADMINISTRATION • First-Pass Effect • Therefore, drugs that exhibit high first-pass metabolism should be given in sufficient quantities to ensure that enough of the active drug reaches the target organ • Example: nitroglcerin • NOT given orally because 90% of the drug is cleared during a single passage through the liver

48. PHARMACOKINETICSABSORPTION • SUBLINGUAL ADMINISTRATION • Allows drug to diffuse into the capillary network, and, therefore, to enter the systemic circulation directly • ADVANTAGES • Rapid absorption • Convenience of administration • Low incidence of infection • Avoidance of harsh GI environment • Avoidance of first-pass metabolism

49. PHARMACOKINETICSABSORPTION • PARENTERAL ADMINISTRATION • Intravenous (IV) • Permits rapid effect and maximal degree of control over the circulating levels of the drug • May inadvertently introduce bacteria through contamination at the site of injection • Intramuscular (IM) • Requires absorption • Drug diffuses out of the muscle  precipitates at the site of infection  dissolves slowly, providing a sustained dose over an extended period of time

50. PHARMACOKINETICSABSORPTION • PARENTERAL ADMINISTRATION • Subcutaneous (SC) • Like IM administration, requires absorption • Slower than IV route but minimizes risks associated with intravascular injection