Pharmacokinetics and pharmacodynamics

Detailed description about two main aspects of Pharmacology, the Pharmacokinetics and Pharmacodynamics.

1. Pharmacokinetics & Pharmacodynamics Dr. Nidhi Sharma

2. Pharmacology I t is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function. It is mainly concerned with safety and efficacy of a drug.

3. Pharmacology This field includes drug : Composition Properties Synthesis Medical Applications Antipathogenic capabilities

4. Pharmacology 2 main areas of Pharmacology are : Pharmacokinetics Pharmacodynamics

5. Importance of Pharmacokinetics and Pharmacodynamics Individualize patient drug therapy Monitor medications with a narrow therapeutic index Decrease the risk of adverse effects while maximizing pharmacologic response of medications

6. Pharmacokinetics What the BODY does to the DRUG ?

7. Pharmacokinetics Study of drug movement in, through and out of the body. It includes the following processes : (ADME)

8. Absorption The process by which drug proceeds from the site of administration to the blood stream within the body. Orally administered solid drugs should break down into particles of the active drug the released drug then dissolve in the aqueous GI contents.

9. Factors Affecting Absorption

10. Routes of Administration Systemic Local Ente ral Parenteral Oral Sublingual Rectal Intravenous Intramuscular Subcutaneous Intradermal Intrathecal Topical Intranasal Ocular Drops Mucosal (Throat, Vagina, Mouth, Ear)

11. First Pass Metabolism A fraction of a drug is lost during the process of absorption generally related to the liver and gut wall and its concentration is greatly reduced before it reaches the systemic circulation. It leads to decreased bioavailability of a drug. Maximum in orally administered drugs.

12. Bioavailability First fundamental parameter of Pharmacokinetics. Rate and extent of absorption of a drug from a dosage form. Determined by concentration-time curve of the drug in blood or its excretion in urine. PLASMA CONCENTRATION TIME C Therapeutic success of a rapidly and completely absorbed drug. Therapeutic failure of a slowly absorbed drug Therapeutic Concentration

13. Bioavailability Fraction of administered dose of a drug that reaches the systemic circulation in the unchanged form. IV injected drug : 100 % bioavailability Orally ingested drug : reduced bioavailability because : Drug may be incompletely absorbed The absorbed drug may undergo first pass metabolism SC or IM injection MAY have reduced bioavailability due to local binding of the drug.

14. Distribution Process by which drug leaves the site of administration and distributed throughout the tissues of the body. Factors affecting volume of drug distribution : Lipid:water partition coefficient of the drug pKa value of the drug Degree of plasma protein binding Affinity for different tissues Fat:Lean body mass ratio Diseases like CHF, Uraemia, Cirrhosis

15. Distribution APPARENT VOLUME OF DISTRIBUTION ( V ) Second fundamental parameter of Pharmacokinetics. Volume of distribution is the volume of plasma that would be necessary to account for the total amount of drug in the patient's body, if that drug were present throughout the body at the same concentration as found in the plasma. V = Dose administered IV Plasma concentration

16. Metabolism (Biotransformation) Chemiacal alteration of the drug in the body. converts non-polar (lipid soluble) compounds polar so they are not reabsorbed in the renal tubules and are excreted. Hydrophilic drugs eg. Gentamycin are not biotransformed and are excreted unchanged. PRIMARY SITES :

17. Metabolism (Biotransformation)

18. Metabolism (Biotransformation) Biotransformation reactions can be classified into : Non synthetic/Phase 1 reactions : Active metabolite Inactive metabolite Synthetic/Conjugation/Phase 2 reactions : Inactive metabolite

19. Metabolism (Biotransformation) NON SYNTHETIC REACTIONS

20. Metabolism (Biotransformation) SYNTHETIC REACTIONS conjugation of the drug or its phase 1 metabolite with an endogenous substrate to form a polar highly ionized organic acid which is easily excreted in urine or bile.

21. Excretion Passage out of systemically absorbed drug in :

22. Kinetics of Elimination Drug Elimination = Metabolic Inactivation + Excretion CLEARANCE (CL) : Third fundamental parameter of Pharmacokinetics. Volume of plasma from which the drug is completely removed in unit time. CL = Rate of Elimination Plasma Concentration

23. Kinetics of Elimination FIRST ORDER (EXPONENTIAL) KINETICS Rate of elimination is directly proportional to drug concentration CL remains constant t ½ is constant ZERO ORDER (LINEAR) KINETICS Rate of elimination is constant irrespective of drug concentration CL decreases with increase in concentration t ½ increases with dose

24. Kinetics of Elimination PLASMA HALF-LIFE (t ½ ) Time taken for the plasma concentration of a drug to be reduced to half of its original value. t ½ = ln 2 = log 2 or (0.693) k Elimination Rate Constant ELIMINATION RATE CONSTANT (k) : Fraction of the total amount of the drug in the body which is removed per unit time. k = CL t ½ = 0.693 × V V CL

25. Kinetics of Elimination 1 half life = 50% drug is eliminated 2 half lives = 75% (50 + 25) 3 half lives = 87.5% (50 + 25 + 12.5) 4 half lives = 93.75% (50 + 25 + 12.5 + 6.25) So 4-5 half lives are needed for nearly complete drug elimination.

26. Kinetics of Elimination

27. Kinetics of Elimination Repeated Drug Administration when a drug is repeated at relatively short intervals, it accumulates in the body until elimination and input become balanced and a steady-state plasma (C pss ) is attained. C pss = Dose rate CL Dose rate and C pss are in linear relation only in case of drugs that follow first order kinetics. Plateau Principle when constant dose is repeated before 4 half lives, it would achieve higher peak concentration, because some remnants of the previous dose will be present in the body. After almost 4-5 half lives, increasing rate of elimination balances the amount administered over the dose interval. Subsequently, plasma concentration plateaus and fluctuates about an average steady-state level.

28. Pharmacodynamics What DRUG does to the BODY ?

29. Pharmacodynamics Principles of Drug action

30. Pharmacodynamics Mechanism of Drug action Physical or chemical properties : Physical mass adsorptive property osmotic activity neutralization of gastric HCl oxidising property

31. Pharmacodynamics Enzymes Drugs can either increase or decrease the rate of enzymatically mediated reactions. Stimulation of an enzyme increases its affinity for the substrate so that rate constant kM of the reaction is lowered. Induction of an enzyme ( synthesis of more protein) also increases enzyme activity. kM does not change. Inhibition of enzymes. Non specific inhibition Specific inhibition

32. Pharmacodynamics Carriers Drugs produce their action by interacting with the carrier protein to inhibit the ongoing physiological transport of the metabolite. eg. Furosemide inhibits the Na-K-2Cl cotransporter in the ascending limb of loop of Henle. Ion channels Drugs affect ion channels either through specific receptors (ligand gated, G-protein operated) or by directly binding to the channel and affecting ion movement through it. Certain drugs modulate opening and closing of the channel. eg. Sulfonylurea hypoglycaemics inhibit pancreatic ATP-sensitive k + channels.

33. Pharmacodynamics Receptors Drugs act through specific receptor ( macromolecule or binding site that serves to recognize and initiate the response to a signal molecule or drug ) which regulate critical functions like enzyme activity, permeability, structural features, template function. Agonist activates receptor to produce effect similar to the physiological signal molecule. Inverse agonist - activates receptor to produce opposite effect. Antagonist - prevents the action of the agonist. Partial Agonist - activates receptor to produce sub-maximal effect but antagonizes the action of a full agonist.

34. Pharmacodynamics Receptor occupation theory Propounded by Clark in 1937 . Intensity of response is proportional to the fraction of receptors occupied by a drug. Drug exert an all or none action on each receptor. A drug and its receptor have Lock and Key relationship. Affinity : ability of the drug to combine with the receptor. Intrinsic activity (Efficacy) : ability of the drug to activate the receptor.

35. Pharmacodynamics The Two-State Receptor Model l Equilibrium ll Response lll No Response lv Partial Response v Opposite Response Ra Ri RaA + Ra Ri RaB + Ra RiB + Ri RaC + Ra Ri +RiC Ra Ri +RiD

36. Pharmacodynamics Action-Effect Sequence Drug Action is the initial combination of the drug with its receptor resulting in a confirmational change in the receptor (AGONIST) or prevention of confirmational change through exclusion of the agonist (ANTAGONIST). Drug Effect is the ultimate change in biological function brought about as a consequence of drug action. Dose-Response Relationship Intensity of response increases with increase in dose. Dose-Response curve is a hyperbola because Drug-Receptor interaction obeys Law of mass action. E = E max × [D] K D + [D]

37. Pharmacodynamics E = observed effect at a dose [D] of the drug E max = maximal response K D = dissociation constant of drug-receptor complex = dose of drug at which half maximum response is produced If dose is plotted on log scale, the curve becomes sigmoid and a linear relationship is seen between log of dose and the response in the intermediate zone (30-70% response) Dose Response Dose Log Dose

38. Pharmacodynamics Drug Potency and Efficacy Drug potency is the amount of drug needed to produce certain response. Drug efficacy is the maximum response achievable from a drug. Upper limit of DRC is the index of efficacy. Steep DRC means moderate increase in dose leads to marked increase in response. Flat DRC means little increase in response over a wide dose range. Drug B is less potent but equally efficacious as A. Drug D is more potent than A, B and C but less efficacious than A and B, and equally efficacious as C. D C A B Log Dose Response

39. Pharmacodynamics A B Log Dose Response Drug Selectivity Extent of separation of DRCs of a drug for different effects is a measure of selectivity. Therapeutic Index Gap between the therapeutic effect DRC and adverse effect DRC Also known as Safety Margin Therapeutic Index = Median Lethal Dose = LD 50 Median Effective Dose ED 50 Therapeutic Effect Adverse Effect Minimal therapeutic effect Maximum acceptable adverse effect Therapeutic Range

40. Pharmacodynamics Combined effect of drugs : given simultaneously or in quick succession Synergism Antagonism Additive Drug A + B = Drug A + Drug B Physiological Physical Chemical Supra-Additive Drug A + B > Drug A + Drug B Receptor Non Competitive Competitive

41. Pharmacodynamics Competitive (Equilibrium Type) Non-Competitive Antagonist binds with same receptor as agonist Binds with different receptor Antagonist chemically resemble agonist Does not resemble Parallel rightward shift of agonist DRC Flattening of agonist DRC Surmountable antagonism Unsurmountable antagonism Antagonist reduces potency of agonist Antagonist reduces efficacy of agonist Response depends on both agonist and antagonist Depends only on antagonist eg. ACh-Atropine Diazepam-Bicuculline

42. Pharmacodynamics Drug Dosage Dose is the amount of drug needed to produce a certain degree of response in a patient. It depends on the potency and pharmacokinetics of the drug. Types of dose Standard dose : Same dose is appropriate for most patients. eg OCP Regulated dose : Dosage is accurately adjusted by repeated measurement of the affected physiological parameter. eg Anti-hypertensives Target Level dose : An emperical dose aimed at attaining the target level is given in the beginning and adjustments are made later by actual monitoring of plasma concentrations. eg Anti-epileptics Titrated dose : Optimal dose is arrived at by titrating it with an acceptable level of adverse effect.

43. Pharmacodynamics Factors modifying drug action

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