Basic principles of pharmacology

ANESTHESIA and basic principles of pharmacology

1. BASIC PRINCIPLES OF PHARMACOLOGY MODERATOR –Dr. Itishri PRESENTED BY- Dr. Richa Kumar 07/11/16

2. BASIC PRINCIPLES OF PHARMACOLOGY PHARMACOKINETICS PHARMACODYNAMICS

3. PHARMACOKINETICS ABSORPTION METABOLISM DISTRIBUTION ELIMINATION PHARMACODYNAMICS RECEPTOR THEORY DOSE RESPONSE CURVE THERAPEUTIC INDEX

4. PHARMACOKINETICS Describes what body does to a drug Determines the concentration of a drug in plasma or at the site of drug effect BASIC PRINCIPLES- absorption, distribution metabolism & elimination.

5. ABSORPTION Drugs are weak acids or weak bases Present in ionized and non-ionized form Non-ionized form is usually lipid soluble form , which easily crosses the cell membrane including BBB, renal tubules, GIT epithelium, placenta and hepatocytes. Non-ionized= pharmacologically active

6. DETERMINANTS OF IONIZATION 1 Dissociation constant of drug : pK 2 p H of surrounding fluid NONIONIZED IONIZED pH= pK 50% 50% Acidic drug(barbiturates) ph > pK BASIC DRUG( opiods,LA ) pH < pK

7. ION TRAPPING Opioids – accumulation of ionized form in acidic environment of stomach Basic drugs like Local anesthetics from mother to fetal blood.(fetal pH lower than maternal blood ph )

8. BIOAVAILABILITY(F) Its the percentage of a drug which enters blood in unchanged form. MAIN FACTOR which determines it is route of drug for injected i.v. drug is 100 percent Clinical significance : amount of drug absorbed Rate at which it is absorbed Drug response in comparison to blood levels in the body

9. HALF LIFE The time in which peak plasma concentration of drug becomes half t ½ = 0.693/k where k is the elimination rate constant It helps in estimating rate of excretion of drug Duration of action of drug

10. Short T ½ means rapid excretion and short duration of action Long T ½ means slow excretion and long duration of action Drug is completely eliminated in 6 half lives Clinical action lies upto 4 half life of a drug.

11. STEADY STATE When plasma concentration stabilizes Rate of administration = rate of elimination Depends of T ½ Takes about five T ½ to reach a steady state Only important for drugs given in infusion form

12. ROUTE OF ADMINISTRATION AND SYSTEMIC ABSORPTION OF DRUGS . Choice of drug administration depends on systemic absorption rate (SAR) determines drug effect and duration of action. Changes in SAR necessitate adjustment in dose or time interval between repeated drug doses depends upon-drug’s solubility, local conditions at site of drug administration like blood flow at that site, area of absorbing surface .

13. ROUTES OF DRUG ADMINISTRATION INTRAVENOUS ADMINISTRATION INHALATIONAL ORAL TRANSMUCOSAL / SUBLINGUAL TRANSDERMAL RECTAL

14. DISTRIBUTION CENTRAL COMPARTMENT- that section of body which dilute the drug within first minute after injection. PERIPHERAL COMPARTMENT Anesthetic drugs distribute extensively into peripheral tissues. Represent additional volumes that are attached to the central volume . Reflects the drug's solubility in tissue relative to blood or plasma. The more soluble a drug is in peripheral tissue relative to blood or plasma, the larger the peripheral volumes of distribution

15. VOLUME OF DISTRIBUTION- Vd = Depends on lipid solubility and plasma protein binding. tells about extent of tissue penetrance  

16. REDISTRIBUTION VESSEL RICH GROUP- concentration of drug rapidly rises to equilibrate with arterial blood levels. But for highly fat soluble drugs the capacity of fat to hold the drugs exceeds the capacity of highly perfused tissues. Muscles play intermediate role. REDISTRIBUTION accounts for offset of drug e g . FENTANYL

17. PROTEIN BINDING Most acidic drugs – albumin Most basic drugs - α -acid glycoprotein Affects –distribution of drug -potency of drug Non-selective Age , hepatic disease, renal failure, and pregnancy DECREASES plasma protein concentration. Alteration important only for drugs which are highly (>90%) protein bound Free fraction

18. PHARMACOKINETIC MODELS FIRST ORDER KINETICS Constant fraction of drug is excreted in unit time Rate of elimination directly proportional to plasma concentration T ½ =constant Clearance =constant ZERO ORDER KINETICS Constant amount of drug is excreted in unit time Rate of elimination =constant T ½ increases Clearance decreases These are hypothetical structures that are used to describe the fate of a drug in a biological system following its administration

19. First order kinetics Zero order kinetics

20. ONE COMPARTMENT MODEL B ody depicted as kinetically homogenous unit Drug achieves instantaneous distribution throughout the body & equilibrates instantaneously between tissues

21. TWO COMPARTMENT MODEL R esolves body into central & peripheral compartment However the drug does not achieve instantaneous distribution i.e. equilibration between the two compartments

22. D rug distributes into more than one compartment Influenced by physiochemical properties of the drug A drug may only enter and leave the model through the central compartment. MULTI COMPARTMENT MODEL

23. CONTEXT SENSITIVE HALF LIFE T ime for plasma concentration to decrease by 50% from an infusion that maintains a constant concentration Context being the duration of infusion On stopping an infusion, decline in plasma conc. by 3 possible processes Distribution to 2 nd compartment Distribution to 3rd compartment E xcretion Relative contribution of these to their initial decline in plasma concentration vary according to the duration of the infusion

24. Context sensitive half life is more for Longer infusion because drug accumulated in peripheral compartment also equilibrates with plasma levels of drug. It is more relevant than half life in characterizing clinical responses. It is important for IV hypnotics as 50% reduction in drug conc. is important for recovery from iv hypnotics at termination of surgery.

25. TIME COURSE OF DRUG EFFECT Plasma is not the site of drug effect for anesthetic agent It must diffuse from blood to target tissue to produce its effect leading to a delay in onset of drug effect relative to plasma conc. Of drug Lag time is known as HYSTERESIS

26. DOSE CALCULATIONS BOLUS DOSING : = Cpss is steay state plasma concentration Vdss is volume of distribution  

27. MAINTENANCE INFUSION RATE = CL= clearance of drug from plasma  

28. METABOLISM Active drug inactive metabolite Active drug active metabolite Inactive drug active metabolite ( prodrug ) Mostly drugs are lipohilic and converted to hydrophilic compound so that they can be easily excreted.

29. PHASES OF METABOLISM PHASE 1 Non synthetic Microsomes :smooth ER Microsomal enzymes (CYP450, MO,GT) MICROSOMAL REACTION Oxidation,reduction,cyclization,decyclization and hydrolysis PHASE 2 Synthetic Cytoplasm(except glucuronidation ) CONJUGATION REACTIONS Acetylation, methylation, sulphation , glucuronidation , conj. w ith glutathione, glycine conjugation

30. PHASE 1 Oxidation of side chain of highly fat soluble thiopental ,coverts it into hydrophilic carboxylic acid derivative Phenobarbital (+) microsomal enzymes Grapefruit juice (-) CYP3A4 (CYP450) PHASE 2 Glucoronidation is important for PROPOFOL, MORPHINE,MIDAZOLAM

31. ELIMINATION / CLEARANCE Volume of plasma in the vascular compartment cleared of drug per unit time by the processes of metabolism and excretion. Defined in units of flow (e.g., litres/minute). CL= U*V/P CL= clearance U= urine concentration of drug P=plasma concentration of drug V=urine flow rate

32. HEPATIC CLEARANCE

33. HEPATIC CLEARANCE R= Q ( C inflow -C outflow ) R = C inflow x Clearance R is rate of drug metabolism Q is blood flow in and out of liver C is concentration of drug

34. Cin X Clearance = Q ( Cin - Cout ) Clearance = Q X  

35. EXTRACTION RATIO Extraction ratio (ER) = Clearance = Q x Clearance = Q x ER    

36. CL= Q X ER 1 . For drugs like Propofol , ER = 1 the clearance is simply liver blood flow. any reduction in liver blood flow will reduce clearance Such drugs with high ER are known as "flow dependent." IMPORTANCE OF EXTRACTION RATIO

37. 2 . For many drugs (e.g. alfentanil ), the ER <<<1 Clearance of these drugs is limited by the capacity of the liver to take up and metabolize the drug. These drugs are said to be "capacity dependent."

38. CREATININE CLEARANCE AS A FUNCTION OF AGE AND SERUM CREATININE(FIG.2-13)

39. RENAL CLEARANCE The kidneys use following mechanisms to clear drug from the body: Filtration at the glomerulus secretion into the tubules Reabsorption into the tubules

40. The glomerular filtration rate is typically approximated using creatinine clearance which can be predicted from age and weight using COCKROFT AND GAULT EQUATION For men:- For women it is 85% of above :   RENAL CLEARANCE

41. PHARMACODYNAMICS

42. PHARMACODYNAMICS Study of intrinsic sensitivity and responsiveness of the body to a drug. It is what drug does to the body Intrinsic sensitivity is determined by measuring plasma concentration of a drug required to evoke specific pharmacological responses. It varies from patient to patient.

43. RECEPTOR THEORY AGONIST ANTAGONIST

44. AGONIST FULL RESPONSE eg MIDAZOLAM on BDZ R. INVERSE AGONIST Opposite response eg RO 19-4063 PARTIAL AGONIST PRODUCES PART OF RESPONSE e g . BRETAZENIL

45. ANTAGONIST NO RESPONSE FUMAZENIL –competitive antagonism on BDZ receptor

46. INTRINSIC ACTIVITY It is capacity to produce a response +1 for agonist 0 to +1 for partial agonist 0 for antagonist -1 to 0 for inverse agonist

47. Time independent relationship between exposure of drug (x axis) and measured effect (y axis) POTENCY is lowest dose at which response begins EFFICACY is maximal response CONCENTRATION vs RESPONSE RELATIONSHIP

48. EFFECTIVE AND LETHAL DOSE ED 50 is dose at which there is therapeutic effect of drug in 50% population to whom the drug was given. Indicates drug potency L D 50 is dose at which there is toxicity in 50% of population. Indicates drug safety . Effective & Lethal Dose

49. THERAPEUTIC INDEX TI = LD 50 / ED 50 Best indicator of drug safety >= 2 indicates Drug is safe <2 means drug is unsafe and has narrow TI