Download as PDF, PPTX
More Related Content
Similar to basicprinciplesofpharmacology-180511150709.pdf
basicprinciplesofpharmacology-180511150709.pdf
- 1. BASIC PRINCIPLES OF PHARMACOLOGY MODERATOR–Dr. Itishri PRESENTED BY- Dr. Richa Kumar 07/11/16
- 2.
- 3. PHARMACOKINETICS • ABSORPTION • METABOLISM •DISTRIBUTION • ELIMINATION PHARMACODYNAMICS • RECEPTOR THEORY • DOSE RESPONSE CURVE • THERAPEUTIC INDEX
- 4. PHARMACOKINETICS • Describes whatbody 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 areweak 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 1Dissociation constant of drug : pK 2 pH 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 thepercentage 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 • Thetime 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 T½ 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 • Whenplasma 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 ADMINISTRATIONAND 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 DRUGADMINISTRATION INTRAVENOUS ADMINISTRATION INHALATIONAL ORAL TRANSMUCOSAL / SUBLINGUAL TRANSDERMAL RECTAL
- 14. DISTRIBUTION CENTRAL COMPARTMENT- thatsection 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 dose administered immediate plasma concentration
- 16. REDISTRIBUTION • VESSEL RICHGROUP- 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 eg. FENTANYL
- 17. PROTEIN BINDING • Mostacidic 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 ORDERKINETICS • 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 kineticsZero order kinetics
- 20. ONE COMPARTMENT MODEL Bodydepicted as kinetically homogenous unit • Drug achieves instantaneous distribution throughout the body & equilibrates instantaneously between tissues
- 21. TWO COMPARTMENT MODEL Resolvesbody into central & peripheral compartment However the drug does not achieve instantaneous distribution i.e. equilibration between the two compartments
- 22. Drug distributes intomore 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 HALFLIFE • Time 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 I. Distribution to 2nd compartment II. Distribution to 3rd compartment III. Excretion Relative contribution of these to their initial decline in plasma concentration vary according to the duration of the infusion
- 24. • Context sensitivehalf 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 OFDRUG 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
- 28. DOSE CALCULATIONS • BOLUSDOSING: = 𝐂𝐏𝐒𝐒 ×𝐕𝐝𝐬𝐬 𝐛𝐢𝐨𝐚𝐯𝐚𝐢𝐥𝐚𝐛𝐢𝐥𝐢𝐭𝐲 • Cpss is steay state plasma concentration • Vdss is volume of distribution
- 29. MAINTENANCE INFUSION RATE = 𝐂𝐏𝐒𝐒×𝐂𝐋 𝐁𝐈𝐎𝐀𝐕𝐀𝐈𝐋𝐀𝐁𝐈𝐋𝐈𝐓𝐘 CL= clearance of drug from plasma
- 30. METABOLISM • Active druginactive 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.
- 31. PHASES OF METABOLISM •PHASE 1 • Non synthetic • Microsomes :smooth ER • Microsomal enzymes (CYP450, MO,GT) • MICROSOMAL REACTION • Oxidation,reduction,cycliz ation,decyclization and hydrolysis • PHASE 2 • Synthetic • Cytoplasm(except glucuronidation) • CONJUGATION REACTIONS • Acetylation, methylation, sulphation, glucuronidation, conj. with glutathione, glycine conjugation
- 32. • 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
- 33. 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
- 34.
- 35. HEPATIC CLEARANCE •R=Q(Cinflow-Coutflow) •R=Cinflow xClearance • R is rate of drug metabolism • Q is blood flow in and out of liver • C is concentration of drug
- 36. Cin X Clearance= Q (Cin- Cout) Clearance= Q X (Cin−Cout) Cin
- 37. EXTRACTION RATIO Extraction ratio(ER) = Clearance = Q x (Cin−Cout) Cin Clearance = Q x ER (Cin−Cout) Cin
- 38. CL= Q XER 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
- 39. 2. For manydrugs (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."
- 40. CREATININE CLEARANCE ASA FUNCTION OF AGE AND SERUM CREATININE(FIG.2-13)
- 41. RENAL CLEARANCE • Thekidneys use following mechanisms to clear drug from the body: Filtration at the glomerulus secretion into the tubules Reabsorption into the tubules
- 42. • The glomerularfiltration 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 : 140−𝐴𝐺𝐸 𝑦𝑒𝑎𝑟𝑠 ×WEIGHT kgs 72×𝑠𝑒𝑟𝑢𝑚 𝑐𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒(𝑚𝑔%) RENAL CLEARANCE
- 43.
- 44. PHARMACODYNAMICS • Study ofintrinsic 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.
- 45.
- 46. AGONIST FULL RESPONSE eg MIDAZOLAM on BDZR. INVERSE AGONIST Opposite response eg RO 19-4063 PARTIAL AGONIST PRODUCES PART OF RESPONSE eg. BRETAZENIL
- 47. ANTAGONIST NO RESPONSE FUMAZENIL –competitiveantagonism on BDZ receptor
- 48. INTRINSIC ACTIVITY • Itis capacity to produce a response • +1 for agonist • 0 to +1 for partial agonist • 0 for antagonist • -1 to 0 for inverse agonist
- 49. • Time independentrelationship 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
- 52. EFFECTIVE AND LETHALDOSE • ED 50 is dose at which there is therapeutic effect of drug in 50% population to whom the drug was given. • Indicates drug potency • LD 50 is dose at which there is toxicity in 50% of population. • Indicates drug safety. Effective & Lethal Dose
- 53. THERAPEUTIC INDEX • TI= LD50 / ED50 Best indicator of drug safety >= 2 indicates Drug is safe <2 means drug is unsafe and has narrow TI