PHARMACOLOGY

1. PHARMACOLOGY PHARMACOKINETICS & PHARMACODYNAMICS October 31, 2007

2. COMPARTMENT MODEL Fuzzy LogicFuzzy Logic

3. Relative Frequency?

4. Outline Didactic lecture with audience participation Intermingled FRCPC questions Discussion of current topic: Maintaining competence during practice

5. BALANCED ANESTHESIA JOHN LUNDY 1926 CONCURRENT ADMINISTRATION OF SEVERAL ANESTHETIC DRUGS TO ACHIEVE THERAPEUTIC EFFECT and therefore NO SINGLE DRUG IS GIVEN IN A DOSAGE THAT PRODUCES TOXICITY No longer toxicity, much more focussed on side effectsNo longer toxicity, much more focussed on side effects

6. PHARMACOKINETICS WHAT BODY DOES TO DRUG ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

7. PHARMACODYNAMICS WHAT THE DRUG DOES TO THE BODY DRUG/ RECEPTOR INTERACTION & EFFECT “CAUSES PARALYSIS” “INTERFERES WITH THE NEUROMUSCULAR JUNCTION”“CAUSES PARALYSIS” “INTERFERES WITH THE NEUROMUSCULAR JUNCTION”

8. ROUTES OF ADMINISTRATION IV INHALATIONAL ORAL IM INTRANASAL SUBLINGUAL RECTAL TRANSDERMAL(IO-NTOPHORESIS) IT EPID REGIONAL TOPICAL

9. COMPARTMENT MODELS

10. MCQ DTOR022: What is true in a one compartment model regarding clearance? A: inversely proportional to Volume of Distribution B: Inversely proportional to infusion rate C: T1/2 plays a significant role D: Not effected by total dose given E: Is mostly dependent upon hepatic clearance Answer is CAnswer is C

11. COMPARTMENT MODELS

12. MCQ DTOR022: What is true in a one compartment model regarding clearance? A: inversely proportional to Volume of Distribution B: Inversely proportional to infusion rate C: T1/2 plays a significant role D: Not effected by total dose given E: Is mostly dependent upon hepatic clearance

13. MCQ ECAN042: What is the reason for the increased dose of succinylcholine for a neonate compared to an adult? A. Immature Ach receptors B. Increased volume of distribution C. Increased pseudocholinesterase activity D. ? responsiveness of ACH receptors Answer: B. The body compartments (fat, muscle, water) change with age (Fig. 59-5) . Total body water content is significantly higher in the premature than in the term infant and in the term infant than in the 2-year-old. [1] Fat and muscle content increase with age. These alterations in body composition have several clinical implications for the neonate: (1) a drug that is water soluble has a larger volume of distribution and usually requires a larger initial dose to achieve the desired blood level (e.g., most antibiotics, succinylcholine); (2) because there is less fat, a drug that depends on redistribution into fat for termination of its action has a longer clinical effect (e.g., thiopental); and (3) a drug that redistributes into muscle may have a longer clinical effect (e.g., fentanyl, for which, however, saturation of muscle tissue has not been demonstrated). Reference: Miller 2092 Pharmacokinetics in neonatesAnswer: B. The body compartments (fat, muscle, water) change with age (Fig. 59-5) . Total body water content is significantly higher in the premature than in the term infant and in the term infant than in the 2-year-old. [1] Fat and muscle content increase with age. These alterations in body composition have several clinical implications for the neonate: (1) a drug that is water soluble has a larger volume of distribution and usually requires a larger initial dose to achieve the desired blood level (e.g., most antibiotics, succinylcholine); (2) because there is less fat, a drug that depends on redistribution into fat for termination of its action has a longer clinical effect (e.g., thiopental); and (3) a drug that redistributes into muscle may have a longer clinical effect (e.g., fentanyl, for which, however, saturation of muscle tissue has not been demonstrated). Reference: Miller 2092 Pharmacokinetics in neonates

14. Total Body H2O vs. Age Figure 59-5 Body composition changes rapidly in premature and term infants during the first 12 months of life. Their high water content provides a large volume of distribution for water-soluble medications, whereas their low fat and muscle content provides a small reservoir for drugs that depend on redistribution into these tissues for termination of drug effects. Thus, body composition may significantly affect pharmacokinetics and pharmacodynamics Figure 59-5 Body composition changes rapidly in premature and term infants during the first 12 months of life. Their high water content provides a large volume of distribution for water-soluble medications, whereas their low fat and muscle content provides a small reservoir for drugs that depend on redistribution into these tissues for termination of drug effects. Thus, body composition may significantly affect pharmacokinetics and pharmacodynamics

15. MCQ 2005CAN062 Which of the following is TRUE regarding the volume of distribution of a drug? A. The volume of distribution is never greater than the total volume of the patient B. It is proportional to the dose of a drug and inversly proportional to its concentration C. Protein binding is not a factor in the volume of distribution D. The volume of distribution equilibrates rapidly E. Units are mL/m2 or mL.m-2 Volume of distribution is calculated as the dose of drug administered IV divided by the resulting plasma concentration of drug before elimination begins(initial Vd or Vd1) or when steady state conditions have been achieved (Vdss). As such, Vd is influenced by physiochemical characteristics of the drug, including lipid solubility, binding to plasma proteins and molecular size. A lipid soluble drug that is highly concentrated in tissues with a resulting low plasma concentration will have a calculated Vd that exceeds total body water. The unit should be a volume unit. P&P p. 10Volume of distribution is calculated as the dose of drug administered IV divided by the resulting plasma concentration of drug before elimination begins(initial Vd or Vd1) or when steady state conditions have been achieved (Vdss). As such, Vd is influenced by physiochemical characteristics of the drug, including lipid solubility, binding to plasma proteins and molecular size. A lipid soluble drug that is highly concentrated in tissues with a resulting low plasma concentration will have a calculated Vd that exceeds total body water. The unit should be a volume unit. P&P p. 10

16. VOLUME OF DISTRIBUTION Definition Ask for Definition: Volume of distribution is calculated as the dose of drug administered IV divided by the resulting plasma concentration of drug before elimination begins(initial Vd or Vd1) or when steady state conditions have been achieved (Vdss). As such, Vd is influenced by physiochemical characteristics of the drug, including lipid solubility, binding to plasma proteins and molecular size. A lipid soluble drug that is highly concentrated in tissues with a resulting low plasma concentration will have a calculated Vd that exceeds total body water. The unit should be a volume unit. P&P p. 10Ask for Definition: Volume of distribution is calculated as the dose of drug administered IV divided by the resulting plasma concentration of drug before elimination begins(initial Vd or Vd1) or when steady state conditions have been achieved (Vdss). As such, Vd is influenced by physiochemical characteristics of the drug, including lipid solubility, binding to plasma proteins and molecular size. A lipid soluble drug that is highly concentrated in tissues with a resulting low plasma concentration will have a calculated Vd that exceeds total body water. The unit should be a volume unit. P&P p. 10

17. VOLUME OF DISTRIBUTION

18. VOLUME OF DISTRIBUTION = Dose given/Plasma Concentration Plasma concentration following the administration of a known amount of drug NOT A TRUE ANATOMICAL VOLUME

19. MCQ 2005CAN062 Which of the following is TRUE regarding the volume of distribution of a drug? A. The volume of distribution is never greater than the total volume of the patient B. It is proportional to the dose of a drug and inversly proportional to its concentration C. Protein binding is not a factor in the volume of distribution D. The volume of distribution equilibrates rapidly E. Units are mL/m2 or mL.m-2 Volume of distribution is calculated as the dose of drug administered IV divided by the resulting plasma concentration of drug before elimination begins(initial Vd or Vd1) or when steady state conditions have been achieved (Vdss). As such, Vd is influenced by physiochemical characteristics of the drug, including lipid solubility, binding to plasma proteins and molecular size. A lipid soluble drug that is highly concentrated in tissues with a resulting low plasma concentration will have a calculated Vd that exceeds total body water. The unit should be a volume unit. P&P p. 10Volume of distribution is calculated as the dose of drug administered IV divided by the resulting plasma concentration of drug before elimination begins(initial Vd or Vd1) or when steady state conditions have been achieved (Vdss). As such, Vd is influenced by physiochemical characteristics of the drug, including lipid solubility, binding to plasma proteins and molecular size. A lipid soluble drug that is highly concentrated in tissues with a resulting low plasma concentration will have a calculated Vd that exceeds total body water. The unit should be a volume unit. P&P p. 10

20. Definitions Elimination Half Time Elimination Half Life

21. Definitions Elimination Half Time Elimination Half Life Context Sensitive Half-time?

22. Definitions Elimination Half Time Time for plasma concentration to decline by 50% Elimination Half Life Time for 50% of a drug to be eliminated from the body

23. 2 COMPARTMENT MODEL Figure 2.2 in Barash Central Compartment – Highly perfused – circulation, heart, brain, kidneys, liver 75% perfusion, 10% mass Problems – elimination half time from central compartment – not applicable to atricurium, Cis, RemiFigure 2.2 in Barash Central Compartment – Highly perfused – circulation, heart, brain, kidneys, liver 75% perfusion, 10% mass Problems – elimination half time from central compartment – not applicable to atricurium, Cis, Remi

24. Plasma Conc’n 2 Compartments

25. PLASMA CONC. CURVE WITH RAPID DISTRIBUTION RAPID INITIAL DECLINE IS DISTRIBUTION ELIMINATION PHASE RENAL AND HEPATIC

26. CONTEXT SENSITIVE 1/2 TIME SHAFER, STANSKI, HUGHES 1992 COMPARED TO ELIMINATION 1/2 TIME IT CONSIDERS COMBINED EFFECTS OF DISTRIBUTION METABOLISM AND DURATION OF ADMINISTRATION

27. Context Sensitive Half-time

28. IONIZATION LESS IONIZED = MORE LIPID SOLUBLE (to pass cell membrane/lipid barriers) More hepatic metabolism Less renal excretion pKa- pH at which 50% of drug is ionized Lipid bariers such as GI tract, blood brain barrier, placenta Acidic drugs such as barbituriates tend to be highly ionized at an alkaline pH. Basic drugs such as opioids and local anesthetics – highly ionized at an acidic pHLipid bariers such as GI tract, blood brain barrier, placenta Acidic drugs such as barbituriates tend to be highly ionized at an alkaline pH. Basic drugs such as opioids and local anesthetics – highly ionized at an acidic pH

29. ION Trapping Placenta hatched linePlacenta hatched line

30. ION Trapping Placenta hatched line Placenta hatched line

31. PROTEIN BINDING Protein binding has important effect on distribution. Only free drug is active, usually all of the drug is determined when measuring levels. ALBUMIN – binds acidic drugs alpha1-acid glycoprotein - basic drugs Drugs very bound – Warfarin, phenytoin, propranolol, diazepam Acidic drugs bind to Albumin (BARBATURIATES) Basic Drugs bind to Alpha 1 Glycoprotein (OPIOIDS & LOCAL ANESTHETICS) Volume of distribution is inversely proportional to protein bindingDrugs very bound – Warfarin, phenytoin, propranolol, diazepam Acidic drugs bind to Albumin (BARBATURIATES) Basic Drugs bind to Alpha 1 Glycoprotein (OPIOIDS & LOCAL ANESTHETICS) Volume of distribution is inversely proportional to protein binding

32. MCQ ECAN077: Factors promoting drug transfer across the placenta: A. High degree of ionization B. Low lipid solubility C. Large Maternal/Fetal drug gradient D. High degree of protein binding E. Large molecular weight Factors that increases drug transfer across the placenta: 1. Increased nonionized form. 2. Increased maternal/fetal serum gradient. 3. Increased lipid solubility. 4. Decrease protein binding. 5. Small molecular weight.Factors that increases drug transfer across the placenta: 1. Increased nonionized form. 2. Increased maternal/fetal serum gradient. 3. Increased lipid solubility. 4. Decrease protein binding. 5. Small molecular weight.

33. CLEARANCE HEPATIC RENAL TISSUE Give ExamplesGive Examples

34. HEPATIC METABOLISM OXIDATION, REDUCTION, HYDROLYSIS, AND CONJUGATION Convert active lipid soluble drugs to water soluble metabolites (inactive, less active) Rate of metabolism First-order Kinetics Zero-order Kinetics Lipid soluble prent drug not easily excreted because of reabsorbtion from the lumens of renal tubules into pericapilary fluid. Without Hepatic metabolism, Thiopental would have a half life of 100 years. Note: NOT ALWAYS INACTIVE METABOLITES FIRST order – linear dependant on plasma concentration, usually unbound ZERO order – constant amount metabolised regardless of concentration – drug exceeds capacity of enzymes, Alcohol, ASA, Phenytoin are examplesLipid soluble prent drug not easily excreted because of reabsorbtion from the lumens of renal tubules into pericapilary fluid. Without Hepatic metabolism, Thiopental would have a half life of 100 years. Note: NOT ALWAYS INACTIVE METABOLITES FIRST order – linear dependant on plasma concentration, usually unbound ZERO order – constant amount metabolised regardless of concentration – drug exceeds capacity of enzymes, Alcohol, ASA, Phenytoin are examples

35. First ORDER KINETICS Depends on the plasma concentration Fixed fraction of available drug is eliminated per unit time Greater concentration the greater the amount of drug eliminated

36. ZERO ORDER KINETICS Enzymes are saturated Constant amount of drug is eliminated per unit time regardless of concentration Alcohol and aspirin

37. PHARMACOGENETICS Pseudocholinesterase Deficiency CYTOCHROME P450 conversion of codeine to morphine? Inherited Pseudocholinesterase Deficiency Note Cytochrome 450 subject to induction (especially by anti-epileptics but also EtOH). Some studies: 15-20% of caucasians unable to convert Codeine to MorphineInherited Pseudocholinesterase Deficiency Note Cytochrome 450 subject to induction (especially by anti-epileptics but also EtOH). Some studies: 15-20% of caucasians unable to convert Codeine to Morphine

38. MCQ ATOR217: All are true regarding the pharmacology of esmolol, EXCEPT: a) half life is 9 minutes b) primarily ß1 selective c) absence of intrinsic sympathomimetic activity d) primarily hepatic elimination e) is not a membrane stabilizer ANSWER: D Esmolol is a beta1-selective antagonist that is metabolised by plasma esterases not related to pseudocholinesterase. Its half-time is 9 minutes. Elimination is independent of renal and hepatic function. Beta blockers do not have any membrane stabilization effects, except at high doses. “Membrane stabilization is probably of little importance in the antidysrhythmic effects produced by usual doses of beta-adrenergic antagonists.” Pharm & Phys, pp. 295-6 Barash4 312: Esmolol is metabolised rapidly in the blood by an esterase in the RBC cytoplasm.ANSWER: D Esmolol is a beta1-selective antagonist that is metabolised by plasma esterases not related to pseudocholinesterase. Its half-time is 9 minutes. Elimination is independent of renal and hepatic function. Beta blockers do not have any membrane stabilization effects, except at high doses. “Membrane stabilization is probably of little importance in the antidysrhythmic effects produced by usual doses of beta-adrenergic antagonists.” Pharm & Phys, pp. 295-6 Barash4 312: Esmolol is metabolised rapidly in the blood by an esterase in the RBC cytoplasm.

39. AGE- NEONATE/PEDS Inhaled agents ? FRC ? Volume of distribution ? Protein binding ? Liver metabolism development ? Renal- GFR

40. AGE - ELDERLY Affects pharmacokinetics ? TBW ? Body fat

41. PREGNANCY ? Protein Binding - Decrease Albumin Concentration ? Volume of Distribution ? Pseudocholinesterase Function

42. DISEASED STATES HEPATIC Volume of Distribution Metabolism RENAL Volume Of Distribution Excretion of Drug ? BBB

43. MCQ ECAN134: Peak respiratory depression effect of Remifentanil occurs at: A. 1 minute B. 2 minutes C. 3 minutes D. 5 minutes E. 10 minutes Answer: D. Reference: Barash Chapter 14 Comment on differing sources – tie into later discussion of maintenance of competenceAnswer: D. Reference: Barash Chapter 14 Comment on differing sources – tie into later discussion of maintenance of competence

44. PHARMACODYNAMICS WHAT THE DRUG DOES TO THE BODY DRUG / RECEPTOR INTERACTION & EFFECT

45. POTENCY Morphine, fentanyl, sufentanyl…Morphine, fentanyl, sufentanyl…

46. STEREOCHEMISTRY CHIRALITY Dextro (D or +) or Levo (L or -) the direction they rotate polarized light S sinister (Left Handed) or R rectus Racemic mixture contains both enantiomers NAME SOME RACEMIC OR SINGLE enantiomers… Thought that many racemic mixtures – side effects most likely due to non-active component NAME SOME RACEMIC OR SINGLE enantiomers… Thought that many racemic mixtures – side effects most likely due to non-active component

47. STEREOCHEMISTRY Racemic mixtures: ketamine, bupivicaine, atracurium Single enantiomers: levobupivicaine, ropivicaine, cisatracurium

48. DEFINITIONS AGONIST ANTAGONIST PARTIAL AGONIST competitive and non competitive ANTAGONISTcompetitive and non competitive ANTAGONIST

49. DEFINITIONS ADDITIVE SYNERGISTIC DEFINITIONS OF DRUG INTERACTIONSDEFINITIONS OF DRUG INTERACTIONS

50. DEFINITIONS HYPERREACTIVE HYPOREACTIVE TOLERANCE TACHYPHYLAXIS

51. AGONIST RECEPTOR INTERACTION COUPLE OF EXCELLENT PICTURES FROM BARASHCOUPLE OF EXCELLENT PICTURES FROM BARASH

52. BENZO/GABA INTERACTION

53. BENZO GABA RECEPTOR

54. OPIOID RECEPTOR INTERACTIONS

55. ED50 / LD50 NB: DEFINE THERAPUTIC INDEX Discuss ED95/LD95 Lethal vs side effectsNB: DEFINE THERAPUTIC INDEX Discuss ED95/LD95 Lethal vs side effects

56. PHARMACOGENETICS MH

57. AGE- NEONATE SENSITIVITY TO INHALATIONAL, SEDATIVES, AND NARCOTICS

58. AGE- ELDERLY ELDERLY MORE SENSITVE TO INHALATIONAL AGENTS, BENZO OPIOIDS

59. PHYSIOLOGY-PREGNANCY AFFECTS PHARMACODYNAMICS SENSITIVITY TO VOLATILE SENSITIVITY TO LOCAL ANESTHETICS CARDIOTOXICITY OF LOCAL ANESTHETICS

60. TIME TO AWAKENING

61. INFUSIONS PHYSICIAN CONTROLLED TARGET CONTROLLED INFUSIONS

62. TARGET CONTROLLED INFUSIONS USE COMPUTER PROGRAM AND PHARMACOKINETIC MODEL TO PREDICT WHAT PLASMA CONCENTRATION IS

63. MODEL

64. CLOSED LOOP INFUSION

65. MCQ?

66. MCQ ACAN039: A 12 year old male with bladder extrophy is having a repeat repair. 30 minutes after the start of the anesthetic he develops increased peak inspired airway pressures, has hypotension and tachycardia. The first management priority is: A. Salbutamol B. Methylprednisolone 10 mg/kg IV C. Diphenhydramine 0.5 mg/kg IV D. Epinephrine 1 microgram/kg IV