Pharmacology Review…Intro?

1. Pharmacology Review…Intro? • Pharmacokinetics • Pharmacodynamics • Drug Interactions • Tolerance

2. Pharmacokinetics • Pharm - drug, kinetics - movement • The interaction of drugs with the body • Primarily: Absorption, distribution and elimination of drugs and the factors that affect this process(s).

3. Absorption Factors affecting absorption of drugs • Route of Administration • Physical properties of the drug and the tissues (organs)

4. AbsorptionFactors affecting absorption of drugs Routes of Administration • Topical: Skin & Eyes • Oral: Gastrointestinal & Sublingual • Rectal • Nasal • Inhalational (Lungs) • Parenteral: Intra- venous or muscular (IV, IM) • Intrathecal

5. AbsorptionFactors affecting absorption of drugs Physical properties of the drug and the tissues (organs) • Solubility of the drug; solubility coefficient • Lipophilic versus Hydrophilic • pH of the solvent (drug is the solute) • Degree of Ionization (pKa) • Concentration of the drug

6. AbsorptionFactors affecting absorption of drugs Physical properties of the drug and the tissues (organs) • Permiability of the tissue and size of the drug molecule • Surface area of the tissue/organ • Blood supply (vasculature) of the route tissue/organ

7. AbsorptionFactors affecting absorption of drugs Routes

8. AbsorptionFactors affecting absorption of drugs Liver Circulation Liver GI Tract - - - - IV

9. AbsorptionFactors affecting absorption of drugs Routes of Administration • Topical: Skin & Eyes • Oral: Gastrointestinal & Sublingual • Rectal • Nasal • Inhalational (Lungs) • Parenteral: Intra- venous or muscular (IV, IM) • Intrathecal

10. Distribution • Most drugs are not distributed evenly throughout the body • Circulatory system is the primary route for distribution • Physico-chemical properties of the drug will determine its distribution

11. DistributionFactors that affect Distribution • Solubility (Polarity & Lipophilicity) • distribution in water versus fat compartments • Binding to serum albumin proteins • pKa • Molecular size

12. DistributionVolume of Distribution • Relationship of Dose to Drug Concentration depends upon the Volume • Drug concentrations are measured in blood (serum) only, but drugs are usually distributed into other compartments as well C = D V

13. DistributionVolume of Distribution • Volume of Distribution therefore refers to the apparent distribution from blood alone • Blood has a very high water content • Blood represents only about 6% of the total body water. C = D Vd

14. DistributionVolume of Distribution C = D Vd • Volume of Blood, Interstitial Fluid and Tissue Fluid = Total Body Water • Plasma = 2.8 L (4%) • Interstitial Fluid = 9.2 L (12 L; 20%) • Intracellular Fluid = 30L (42 L; 60%) • TBW: Males = 60-70 % / Females 50-60 %

15. DistributionVolume of Distribution C = D Vd • A drug which is poorly distributed beyond the blood will have a lower Vd than a drug which distributes throughout the body, which will have a lower Vd from a drug that distributes in fat • Barbiturates : Vd << 1 L/kg • Ethanol : Vd = 0.53 L/kg • THC: Vd = 4 to 14 L/kg

16. DistributionFactors that affect Distribution • Solubility (Polarity & Lipophilicity) • distribution in water versus fat compartments • fat soluble drugs pass through membranes and low water tissues more rapidly • may be distributed/stored in fat • may be poorly taken up in the blood/need a carrier

17. DistributionFactors that affect Distribution • Binding to serum albumin proteins • Drug distribution to other compartments is reduced and slowed • eg. Barbiturates. ~ 99% protein bound. • Apparent distribution is in 2.8 L; blood concentrations are much higher than target tissues (eg. Brain cells).

18. DistributionFactors that affect Distribution • Solubility (Polarity & Lipophilicity) • distribution in water versus fat compartments • Binding to serum albumin proteins • pKa • Molecular size

19. DistributionFactors that affect Distribution • pKa (Ionization) • CH3-CH3-COOH CH3-CH3-COO- • Ionized forms are more polar, thus retarded by cell membranes, but more soluble in water

20. DistributionFactors that affect Distribution • Molecular Size • Small molecules (Ethanol) CH3-CH20H pass rapidly through cell membranes without uptake mechanisms • Larger molecules (Mannitol) are retarded and may be excluded from some compartments

21. Elimination • Definition • Removal of the drug by either • metabolism (conversion) to another subtance • excretion of the drug in unchanged form

22. EliminationRoutes • Liver • Kidney • Lungs • Sweat • Hair

23. EliminationLiver • Major site of metabolism • Enzymatic • Type I - modification of the drug by hydrolysis, methylation, oxidation etc. • Type II - conjugation to a large polar molecule (eg glucuronidation)

24. EliminationLiver • “Goal” to make the drug more • soluble in water (excretion via Kidneys) • soluble in bile (excretion via feces). • Liver takes 100% of blood from stomach and intestines and 40% total circulation • Major metabolic and de-toxifying organ

25. EliminationKidneys • Major site of water and salt balance and nitrogen (urea) elimination. • Filters the blood • Polar drugs and metabolites will pass into the urine with water • Ionization status will also affect excretion

26. Minor Routes of Elimination • Lungs • Drug must be volatile (eg. Inhaled anaesthetics and alcohols) • Sweat • polar, water soluble drugs will pass into the sweat • Hair • deposition from growing end, drugs sequestered in dead hair cells outside of body

27. Elimination Kinetics • Enzymatic elimination of drugs primarily First Order Kinetics (Michaelis-Menton) C =Coe-kt • Elimination half life t 1/2 = 0.693/k

28. Elimination Kinetics (Michaelis-Menton) Actual change in concentration over time Logarithimic change in concentration over time

29. Elimination Kinetics • Elimination is dependent upon concentration, but almost 97% will be eliminated after 5 half-lives Initial concentration 1 mg% One half life 0.5 mg% Two half lives 0.25 mg% Three half lives 0.125 mg% Four half lives 0.0625 mg% Five half lives 0.03125 mg% or 0.96875 mg% (97%) eliminated

30. Non-Enzymatic Breakdown • Some drugs are unstable at physiological pH or in either acid or base conditions • These drugs will breakdown to products over time (the equivalent of metabolism and elimination) • The problem for Forensic Toxicology is that these processes can occur postmortem and especially in-vitro.

31. Non-Enzymatic BreakdownExample Cocaine • Cocaine is metabolized to ecgonine methylester (EME) by an esterase in the blood (pseudocholinesterase) • Cocaine also breaks down over time to Benzoylecgonine (BE), especially at physiological and alkaline pH

32. Non-Enzymatic BreakdownExample Cocaine • Preservatives (chemicals which bind enzymes and prevent postmortem enzymatic changes and tissue breakdown) will stop the metabolism of cocaine to EME, but not the breakdown of cocaine to BE. • Thus some or all of the BE detected in a sample may have been cocaine prior to death

33. Steady State • At therapeutic concentrations drugs taken over a period of time attain Css Steady state concentration Mean Css Blood concentration Time

34. Kinetics in Overdose • Absorption, Distribution and especially elimination of drugs can change in overdose • Large amounts of drugs in the stomach cause ‘concretions’ which reduces absorption

35. Kinetics in Overdose • Distribution may be altered, for example protein binding sites in the blood may become saturated - Vd may change • Elimination kinetics may change; often dramatically, when enzymes become saturated and enter zero-order kinetics, an increase in dose will now lead too much greater blood concentrations with an altered half-life

36. PharmacodynamicsThe Site of Drug Action • Agonist -a molecule that ‘fits’ a receptor by either its spacial and/or ionic properties • Antagonist - a molecule which blocks a receptor by either binding to a non-activating site or physically blocking the site (or causing only very weak activity). • Most drugs mimic natural agonists

37. PharmacodynamicsThe Site of Drug Action • Lock and Key Natural Agonist Antagonist Drug Agonist

38. PharmacodynamicsThe Site of Drug Action • Antagonist effects • Blocking metabolism - re-uptake inhibitors allow the natural molecule (cocaine - dopamine; Prozac etc - serotonin) to remain longer at the site of action • May have beneficial or detrimental effects • May also act as an antidote

39. PharmacodynamicsThe Site of Drug Action • Some drug families are based on receptor binding eg. Opioids- related to morphine; all opioids bind to one or more of the three classes of opioid receptors • Receptors may activate inhibitory pathways; thus agonists may produce inhibitory responses while antagonists may produce excitatory responses (e.g. GABA pathways).

40. Drug - Drug InteractionsKinetic Effects • Drugs may be metabolised by the same enzyme system(s). • Consequence: Induction or inhibition of metabolic pathways by one drug resulting in increasing or decreasing blood concentrations of the other drug (Has implications for the drug with the lowest therapeutic index/greatest disease impact).

41. Drug - Drug InteractionsExample Warfarin • Warfarin is taken as an anticoagulant to combat thrombosis (blood clots) which may break free and damage the heart or lungs. • Warfarin is highly protein bound • Warfarin is metabolised by P450 enzyme system (more about this later).

42. Drug - Drug InteractionsExample Warfarin • Phenobarbital is also highly protein bound and induces the P450 system. • Consequence of someone on warfarin who takes a course of phenobarbital: • Increased free warfarin offset by increased metabolism; net result is increased dose of warfarin needed to achieve anticoagulation. • If dose not lowered at end of phenobarbital treatment, bleeding due to warfarin may result

43. Drug - Drug InteractionsKinetic Effects • Drug Interactions may also be beneficial, e.g. probenecid blocks movement of penicillin into the urine resulting in higher blood concentrations at lower doses and more effective antibiotic treatment.

44. Drug - Drug InteractionsTarget Effects • Drugs may have similar (synergistic) effects (e.g. sedation) which may be additive (similar recptors) or supra-additive (two or more targets) or infra-additive (similar receptors; agonist and antagonist) A+B = C A+B > C A+B < A or B

45. Drug - Drug InteractionsPharmacokinetics • Absorption • Chemical incompatability of two drugs • Prevention of absorption or delay (e.g. decreased gastric motility by opioids) • Distribution • Changes in protein binding • Inhibition in Liver uptake • Change in circulatory flow

46. Drug - Drug InteractionsPharmacokinetics • Elimination • Enzyme Induction • Enzyme inhibition or competition • Inhibition of recirculation from the bile • Changes in Renal processes • acidic urine facilitates the uptake of bases (and vice versa) into the urine • Reabsorption of some drugs back into the circulation may be blocked

47. Tolerance • Two primary aspects of tolerance are Metabolic and Functional • Metabolic (primarily hepatic). • Functional (CNS)

48. Metabolic Dispositional Kinetic Primarily Liver Can involve all drugs Change in [blood] enzyme induction no abstinance (withdrawl) syndrome Functional CNS Dynamic (receptor) Brain CNS drugs only No Change in [blood] learning-like/change in excitation status abstinance syndrome Tolerance

49. Cross tolerance for drugs using the same Tolerance level is moderate (up to 35% increase in dose) Cross tolerance for drugs with the same effect Tolerance level is high (up to 200% increase in dose) Tolerance

50. ToleranceStimulants • Functional tolerance develops rapidly and large increases in dose can occur over one drug session e.g. crack cocaine binges • however metabolic tolerance dose not develop as rapidly; deaths due to non-CNS effects, especially cardiac or vascular and/or thermoregulatory causes are common.