pharmacology review…intro?

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Pharmacology Review…Intro?

• Pharmacokinetics

• Pharmacodynamics

• Drug Interactions

• Tolerance

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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).

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Absorption

Factors affecting absorption of drugs

– Route of Administration

– Physical properties of the drug and the tissues

(organs)

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Absorption Factors 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

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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

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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

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Routes

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Liver Circulation

IV - - - -GI Tract

Liver

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Routes of Administration– Topical: Skin & Eyes– Oral: Gastrointestinal & Sublingual – Rectal– Nasal– Inhalational (Lungs)– Parenteral: Intra- venous or muscular (IV, IM)– Intrathecal

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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

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DistributionFactors that affect Distribution

• Solubility (Polarity & Lipophilicity)– distribution in water versus fat compartments

• Binding to serum albumin proteins

• pKa

• Molecular size

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• 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

DistributionVolume of Distribution

C = D

V

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• 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

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• 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 %


C = D

Vd

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• 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


C = D

Vd

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• 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

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• 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).

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• pKa

• Molecular size

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• pKa (Ionization)

• CH3-CH3-COOH CH3-CH3-COO-

• Ionized forms are more polar, thus retarded by cell membranes, but more soluble in water

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• 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

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Elimination

• Definition

• Removal of the drug by either – metabolism (conversion) to another subtance– excretion of the drug in unchanged form

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EliminationRoutes

• Liver

• Kidney

• Lungs

• Sweat

• Hair

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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)

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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

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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

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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

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Elimination Kinetics

• Enzymatic elimination of drugs primarily First Order Kinetics (Michaelis-Menton)

C =Coe-kt

• Elimination half life t 1/2 = 0.693/k

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Elimination Kinetics (Michaelis-Menton)

Actual change in concentration over time

Logarithimic change in concentration over time

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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

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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.

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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

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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

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Steady State

• At therapeutic concentrations drugs taken over a period of time attain Css Steady state concentration

Blo

od c

once

ntra

tion

Time

Mean Css

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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

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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

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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

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• Lock and Key

Natural Agonist

Drug Agonist

Antagonist

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• 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

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• 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).

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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).

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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).

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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

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Drug - Drug Interactions Kinetic 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.

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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

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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

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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

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Tolerance

• Two primary aspects of tolerance are Metabolic and Functional

• Metabolic (primarily hepatic).

• Functional (CNS)

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Tolerance

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

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Tolerance

• 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)

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Tolerance Stimulants

• 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.

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ToleranceCNS Depressants

• Functional tolerance develops more slowly and is lost over a shorter period than acquisition.

• One major problem is respiratory depression; the respiratory centre is located in the medulla and most if not all sedatives depress respiration - tolerance to this effect, especially for opioids, dose not occur

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References

• Principles of Medical Pharmacology (Kalant & Roschlau eds.) 6th ed., Oxford Publ., 1998.

• Goodman and Gilman’s The Pharmacological basis of Therapeutics (Hardman & Limbird eds-in-chief) 9th ed., McGraw-Hill, 1996

pharmacology review…intro?

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