Introduction to PharmacologyIntroduction to Pharmacology

Prof. NassiriProf. NassiriDirector, Institute of International HealthDirector, Institute of International Health

Michigan State UniversityMichigan State University

Medical Mission TripMay 9-16, Dominican Republic

What is Pharmacology?What is Pharmacology?

Broadly defined as the study of how Broadly defined as the study of how chemical agents affect living processes.chemical agents affect living processes.

HormonesHormonesNeurotransmittersNeurotransmittersGrowth factorsGrowth factorsLocal Local autocrineautocrine factorsfactorsDrugs (Pharmaceuticals)Drugs (Pharmaceuticals)Toxic agents in the environmentToxic agents in the environment

From the Greek pharmakon (drug),legein (to speak)

The medicinal/ organic chemist may create the The medicinal/ organic chemist may create the candidate compound (sometimes referred to as candidate compound (sometimes referred to as a new chemical entity, NCE), it is the a new chemical entity, NCE), it is the pharmacologist who is responsible for testing it pharmacologist who is responsible for testing it for pharmacological activity. for pharmacological activity.

Ultimately will lead to the discovery of novel Ultimately will lead to the discovery of novel drug targets for therapeutic intervention in drug targets for therapeutic intervention in diseases where distal steps in signal diseases where distal steps in signal transduction have gone awry.transduction have gone awry.

Pharmacology studies the effects of drugs and Pharmacology studies the effects of drugs and how they exert their effects.how they exert their effects.Acetylsalicylic acid (ASA)Acetylsalicylic acid (ASA) can reduce can reduce inflammationinflammation, , painpain and and feverfeverinhibit the action of a human cell membrane inhibit the action of a human cell membrane enzyme known as cyclooxygenase, which is enzyme known as cyclooxygenase, which is responsible for the synthesis of a number of responsible for the synthesis of a number of inflammatory mediators. inflammatory mediators. PenicillinPenicillin cures certain bacterial infections cures certain bacterial infections disrupt the synthesis of cell walls in susceptible disrupt the synthesis of cell walls in susceptible bacterial strains by inhibiting a key enzyme.bacterial strains by inhibiting a key enzyme.

PharmacotherapeuticsPharmacotherapeutics -- use of drugs use of drugs to treat to treat disordersdisorders; the emphasis is on clinical ; the emphasis is on clinical management management PharmacoepidemiologyPharmacoepidemiology -- study of the effect study of the effect of drugs on of drugs on populationspopulations; questions dealing with ; questions dealing with the influence of the influence of geneticsgenetics are particularly are particularly important important PharmacoeconomicsPharmacoeconomics -- study of the coststudy of the cost--effectiveness of drug treatments; the effectiveness of drug treatments; the costcost of of medications is of worldwide concern, particularly medications is of worldwide concern, particularly among certain groups such as the elderly and among certain groups such as the elderly and AIDS patients AIDS patients

Some Pharmacology Definitions

and Areas of Study

Pharmacokinetics Pharmacokinetics Study the Study the fatefate of drugs once ingested and the of drugs once ingested and the variability of drug response in varying patient variability of drug response in varying patient populationspopulationsHow the body How the body absorbs, distributes, absorbs, distributes, metabolizes, and excretes drugsmetabolizes, and excretes drugsCalculation of various rates brings a Calculation of various rates brings a quantitative component to assessing drug quantitative component to assessing drug actionaction

PharmacodynamicsPharmacodynamicsStudy the Study the mechanismsmechanisms by which drugs workby which drugs workAlso study endogenous agentsAlso study endogenous agents

Pharmacokinetics PrinciplesPharmacokinetics PrinciplesMovement of drugs in the bodyMovement of drugs in the bodyAbsorptionAbsorptionDistributionDistributionEliminationEliminationDosage regimensDosage regimens

PharmacodynamicPharmacodynamic PrinciplesPrinciplesReceptor typeReceptor typeDrugDrug--receptor interactionsreceptor interactionsGraded doseGraded dose--response relationshipsresponse relationshipsQuantalQuantal dosedose--response relationshipsresponse relationshipsDrugDrug--drug antagonismdrug antagonism

Binding StudiesBinding StudiesAssociation to receptorAssociation to receptorDissociation from receptorDissociation from receptorForces of bindingForces of binding

CovalentCovalentElectrostaticElectrostaticHydrophobicHydrophobic

Clearance Clearance AdsorptionAdsorptiontt1/21/2

Steps in Manufacture of DrugsSteps in Manufacture of Drugs

Scientific Research to Scientific Research to discover/synthesizediscover/synthesize new new compounds, or improve existing compounds compounds, or improve existing compounds (R & D)(R & D)

Computer simulationComputer simulationCombinatorial chemistryCombinatorial chemistry

Develop Develop safesafe and and effectiveeffective applications of applications of promising compoundspromising compoundsScreenScreen compounds in bacterial cultures or compounds in bacterial cultures or animal subjectsanimal subjectsClinical trialsClinical trials on humanson humans

Clinical TrialsClinical TrialsKidneys and liver are two most important organsKidneys and liver are two most important organs

In In Phase I trialsPhase I trials, researchers test a new drug or treatment in a , researchers test a new drug or treatment in a small group of people (20small group of people (20--80) for the first time to evaluate its 80) for the first time to evaluate its safetysafety, determine a safe dosage range, and identify side effects. , determine a safe dosage range, and identify side effects.

In In Phase II trialsPhase II trials, the study drug or treatment is given to a , the study drug or treatment is given to a larger group of people (100larger group of people (100--300) to see if it is 300) to see if it is effectiveeffective and to and to further evaluate its safety. further evaluate its safety.

In In Phase III trialsPhase III trials, the study drug or treatment is given to large , the study drug or treatment is given to large groups of people (1,000groups of people (1,000--3,000) to confirm its 3,000) to confirm its effectivenesseffectiveness, , monitor side effectsmonitor side effects, compare it to commonly used treatments, , compare it to commonly used treatments, and collect information that will allow the drug or treatment toand collect information that will allow the drug or treatment to be be used safely. used safely.

In In Phase IV trialsPhase IV trials, , post marketing studiespost marketing studies delineate additional delineate additional information including the information including the drug's risks, benefits, and optimal usedrug's risks, benefits, and optimal use. .

Purpose of Drug TherapyPurpose of Drug Therapy“…“… to prevent, control or cure various to prevent, control or cure various disease states.disease states.””To achieve this, the right drug dose must To achieve this, the right drug dose must be delivered to the tissuesbe delivered to the tissuesImportant to knowImportant to know……

Speed of onset of drug actionSpeed of onset of drug actionIntensity of drug effectIntensity of drug effectDuration of drug actionDuration of drug action

A Graphical Example:A Graphical Example:

Time in Hours

Dru

g C

once

ntra

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⎬Therapeutic

RangeSub-

Therapeutic

LethalDose

Peak Onset

Duration

How Do We Study How Do We Study Pharmacology?Pharmacology?

General ConceptsGeneral ConceptsDrug Dose

Administration

Drug Effector Response

Pharmaceutical

Pharmacokinetics

Pharmacodynamics

Pharmacotherapeutics

Disintegrationof Drug

Absorption/distributionmetabolism/excretion

Drug/ReceptorInteraction

Routes of Drug DeliveryRoutes of Drug DeliveryParenteral

(IV)Inhaled

Oral

Transdermal

Rectal

TopicalParenteral(SC, IM)

What Happens After Drug What Happens After Drug Administration?Administration?

Drug at site Drug at site of administrationof administration

Drug in plasmaDrug in plasma

Drug/metabolitesDrug/metabolitesin urine, feces, bilein urine, feces, bile

Drug/metabolitesDrug/metabolites

in tissuesin tissues

1. Absorption

2. Distribution

4. Elimination

3. Metabolism

Modified from Mycek et al. (1997)

Movement of Drug in the BodyMovement of Drug in the BodyPassive diffusionPassive diffusion

Occurs across lipid membranesOccurs across lipid membranesRequires some degree of lipid solubilityRequires some degree of lipid solubility

Lipid solubility is determined in part by the Lipid solubility is determined in part by the electrical charge on the molecule.electrical charge on the molecule.Majority of drugs are weak acid or weak bases.Majority of drugs are weak acid or weak bases.The charge is determined by the pH of the The charge is determined by the pH of the medium according to the medium according to the HendersonHenderson--HasselbalchHasselbalch equation:equation:

Log (Log (protonatedprotonated form/form/unprotonatedunprotonated form) = form) = pKapKa -- pHpH

Movement of Drug in the BodyMovement of Drug in the BodyPassive diffusionPassive diffusion

Log (Log (protonatedprotonated form/form/unprotonatedunprotonated form) = form) = pKapKa -- pHpH

ProtonatedProtonated form of a weak acidform of a weak acidUncharged, more lipid soluble formUncharged, more lipid soluble form

UnprotonatedUnprotonated form of a weak baseform of a weak baseUncharged, more lipidUncharged, more lipid--soluble formsoluble form

Movement of Drug in the BodyMovement of Drug in the BodyActive transportActive transport

Requires special carrier moleculesRequires special carrier moleculesDrugs should be structurally related to Drugs should be structurally related to endogenous molecules such as endogenous molecules such as amino acidsamino acids or or sugarssugarsSome very Some very largelarge or very or very polarpolar drugs (drugs (vitamin vitamin BB1212, Iron, Iron) are ) are complexedcomplexed with proteins and with proteins and actively transported into cells by actively transported into cells by endocytosisendocytosis..Very Very small moleculessmall molecules ((lithium, alcohols, lithium, alcohols, gasesgases) diffuse rapidly.) diffuse rapidly.

Drug AbsorptionDrug AbsorptionFirstFirst--pass effectpass effectBioavailabilityBioavailability

FirstFirst--pass effectpass effectRefers to the Refers to the elimination elimination that occurs when a that occurs when a drug is first absorbed from the drug is first absorbed from the intestine intestine and and passes through the passes through the liverliver via the portal via the portal circulation.circulation.Because the liver is the primary drugBecause the liver is the primary drug--metabolizing organ of the body, drugs are metabolizing organ of the body, drugs are easily metabolized have a large firsteasily metabolized have a large first--pass effect pass effect and low bioavailability.and low bioavailability.

Drug AbsorptionDrug AbsorptionBioavailability (Bioavailability (F F ))

Describe the fraction of an administered Describe the fraction of an administered dosedose of of unchanged drug that reaches the unchanged drug that reaches the systemic circulationsystemic circulation..By definition, when a medication is administered By definition, when a medication is administered intravenouslyintravenously, its , its bioavailability is 100%.bioavailability is 100%.However, when a medication is administered via However, when a medication is administered via other other routesroutes (such as orally), its bioavailability decreases (such as orally), its bioavailability decreases (due to incomplete absorption and (due to incomplete absorption and firstfirst--pass pass metabolismmetabolism). ). Bioavailability is one of the essential tools in Bioavailability is one of the essential tools in pharmacokinetics, as bioavailability must be considered pharmacokinetics, as bioavailability must be considered when calculating dosages for nonwhen calculating dosages for non--intravenous routes of intravenous routes of administration. administration.

An Important Concept:An Important Concept:BIOAVAILABIITYBIOAVAILABIITY

Definition:Definition:Fraction of a drug that Fraction of a drug that reaches systemic reaches systemic circulation after a particular circulation after a particular route of administrationroute of administration

Affected by:Affected by:1st pass metabolism 1st pass metabolism ((egeg: : LidocaineLidocaine, , propranololpropranolol))SolubilitySolubilityInstability Instability ((egeg: : Penicillin G, insulinPenicillin G, insulin))

Seru

m C

once

ntra

tion

Time

Injected Dose

Oral Dose

An Important Concept:An Important Concept:BIOAVAILABIITYBIOAVAILABIITY

Factors Affecting Drug Factors Affecting Drug AbsorptionAbsorption

TransportTransportActive vs. passiveActive vs. passive

pHpHPhysical factorsPhysical factors

Blood flowBlood flowSurface areaSurface areaContact timeContact time

ATP

ADP+ Pi

A-

BH+

Drug DistributionDrug DistributionBlood flow to the tissueBlood flow to the tissueSize of the organSize of the organSolubility of the drugSolubility of the drugBindingBindingVolume of distributionVolume of distribution

Drug DistributionDrug DistributionBlood flow to the tissueBlood flow to the tissue

Tissues with high blood flow (Tissues with high blood flow (viscera, brain, viscera, brain, musclemuscle) receive significant amount of drug on a ) receive significant amount of drug on a short time.short time.Organs with low perfusion (Organs with low perfusion (fat, bonefat, bone) receive ) receive the drug more slowly.the drug more slowly.

Size of the organSize of the organVery large organs (Very large organs (egeg., ., skeletal muscleskeletal muscle) can ) can take up large quantities of drug if allowed to take up large quantities of drug if allowed to reach steady state.reach steady state.

Drug DistributionDrug DistributionBindingBinding

Drugs that bind to macromolecules in a tissue Drugs that bind to macromolecules in a tissue may be restricted in distribution.may be restricted in distribution.

For example, drugs that bind avidly to plasma For example, drugs that bind avidly to plasma albuminalbumin ((egeg. . WarfarinWarfarin) may be effectively restricted ) may be effectively restricted to the vascular compartment.to the vascular compartment.

Volume of distribution (Volume of distribution (VVdd))VVdd of a drug is a proportionality constant of a drug is a proportionality constant defined as:defined as:

VVdd = amount of drug in the body/plasma concentration= amount of drug in the body/plasma concentration

Volume of Drug DistributionVolume of Drug Distribution

Drugs may distribute Drugs may distribute into any or all of the into any or all of the following compartments:following compartments:

PlasmaPlasmaInterstitial FluidInterstitial FluidIntracellular FluidIntracellular Fluid

Plasma(4 litres)

Interstitial Fluid(10 litres)

Intracellular Fluid(28 litres)

What Factors Affect Distribution?What Factors Affect Distribution?

Blood flowBlood flowBrain vs. fatBrain vs. fat

Capillary permeabilityCapillary permeabilityDifferences in capillary Differences in capillary structurestructure

Binding to proteinsBinding to proteinsRole of albuminRole of albumin

Endothelial cellsin liver capillary

Endothelial cellsin brain capillary Glial cell

More More ““So What?So What?””It takes time for a drug to distribute in the It takes time for a drug to distribute in the bodybodyDrug distribution is affected by eliminationDrug distribution is affected by elimination

Time

Seru

m C

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0

0.5

1.0

1.5

0

Elimination Phase

Distribution Phase Drug is eliminated

Drug is not eliminated

Albumin Affects DistributionAlbumin Affects DistributionDrugs bind Drugs bind differentially to differentially to albumin albumin 2 drug classifications:2 drug classifications:

Class IClass I: dose less : dose less than available binding than available binding sites (sites (egeg: most drugs): most drugs)Class IIClass II: dose greater : dose greater than binding sites than binding sites ((egeg: : sulfonamidesulfonamide))

The problem:The problem:One drug may outOne drug may out--compete the othercompete the other Sulfonamide

Drug X

Albumin

Drug MetabolismDrug Metabolism

First passFirst passMetabolism of drugs may occur as they cross Metabolism of drugs may occur as they cross the intestine or transit the liverthe intestine or transit the liver

egeg: : NitroglycerinNitroglycerin

Other drugs may be destroyed before Other drugs may be destroyed before absorptionabsorption

egeg: : PenicillinPenicillin

Such reactions decrease delivery to the Such reactions decrease delivery to the target tissuestarget tissues

Drug Metabolism (contDrug Metabolism (cont’’d)d)

Two Phases: I and IITwo Phases: I and IIPhase I: conversion to Phase I: conversion to lipophiliclipophilic compoundscompoundsPhase II: Phase II: conjugationconjugation

Phase I involves the Phase I involves the cytochromecytochrome PP--450 450 systemsystemUltimate effect is to Ultimate effect is to facilitate eliminationfacilitate elimination

Drug

Phase I

Phase II

OxidationReductionHydrolysis

Activation/Inactivation

Conjugation Products

Glucuronidation

Example of First Pass EffectExample of First Pass Effect

Drug EliminationDrug Elimination

Most important route is the kidneyMost important route is the kidney

May also involve bile, intestine, lung, breast May also involve bile, intestine, lung, breast milkmilk

What clinical scenarios may affect drug What clinical scenarios may affect drug elimination?elimination?

Drug EliminationDrug EliminationMetabolites of drugs must eventually be Metabolites of drugs must eventually be excreted, but termination of action is of excreted, but termination of action is of greater importance.greater importance.

The vast majority drugs follow firstThe vast majority drugs follow first--order order elimination kineticselimination kinetics

The rate of elimination is proportionate to plasma The rate of elimination is proportionate to plasma concentration.concentration.

Drug EliminationDrug EliminationOnly three clinically important drugs follow Only three clinically important drugs follow zerozero--order elimination kineticsorder elimination kinetics

EthanolEthanolPhenytoinPhenytoin (high dose)(high dose)Aspirin (high dose)Aspirin (high dose)

The rate of elimination isfixed and independent ofplasma concentration.

Drug EliminationDrug EliminationThe elimination of drugs that follow The elimination of drugs that follow firstfirst--order kineticsorder kinetics can be characterized by a can be characterized by a proportionality constant, proportionality constant, clearanceclearance, , ClCl..Clearance is defined as:Clearance is defined as:ClCl = rate of elimination/plasma concentration= rate of elimination/plasma concentration

Drug EliminationDrug EliminationFor elimination For elimination halfhalf--lifelife (t(t1/21/2) of drugs that follow ) of drugs that follow firstfirst--order kinetics is defined as the order kinetics is defined as the timetime required required (after distribution is complete) for the (after distribution is complete) for the amount amount of of drug in any compartment to drug in any compartment to fall by 50%.fall by 50%.HalfHalf--life can be derived from graphs of plasma life can be derived from graphs of plasma concentration versus tine, concentration versus tine, otot it can also be it can also be obtained by calculation:obtained by calculation:

TT1/21/2 = 0.693 x = 0.693 x Vd/ClVd/ClAfter 4 half lives, elimination is 94% complete.After 4 half lives, elimination is 94% complete.

Concept of Concept of ““HalfHalf--LifeLife””

Time required to metobolize 1/2 of Time required to metobolize 1/2 of the original dose of the drugthe original dose of the drugUse of this terms helps in determining Use of this terms helps in determining how long a drug will remain in the how long a drug will remain in the bodybody

Elimination of a drug is usually Elimination of a drug is usually linked to renal filtration, linked to renal filtration,

secretion and secretion and reabsorptionreabsorption..

Example: Intravenous InfusionsExample: Intravenous Infusions

Plasma concentration Plasma concentration rises until rises until elimination = inputelimination = inputFaster infusions get Faster infusions get more drugs on more drugs on board, but does not board, but does not change the time to change the time to achieve a steady achieve a steady statestate Pl

asm

a C

once

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tion

Time

Slow Infusion

Fast Infusion

Time at whichsteady state is achieved

Example: Intravenous InjectionExample: Intravenous Injection

Peak plasma Peak plasma concentration of the concentration of the drug is achieved at drug is achieved at time = 0time = 0There is no steady There is no steady state concentration. state concentration. Why?Why?

Plas

ma

Con

cent

ratio

n

Time

100 mg injected

50 mg injected

Example: Oral DoseExample: Oral DoseA single oral dose A single oral dose will give you a will give you a single peak plasma single peak plasma concentrationconcentrationThe drug The drug concentration then concentration then continuously continuously declinesdeclinesRepeated doses Repeated doses result in oscillations result in oscillations in plasma in plasma concentrationconcentration

Plas

ma

Con

cent

ratio

n

Time

Aerosolized Agents: 7 CategoriesAerosolized Agents: 7 Categories

Adrenergic AgentsAdrenergic AgentsAnticholinergic AgentsAnticholinergic AgentsMucoactive agentsMucoactive agentsCorticosteroidsCorticosteroidsAntiasthmaticsAntiasthmaticsAntiinfectivesAntiinfectivesExogenous SurfactantsExogenous Surfactants

Adrenergic AgentsAdrenergic AgentsActionAction -- stimulation of sympathetically stimulation of sympathetically mediated bronchorelaxation of smooth mediated bronchorelaxation of smooth musclemuscle

Examples: Examples: Epinephrine; Isoetharine; Epinephrine; Isoetharine; Isoproterenol; Metaproterenol; Albuterol; Isoproterenol; Metaproterenol; Albuterol; Pibuterol; Bitolterol; SalmeterolPibuterol; Bitolterol; Salmeterol

AntiAnti--cholinergic Agentscholinergic Agents

Blockage of vagallyBlockage of vagally--induced induced bronchospasm bronchospasm

This results in bronchorelaxationThis results in bronchorelaxationExample: Example: Iptratroprium bromideIptratroprium bromide

Mucoactive AgentsMucoactive Agents

Improve viscosity of mucus and Improve viscosity of mucus and enhance clearance of secretionsenhance clearance of secretions

Examples: Examples: AcetylcysteineAcetylcysteine, , DornaseDornasealphaalpha

CorticosteroidsCorticosteroids

Reduce and control inflammatory Reduce and control inflammatory response associated with asthma and response associated with asthma and other lung diseasesother lung diseases

Examples: Examples: Dexamethasone; Dexamethasone; Beclamethasone; Triamcinolone; Beclamethasone; Triamcinolone; FlunisolideFlunisolide

AntiAnti--asthmatic Agentsasthmatic AgentsPrevention of the inflammatory Prevention of the inflammatory response seen in asthma by inhibition response seen in asthma by inhibition of chemical mediators necessary for of chemical mediators necessary for inflammation to occurinflammation to occur

CorticosteroidsCorticosteroidsPrednisolonePrednisolone, , BetamethasoneBetamethasone, etc., etc.

BetaBeta--2 agonists (bronchodilators)2 agonists (bronchodilators)SamleterolSamleterol, , BambuterolBambuterol, etc., etc.

AntiAnti--asthmatic Agentsasthmatic AgentsPrevention of the inflammatory Prevention of the inflammatory response seen in asthma by inhibition response seen in asthma by inhibition of chemical mediators necessary for of chemical mediators necessary for inflammation to occurinflammation to occur

AntiAnti--leukotrienesleukotrienesMontelukastMontelukast, , ZafirleukastZafirleukast

XanthinesXanthinesTheophyllineTheophylline

AntiAnti--infective Agentsinfective Agents

To inhibit or kill selected bacterial, To inhibit or kill selected bacterial, protozoal, fungal or viral organismsprotozoal, fungal or viral organisms

Examples: Examples: PentamidinePentamidine, , RibavirinRibavirin

Exogenous SurfactantsExogenous Surfactants

Used by instillation in the tracheas of Used by instillation in the tracheas of premature newborns suffering from premature newborns suffering from respiratory distress syndromerespiratory distress syndrome

Examples: Examples: BeractantBeractant, , ColfoscerilColfoscerilpalmitatepalmitate

Drug dosage formsDrug dosage forms

OralOralInjectable (parenteral)Injectable (parenteral)

SubcutaneousSubcutaneousIntramuscularIntramuscularIntravenousIntravenousSpinalSpinal

TopicalTopicalInhalationalInhalational

Concept of Critical ThresholdConcept of Critical Threshold

Defined as the Defined as the minimumminimum level of level of drug concentration needed for the drug concentration needed for the desired therapeutic effect to be desired therapeutic effect to be present.present.

Other DoseOther Dose--related Termsrelated Terms

Maximal Effect:Maximal Effect: greatest response that can greatest response that can be produced by a drug, above which no be produced by a drug, above which no further response can be created further response can be created (sometimes called (sometimes called ““peak effectpeak effect””Onset:Onset: how long before a drug is able to how long before a drug is able to exert a therapeutic effectexert a therapeutic effectDurationDuration: how long a drug effect lasts: how long a drug effect lasts

Agonists and AntagonistsAgonists and AntagonistsAn An agonistagonist causes a particular effect by causes a particular effect by binding to the correct binding to the correct ““receptorreceptor””

What is an What is an ““antagonistantagonist””??

An agent that blocks are reverses the An agent that blocks are reverses the actions of another medication.actions of another medication.

Concept of PotencyConcept of PotencyComparison of different drugs at the Comparison of different drugs at the same same dosedose to determine which is stronger.to determine which is stronger.