Basic Principles of Basic Principles of

PharmacologyPharmacology Prof. Suheil ZmeiliProf. Suheil ZmeiliFaculty of MedicineFaculty of Medicine

Department of PharmacologyDepartment of PharmacologyUniversity of JordanUniversity of Jordan

** Pharmacology** Pharmacology Pharmakon = Drug; Logos = Pharmakon = Drug; Logos =

ScienceScienceThe study of drugs and their interactions The study of drugs and their interactions

with living systemswith living systemsWide term which includes:Wide term which includes:- The investigation of the biochemical and The investigation of the biochemical and

physiological effects of drugsphysiological effects of drugs- The study of drug absorption; The study of drug absorption;

distribution; metabolism and excretiondistribution; metabolism and excretion- The knowledge about the history; sources; The knowledge about the history; sources;

physical and chemical properties and physical and chemical properties and therapeutic uses of drugstherapeutic uses of drugs

** Drug** Drug

- A chemical substance that is - A chemical substance that is primarily used to reverse a primarily used to reverse a pathophysiological defect = pathophysiological defect = diseasedisease

= Virtually all chemicals may be = Virtually all chemicals may be drugsdrugs

= All drugs are toxins but not all = All drugs are toxins but not all toxins are drugstoxins are drugs

HumanMan; Woman

Pathophysiological Process=Disease

ManagementDrugs

FDA approved definition of drugsFDA approved definition of drugsA chemical substance that is mainly A chemical substance that is mainly

used to treat, control, prevent, or used to treat, control, prevent, or diagnose a specific disease or to diagnose a specific disease or to prevent pregnancy!!!prevent pregnancy!!!

Chemical nature of drugsChemical nature of drugs- Acidic; Aspirin, barbiturates...etc- Acidic; Aspirin, barbiturates...etc- Basic or alkaline; Morphine, - Basic or alkaline; Morphine,

Atropine, Alkaloids...etcAtropine, Alkaloids...etc- Neutral; Steroids- Neutral; Steroids

MAJOR OBJECTIVEMAJOR OBJECTIVE

TO HAVE DRUG AT SITE OF TO HAVE DRUG AT SITE OF ACTION IN PROPER ACTION IN PROPER

CONCENTRATION GOOD CONCENTRATION GOOD ENOUGH TO REVERSE DEFECT ENOUGH TO REVERSE DEFECT WITHOUT PRODUCING SIDE OR WITHOUT PRODUCING SIDE OR

TOXIC EFFECTS TOXIC EFFECTS

Drug discovery and Drug discovery and pharmaceutical processpharmaceutical process

Hypothesis=Idea

Assessment of efficacyIn vitro & in vivo studies

Assessment of safety

PharmaceuticalProcess Kinetics

Administration

• Pharmaceutical process; drug in dosage form:Pharmaceutical process; drug in dosage form:Is the drug getting into patient?Is the drug getting into patient?• Pharmacokinetic process:Pharmacokinetic process:Is the drug getting to its site of action?Is the drug getting to its site of action?• Pharmacodynamic process:Pharmacodynamic process:Is the drug producing the required pharmacological Is the drug producing the required pharmacological

effect?effect?• Therapeutic process (clinical pharmacology):Therapeutic process (clinical pharmacology):Is the pharmacological effect being translated into Is the pharmacological effect being translated into

therapeutic effect?therapeutic effect?• PhrmacogeneticsPhrmacogeneticsIndividual variations in responding to drugs + gene Individual variations in responding to drugs + gene

therapytherapy

Drug discovery & developmentDrug discovery & development1. Starts with prediction=an idea & 1. Starts with prediction=an idea &

hypothesishypothesisWhat helps?What helps?- Awareness of the beneficial effects of Awareness of the beneficial effects of

plants and animal products (natural plants and animal products (natural sources)sources)

- Chemical identification of a wide Chemical identification of a wide variety of natural mediators and the variety of natural mediators and the possibility of modifying them possibility of modifying them chemically chemically

e.g. epinephrine, norepinehrinee.g. epinephrine, norepinehrine acetylcholineacetylcholine histaminehistamine prostaglandinsprostaglandins endogenous opioidsendogenous opioids hormoneshormones……etcetc- Avoid chemicals with highly - Avoid chemicals with highly

reactive groups (toxic) reactive groups (toxic)

22 . .Design and synthesis of useful drugs Design and synthesis of useful drugs or substances through simple or substances through simple techniques or with the help of techniques or with the help of advanced technologyadvanced technology

e.g. a plant → fractionation, e.g. a plant → fractionation, chromatographic experiments → chromatographic experiments → identification of the active identification of the active ingredients → isolation → purification ingredients → isolation → purification → good drug (recently most drugs of → good drug (recently most drugs of plant source could be synthesized)plant source could be synthesized)

An animal → isolation of a substance An animal → isolation of a substance (insulin)(insulin)

Simple peptides → a.a sequencing Simple peptides → a.a sequencing machinemachine

Complex proteins → recombinant Complex proteins → recombinant DNA technologyDNA technology

- Receptology studiesReceptology studies

Allowed synthesis of huge number Allowed synthesis of huge number of agonists and antagonistsof agonists and antagonists

3. Preclinical studies3. Preclinical studiesStudies on tissues and whole Studies on tissues and whole

animalsanimals- Determine efficacyDetermine efficacyIsolated tissue e.g. bronchi → Isolated tissue e.g. bronchi →

organ path → testing drug…etcorgan path → testing drug…etcAnimal models Animal models → → drug ↓ BPdrug ↓ BP→ → drug ↓ blood sugar leveldrug ↓ blood sugar level

- Determine pharmacokinetic parametersDetermine pharmacokinetic parametersAbsorption, distribution, metabolismAbsorption, distribution, metabolism……

etcetc- Determine pharmacodynamics (MOA)Determine pharmacodynamics (MOA)- Assessment of drug toxicity=safetyAssessment of drug toxicity=safety. Acute toxicity studies. Acute toxicity studiesDetermination of LD50; Margin of Determination of LD50; Margin of

safety…etcsafety…etc. Subacute and chronic toxicity studies. Subacute and chronic toxicity studiesRepeated dose studiesRepeated dose studies

Daily observation of animals Daily observation of animals (wt., food and water intake ..)(wt., food and water intake ..)

Obtaining biological samples Obtaining biological samples (blood; urine)(blood; urine)

Obtaining tissues (liver; Obtaining tissues (liver; spleen; stomachspleen; stomach……etc) for etc) for histopathological exam or histopathological exam or studiesstudies

- Special toxicology studiesSpecial toxicology studies

. Mutagenicity (genotoxicity) tests. Mutagenicity (genotoxicity) tests

Could delineate the induction of Could delineate the induction of gene mutations (bacterial gene mutations (bacterial mutagenicity test or mutagenicity test or administration of drug to administration of drug to pregnant animalspregnant animals……etc)etc)

Some mutations could result in the Some mutations could result in the development of cancerdevelopment of cancer

. Carcinogenicity studies. Carcinogenicity studies

Not always required prior to early Not always required prior to early studies in man unless there is a high studies in man unless there is a high suspicion that the drug could be suspicion that the drug could be carcinogenic e.g. suspicion of carcinogenic e.g. suspicion of mutagenicity; highly reactive groups on mutagenicity; highly reactive groups on drug; histopathological abnormalitiesdrug; histopathological abnormalities……

Required if the use of drug in man for Required if the use of drug in man for more than one year or +ve mutagenic more than one year or +ve mutagenic test test

Clinical drug trials ( mainly 4 phases)Clinical drug trials ( mainly 4 phases)- Phase 0- Phase 0Phase 0 or first-in-human trials is a Phase 0 or first-in-human trials is a

recent phase approved in accordance recent phase approved in accordance with the United States FDA’s 2006 with the United States FDA’s 2006 GuidelinesGuidelines

Phase 0 trials are also known as human Phase 0 trials are also known as human microdosing studies and are designed to microdosing studies and are designed to speed up the development of promising speed up the development of promising drugs by establishing very early on whether drugs by establishing very early on whether the drug or agent behaves in human the drug or agent behaves in human subjects as was expected from preclinical subjects as was expected from preclinical studiesstudies

Distinctive features of Phase 0 trials Distinctive features of Phase 0 trials include the administration of single include the administration of single subtherapeutic doses of the study drug to subtherapeutic doses of the study drug to a small number of subjects (10 to 15) to a small number of subjects (10 to 15) to gather preliminary data on the agent's gather preliminary data on the agent's pharmacokinetics and pharmacodynamics pharmacokinetics and pharmacodynamics

A Phase 0 study gives no data on safety or A Phase 0 study gives no data on safety or efficacy, being by definition a dose too low efficacy, being by definition a dose too low to cause any therapeutic effect. Drug to cause any therapeutic effect. Drug development companies carry out Phase 0 development companies carry out Phase 0 studies to rank drug candidates in order studies to rank drug candidates in order to decide which has the best to decide which has the best pharmacokinetic parameters in humans pharmacokinetic parameters in humans to take forward into further development to take forward into further development

Phase 0 studies enable go/no-go Phase 0 studies enable go/no-go decisions to be based on relevant decisions to be based on relevant human models instead of relying on human models instead of relying on sometimes inconsistent animal datasometimes inconsistent animal data

Questions have been raised by Questions have been raised by experts about whether Phase 0 experts about whether Phase 0 trials are useful, ethically trials are useful, ethically acceptable, feasible, speed up the acceptable, feasible, speed up the drug development process or save drug development process or save money, and whether there is room money, and whether there is room for improvementfor improvement

- Phase IPhase I

Involves the use of a drug in Involves the use of a drug in humans for the first timehumans for the first time

It establishes dose level at which It establishes dose level at which signs of toxicity first appearsigns of toxicity first appear

Conducted on 20-80 Conducted on 20-80 healthyhealthy men men with ages 18-45 yrswith ages 18-45 yrs

Usually a single dose is used initially and Usually a single dose is used initially and if no side effects exhibited, the dose is if no side effects exhibited, the dose is increased progressively until sufficient increased progressively until sufficient serum level is achieved (therapeutic serum level is achieved (therapeutic level) or some toxic effects appearlevel) or some toxic effects appear

Such studies are conducted in hospitalSuch studies are conducted in hospitalIf no side effects result from single dose, If no side effects result from single dose,

multiple dose studies should be initiatedmultiple dose studies should be initiated=bioavailability-bioequivalence studies=bioavailability-bioequivalence studies

- Phase IIPhase IIIf phase I studies prove that the drug If phase I studies prove that the drug

is safe to continue, the new drug is is safe to continue, the new drug is administered to administered to patientspatients for the first for the first timetime

All patients should have only one All patients should have only one problem (one disease)problem (one disease)

It assesses efficacy and establishes It assesses efficacy and establishes optimal dose range in patients (dose-optimal dose range in patients (dose-response studies are important)response studies are important)

Phase II studies are conducted on 80-100 Phase II studies are conducted on 80-100 patients (certain countries ask for 50-patients (certain countries ask for 50-300 patients)300 patients)

Also patients are observed for toxicity to Also patients are observed for toxicity to assess safety of the drugassess safety of the drug

- Phase III- Phase IIISimilar to phase II but conducted on large Similar to phase II but conducted on large

number of patients (several hundreds to number of patients (several hundreds to thousands; 250-1000 reasonable)thousands; 250-1000 reasonable)

It also assesses safety and efficacyIt also assesses safety and efficacyCould detect effects/side effects not Could detect effects/side effects not

observed in phase IIobserved in phase II

- Phase IVPhase IV

Post-marketing studiesPost-marketing studies

Controlled and uncontrolled studies are Controlled and uncontrolled studies are often conducted after drug approval often conducted after drug approval and marketingand marketing

It further assesses safety & efficacy of It further assesses safety & efficacy of drugsdrugs

It allows for comparisons between It allows for comparisons between different drugs used for the same different drugs used for the same diseasedisease

In addition, phase IV studies In addition, phase IV studies provide evidence of a new use to provide evidence of a new use to the drug e.g. the drug e.g.

aspirin-antiplateletaspirin-antiplatelet

sildenafil citrate-EDsildenafil citrate-ED

Double-blind; single-blind placebo Double-blind; single-blind placebo controlled studies are usually controlled studies are usually conductedconducted

AFTER ALL THESE CLINICAL DRUG AFTER ALL THESE CLINICAL DRUG

TRIALS THE DRUG IS USUALLYTRIALS THE DRUG IS USUALLY

APPROVED BY NATIONAL ORAPPROVED BY NATIONAL OR

INTERNATIONAL REGULATORY INTERNATIONAL REGULATORY

AUTHORITIES AND IS LICENSED AUTHORITIES AND IS LICENSED FORFOR

GENERAL PRESCRIBING GENERAL PRESCRIBING

Ethics of the use of drugs in Ethics of the use of drugs in humanshumans

• Full detailed protocol has to be Full detailed protocol has to be approved by the ethical committee, approved by the ethical committee, the institutional review board (IRB)the institutional review board (IRB)

• All subjects should sign an All subjects should sign an informed consent forminformed consent form

• All subjects should be insured for All subjects should be insured for life and damage life and damage

** Branches of pharmacology usually ** Branches of pharmacology usually answer all of the following questions:answer all of the following questions:

- How much of a drug to give? DoseHow much of a drug to give? Dose- How frequent a drug should be given? How frequent a drug should be given?

Related to the biological half-life (tRelated to the biological half-life (t1/21/2))- When to give it? Before or after meals; When to give it? Before or after meals;

at bed time, PRN...at bed time, PRN...- How to give it? administration ... etc How to give it? administration ... etc

** Administration** Administration (Routes) = Systemic or local (Routes) = Systemic or local

- Oral (tablets [IR; SR)], syrups, susp...), - Oral (tablets [IR; SR)], syrups, susp...), - Parenteral route = Subcutaneous S.C - Parenteral route = Subcutaneous S.C

(solution), intramuscular I.M (sol.) (solution), intramuscular I.M (sol.) intravenous = I.V (sol.); depo-injectableintravenous = I.V (sol.); depo-injectable

- Buccal (tab.) sublingual (tab.) rectal - Buccal (tab.) sublingual (tab.) rectal (suppositories)(suppositories)

- Transdermal (patches); subdermal implants- Transdermal (patches); subdermal implants

- Inhalational (sprays)- Inhalational (sprays)

** Topical = local administration** Topical = local administration - Liquid forms (sprays, lotions, Liquid forms (sprays, lotions,

solutions = ear or ophthalmic solutions = ear or ophthalmic drops, mouth washes, S.C drops, mouth washes, S.C infiltration e.g. local anesthetics...)infiltration e.g. local anesthetics...)

- Semisolid forms (creams, Semisolid forms (creams, ointments...)ointments...)

- Solid forms (suppositories, Solid forms (suppositories, pessaries = vaginal tablet...)pessaries = vaginal tablet...)

Factors affecting the doseFactors affecting the dose- AgeAge- WeightWeight- Route of administrationRoute of administration- SexSexFactors affecting administrationFactors affecting administration- Physicochemical properties of drugsPhysicochemical properties of drugs- Site of actionSite of action- Status of patientStatus of patient- Dosage intervalDosage interval

Drug sources:Drug sources:- NaturalNatural

Plants (atropine, digoxin), animals Plants (atropine, digoxin), animals (insulin), human (growth (insulin), human (growth hormone)hormone)

- Semisynthetic (human insulin)Semisynthetic (human insulin)- Synthetic (agonists; antagonists)Synthetic (agonists; antagonists)

Drug nomenclature:Drug nomenclature:- Chemical name e.g. acetyl salicylic Chemical name e.g. acetyl salicylic

acidacid- Generic name; nonproprietary; official; Generic name; nonproprietary; official;

approved name... Aspirin (most widely approved name... Aspirin (most widely used in pharmacology)used in pharmacology)

- Official name... Aspirin BP; Aspirin Official name... Aspirin BP; Aspirin USPUSP

- Trade name; Proprietary; brand name Trade name; Proprietary; brand name RemineRemine®®; Bufferin; Bufferin®®...etc...etc

** Pharmacokinetic process** Pharmacokinetic process

It is the study of what the body It is the study of what the body does to a drugdoes to a drug

It includes the processes:It includes the processes:- AbsorptionAbsorption- DistributionDistribution- MetabolismMetabolism- Excretion = eliminationExcretion = elimination

Drug absorptionDrug absorption

Passage of drug from site of administration Passage of drug from site of administration to circulation and then distributes to to circulation and then distributes to reach its target organ (site of action)reach its target organ (site of action)

Behavior of drugs in the plasma:Behavior of drugs in the plasma:

- - BioavailabilityBioavailability::

The fraction of the given dose that gets The fraction of the given dose that gets into bloodinto blood

The bioavailability of an I.V given drug is The bioavailability of an I.V given drug is 100% 100%

- - Protein bindingProtein binding:: Represents: Represents: - A reservoir to the drugA reservoir to the drug- A mean by which drug reaches its site of A mean by which drug reaches its site of

actionaction- A major site of drug-drug interactionsA major site of drug-drug interactionsStrongly bound drugs to blood proteins remain Strongly bound drugs to blood proteins remain

longer in blood, have longer tlonger in blood, have longer t1/2 1/2 & DOA& DOA** The free form of the drug, is the form which ** The free form of the drug, is the form which

is active and crosses membranesis active and crosses membranes(e.g. 50% of a given drug is albumin bound, (e.g. 50% of a given drug is albumin bound,

means that 50% of the drug which is present means that 50% of the drug which is present in plasma is albumin bound)in plasma is albumin bound)

Sites of drug absorption:Sites of drug absorption:- Oral mucosa (buccal; sublingual Oral mucosa (buccal; sublingual

tab.)tab.)- Stomach (aspirin)Stomach (aspirin)- Intestine (iron; vit. BIntestine (iron; vit. B1212))- Lungs (general anesthetics)Lungs (general anesthetics)- Rectum (suppositories)Rectum (suppositories)- Skin (local preparations)Skin (local preparations)

Factors affecting absorption:Factors affecting absorption:- Drug size (Most drugs have MW’s Drug size (Most drugs have MW’s

between 100 and 1,000)between 100 and 1,000)- Lipid solubility (major factor)Lipid solubility (major factor)Lipid/water partition coefficientLipid/water partition coefficient- Degree of ionization or environmental Degree of ionization or environmental

pH:pH:

Henderson-Hasselbalch EquationHenderson-Hasselbalch EquationpH = pKa + log [ApH = pKa + log [A--]/[HA]]/[HA]pH = pKb + log [BOH]/[BpH = pKb + log [BOH]/[B++]]

Polar groups: O; NOPolar groups: O; NO22; COOH; OH...etc; COOH; OH...etcNon polar groups: - S; halogens; ChNon polar groups: - S; halogens; Ch33; ;

Non polar (unionized; lipid soluble) Non polar (unionized; lipid soluble)

form crosses membranesform crosses membranesPolar (ionized; water soluble form is Polar (ionized; water soluble form is

the pharmacologically active formthe pharmacologically active form

Example:Example:

Sulfanilamide Sulfathiazole Sulfanilamide Sulfathiazole SulfacetamideSulfacetamide

pKa 10 pKa 7 pKa 10 pKa 7 pKa 6pKa 6

At pH 7At pH 7- nilamide 0.1% I 99.9% NInilamide 0.1% I 99.9% NI- thiazole 50% I 50% NIthiazole 50% I 50% NI- cetamide 99% I 1% NI cetamide 99% I 1% NI

Cont. factors affecting absorption:Cont. factors affecting absorption:- Concentration of drug = doseConcentration of drug = dose- Surface area of absorptionSurface area of absorption- Blood circulation to absorbing Blood circulation to absorbing

areaarea- Route of administration (I.V the Route of administration (I.V the

fastest)fastest)- Dosage formsDosage forms

Mechanisms of drug transfer across Mechanisms of drug transfer across membranes:membranes:

- Simple diffusionSimple diffusion

Crossing through water pores of membranes, Crossing through water pores of membranes, no energy or carrier required, from high to no energy or carrier required, from high to low concentration, drugs with low M.W low concentration, drugs with low M.W (must be lipid soluble and concentration (must be lipid soluble and concentration gradient is the driving force) gradient is the driving force)

DD

- Passive diffusion (major mechanism)Passive diffusion (major mechanism) Crossing through cells or the lipid Crossing through cells or the lipid

bilayer, no energy or carrier required, bilayer, no energy or carrier required, from high to low concentrationfrom high to low concentration

D D DD D D

The only requirement for passive The only requirement for passive diffusion is that the drug should be diffusion is that the drug should be lipid solublelipid soluble

- Facilitated diffusionFacilitated diffusionRequires a carrier, no energy required, from high Requires a carrier, no energy required, from high

to low concentrationto low concentration- Active transportActive transportRequires energy ± carrier, could be from low to Requires energy ± carrier, could be from low to

high concentrationhigh concentration(Facilitated diffusion and active transport follow (Facilitated diffusion and active transport follow

saturation kinetics because No. of carriers is saturation kinetics because No. of carriers is limited)limited)

- EndocytosisEndocytosis Phagocytosis (solid particles)Phagocytosis (solid particles) Pinocytosis (fluid particles)Pinocytosis (fluid particles)

Drug distributionDrug distributionPassage of drugs from blood to different Passage of drugs from blood to different

tissues (site of action) Extent of tissues (site of action) Extent of distribution could be measured by a distribution could be measured by a constant known as AVDconstant known as AVD

70 Kg man 60% H70 Kg man 60% H22O ≈ 42 litersO ≈ 42 litersPlasma extracellular fluid Plasma extracellular fluid

intracellular fluidintracellular fluid[F] [F] [F][F] [F] [F]2.8 L 10.5 L 28.7 2.8 L 10.5 L 28.7

LL

Apparent volume of distribution Apparent volume of distribution (AVD)(AVD)::The total volume in which the free form The total volume in which the free form

of a given drug distributes in different of a given drug distributes in different body compartments at equilibriumbody compartments at equilibrium

AVD = Dose (mg)/CAVD = Dose (mg)/C00 (mg/L) (mg/L)

CC0 0 == Concentration of drug in blood at Concentration of drug in blood at time zerotime zero

Highly lipid soluble drugs e.g. Highly lipid soluble drugs e.g. digoxin, have a very high Vd (500 digoxin, have a very high Vd (500 liters). liters).

Drugs which are lipid insoluble Drugs which are lipid insoluble e.g. neuromuscular blockers, e.g. neuromuscular blockers, remain in the blood, and have a remain in the blood, and have a low Vdlow Vd

Very very high Vd indicates Very very high Vd indicates extensive tissue binding extensive tissue binding

Factors affecting drug distribution:Factors affecting drug distribution:- Compartmental selectivityCompartmental selectivity- Organ selectivityOrgan selectivity- Protein binding ( Major factor)Protein binding ( Major factor)- Natural barriersNatural barriers BBB BBB Placenta Placenta Mammary glands Mammary glands

Drug metabolismDrug metabolismA change in the chemical structure of the A change in the chemical structure of the

drug, or addition of a hydrophilic groups drug, or addition of a hydrophilic groups to an initially lipophilic drug until it to an initially lipophilic drug until it becomes sufficiently ionic so as to be becomes sufficiently ionic so as to be easily filtered and excreted by the easily filtered and excreted by the kidneyskidneys

The rate of metabolism (KThe rate of metabolism (Kmm) of a given ) of a given drug depends upon the chemical drug depends upon the chemical characteristics of the drug and has characteristics of the drug and has nothing to do with the benefit or harm of nothing to do with the benefit or harm of the drugthe drug

Drug metabolism involves 2 major Drug metabolism involves 2 major pathways:pathways:

1. Pathway I1. Pathway I = Oxidation reduction = Oxidation reduction reactionsreactions

Also known as mixed function oxidase Also known as mixed function oxidase system and cytochrome Psystem and cytochrome P450450 system system (CYPs=A;B...)(CYPs=A;B...)

Examples:Examples:. Aromatic hydroxylation. Aromatic hydroxylation

R R OHR R OH

. Aliphatic hydroxylation. Aliphatic hydroxylation

R CHR CH33 R R COOHCOOH

. O-dealkylation. O-dealkylation

R-O-R-O-CHCH33 R-OH+HCHO R-OH+HCHO

. N-dealkylation. N-dealkylation HH

R-N-R-N-CHCH33 R-NH R-NH22+HCHO+HCHO

. N-oxidation; N-hydroxylation. N-oxidation; N-hydroxylation

(CH(CH33)N (CH)N (CH33))33NNOO HH

R-CHR-CH22-NH-NH22 R-CH R-CH22-N-N OHOH

. Sulfoxidation O. Sulfoxidation O S SS S N NN N. Hepatic reduction. Hepatic reductionAzo reductionAzo reduction

RR11-N=N-R-N=N-R22 R R11-NH-NH22+H+H22N-RN-R22

NitroreductionNitroreduction

R-NOR-NO22 R-NH R-NH22

- Nonmicrosomal oxidation and reductionNonmicrosomal oxidation and reductionAlcohol oxidation; chloral hydrate Alcohol oxidation; chloral hydrate

reductionreduction- Hydrolysis reactionsHydrolysis reactions

NHNH2 2 NH NH22

HH22O O Esterases +HO-Esterases +HO-

CHCH22-R-R

C-O-CHC-O-CH22-R C-R C O O OHO O OH

2. Pathway II = Conjugation reactions2. Pathway II = Conjugation reactionsAddition of certain groups to a drug to become Addition of certain groups to a drug to become

more polar and readily excretedmore polar and readily excreted soluble enzymes in cytosolesoluble enzymes in cytosoleAcceptor + Donor Acceptor + Donor

conjugate conjugate (Drug) (activated) of liver (transferases)(Drug) (activated) of liver (transferases)- MetylationMetylation- AcetylationAcetylation- Glucuronic acid conjugateGlucuronic acid conjugate- Etheneal sulfatesEtheneal sulfates- Glycine conjugate (mercaptopuric acid Glycine conjugate (mercaptopuric acid

formation) formation)

Inactive DInactive D

*Active D*Active D kidneykidney II

IIII

II IIII

II III I

Characteristics of an ideal metabolite:Characteristics of an ideal metabolite:- Water solubleWater soluble- Pharmacologically inactivePharmacologically inactive- Not to be toxicNot to be toxicSites of drug metabolism:Sites of drug metabolism:- Liver (major site)Liver (major site)- IntestineIntestine- Lungs; brain; kidney; plasma, Lungs; brain; kidney; plasma,

adrenals...etcadrenals...etc

Factors affecting drug metabolism:Factors affecting drug metabolism:- Genetic factors and species differences Genetic factors and species differences

(major factor) (slow and rapid (major factor) (slow and rapid metabolizers)metabolizers)

- Sex Sex - Drug-drug interactionsDrug-drug interactions- Age (paracetamol vs chloramphenicol)Age (paracetamol vs chloramphenicol)- General health of patients and General health of patients and

nutritional statusnutritional status- Dose and frequency of administrationDose and frequency of administration

First-pass effect = rapid First-pass effect = rapid metabolismmetabolism

Enterohepatic circulationEnterohepatic circulation

Drug excretion = eliminationDrug excretion = elimination

A process by which a drug or itA process by which a drug or it’’s s metabolites are eliminated from metabolites are eliminated from the bodythe body

Major sites:Major sites:- Kidney (most drugs)Kidney (most drugs)- Liver Liver

Kidney function (old people)!!!!!Kidney function (old people)!!!!!

Methods of excretion:Methods of excretion:- FiltrationFiltration- Tubular secretionTubular secretion• Specific secretory mechanism for weak Specific secretory mechanism for weak

acids and another one for weak basesacids and another one for weak bases• Still some drugs remain lipophylic so Still some drugs remain lipophylic so

could be reabsorbed (this could be could be reabsorbed (this could be inhibited by changing pH and provides inhibited by changing pH and provides the use of alkali in enhancing excretion the use of alkali in enhancing excretion of acidic drugs)of acidic drugs)

ProbenecidProbenecidPenicillinPenicillinThe rate of excretion of a given drug The rate of excretion of a given drug

is determined by a specific constant is determined by a specific constant known as Kknown as Ke e which depends on AVD which depends on AVD and clearanceand clearance

UUxx (mg/ml) x V (mg/ml) x VClearance = Clearance = ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ PPxx (mg/ml) (mg/ml)

KKee = Clearance (ml/min)/AVD = Clearance (ml/min)/AVD (ml) (ml)

Ke unit: minKe unit: min-1-1 = 1/min = 1/min

KKe e = 0.693/t= 0.693/t1/21/2 (min) (min)

tt1/2 1/2 = o.693 × AVD/clearance= o.693 × AVD/clearance

KKT T = K= Kmm+ K+ Kee

toxictoxic

Blood I.V I.M Oral Blood I.V I.M Oral therapeutictherapeutic

Conc. Conc. levellevel

ineffectiveineffective

Time (hr; min)Time (hr; min)

3hrs 3hrs 3hrs3hrs 3hrs 3hrs

CC0 100 50 25 12.50 100 50 25 12.5

Blood Blood αα-phase-phase

Conc. 50% Conc. 50% ββ-phase-phase

(%)(%)

tt1/21/2

Time (hr; min)Time (hr; min)

Steady state level (chronic administration)Steady state level (chronic administration)

PlateauPlateauBloodBloodConc. Conc.

input=outputinput=output

TimeTimeReached after 5 tReached after 5 t1/2 1/2 lives lives Loading dose (initial large dose) followed by Loading dose (initial large dose) followed by

maintenance dose e.g. digitalization...etcmaintenance dose e.g. digitalization...etc

Steady state level could be calculated from this Steady state level could be calculated from this equation:equation:

ƒ . D ƒ . D Tƒ . D ƒ . D T1/21/2

Cp = Cp = 1.441.44 = = ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ x x ــــــــــــــــــــــــــــ x x ــــــــــــــــــــــ AVD . KAVD . Kee .T AVD T .T AVD TCp = Average steady state plasma conc. of drugCp = Average steady state plasma conc. of drugƒ = fraction of dose absorbed; bioavailable fractionƒ = fraction of dose absorbed; bioavailable fractionD = dose of given drugD = dose of given drugKKe e == first order reaction rate constantfirst order reaction rate constant

AVD = apparent volume of distributionAVD = apparent volume of distributionT = time interval between dosesT = time interval between dosesTT1/21/2 = biological half-life = biological half-life1.44 = 1/0.6931.44 = 1/0.693

Trough and peak drug levels:Trough and peak drug levels:Used to establish the effectiveness of a Used to establish the effectiveness of a

drugdrugTrough is the lowest drug level that is Trough is the lowest drug level that is

needed to reach therapeutic rangeneeded to reach therapeutic range Peak is drawing the serum blood levels (30 Peak is drawing the serum blood levels (30

min parenteral; 1-2 hr oral) after the min parenteral; 1-2 hr oral) after the drug is administereddrug is administered

Trough is drawing the serum blood levels Trough is drawing the serum blood levels right (30 min-1 hr) before the next doseright (30 min-1 hr) before the next dose

(If trough or peak levels are > than (If trough or peak levels are > than normal, the patient is at risk for adverse normal, the patient is at risk for adverse effects)effects)

Bioavailability-bioequivalence Bioavailability-bioequivalence studies:studies:

To prove that 2 drugs have the To prove that 2 drugs have the samesame

- Chemical structureChemical structure- BioavailabilityBioavailability- Biochemical activityBiochemical activity- Therapeutic effectsTherapeutic effects

A B AUCA B AUC

BloodBlood Conc.Conc.

TTlag lag T Tmaxmax

Time (hrs; days)Time (hrs; days)KKTT; K; Kmm; K; Kee; T; T1/2; 1/2; clearance...etc clearance...etc

Terms:Terms:- Capacity limited processes- Capacity limited processes1. first-order (exponential) kinetics1. first-order (exponential) kineticsAll pharmacokinetic processes (abs., distr., met. All pharmacokinetic processes (abs., distr., met.

excr.) occur at a rate directly proportional to excr.) occur at a rate directly proportional to conc. of drug e.g. increasing dose increases these conc. of drug e.g. increasing dose increases these processesprocesses

2. zero-order (saturation) kinetics2. zero-order (saturation) kineticsApply mainly to met. And elimination where their Apply mainly to met. And elimination where their

rates reach saturation (maximum) and a further rates reach saturation (maximum) and a further increase in rates is impossible despite an increase increase in rates is impossible despite an increase in dose (these processes are independent of the in dose (these processes are independent of the conc. (absorption from SR tab. Or continuous conc. (absorption from SR tab. Or continuous infusion are good examles)infusion are good examles)

First order kinetics may become zero order when First order kinetics may become zero order when high conc.’s of drug are presenthigh conc.’s of drug are present

- Indication: - Indication:

Clinical uses of drugsClinical uses of drugs

- Contraindications:- Contraindications:

Situations when not to use drugsSituations when not to use drugs

- Drug tolerance:- Drug tolerance:

↓ ↓ response after repeated doses response after repeated doses e.g. drugs of addictione.g. drugs of addiction

- Tachyphylaxis:- Tachyphylaxis:

Rapidly developing toleranceRapidly developing tolerance

- Drug interactions:- Drug interactions:

The effect of one drug on another. The effect of one drug on another. Takes many forms:Takes many forms:

↑ ↑ or ↓ absorption; ↑ or ↓ protein or ↓ absorption; ↑ or ↓ protein binding; ↑ or ↓ metabolism; ↑ or ↓ binding; ↑ or ↓ metabolism; ↑ or ↓ excretion; ↑ or ↓ toxicity; excretion; ↑ or ↓ toxicity; ↑ or ↓ binding to receptors… etc ↑ or ↓ binding to receptors… etc

** Rule: one drug is better than two; ** Rule: one drug is better than two; two drugs are better than three…etctwo drugs are better than three…etc

- Side effects and drug toxicity:- Side effects and drug toxicity:

Unwanted, untoward, undesirable, Unwanted, untoward, undesirable, adverse reactions to a given drugadverse reactions to a given drug

- Idiosynchracy:- Idiosynchracy:

Abnormal genetically reaction to a Abnormal genetically reaction to a given drug (inherited abnormal given drug (inherited abnormal response to a drug)response to a drug)