IntroductionBasic principles of pharmacology

Prof. Suheil Zmeili, MD; PhDFaculty of Medicine

Department of PharmacologyUniversity of Jordan

** Pharmacology Pharmakon = Drug; Logos = Science** Drug- A chemical substance that is primarily used

to reverse a pathophysiological defect =disease

- A chemical substance that is mainly used totreat, control, prevent, or diagnose aspecific disease

** Drug discoveryThe first step usually starts with an idea =a hypothesisWhat helps?Previous experience and availability of old drugs;

existence of plants of clinical benefits; chemicalidentification of endogenous substances e.g.hormones; availability of new preparatorytechniques ... etc

** Drug discovery Cont..- Animal studies = toxicity studies- In vitro studies, acid = antacid ...** Pharmaceutical processIt involves making a drug in a suitable dosage

form

** Administration (Routes) = Systemic orlocal

** Systemic administration :- Oral (tablets, syrups, suspensions...),- Prenteral route = Subcutaneous S.C

(solution), intramuscular I.M (solution)intravenous = I.V (solution)

- Buccal (tablets) sublingual (tablets) rectal(suppositories)

- Transdermal (patches)- Inhalational (sprays)

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

ear or ophthalmic drops, mouth washes, S.Cinfiltration e.g. local anesthetics...)

- Semisolid forms (creams, ointments...)- Solid forms (suppositories, pessaries =

vaginal tablet...)

** Pharmacokinetic processIt is the study of what the body does to a drugIt includes the processes:- Absorption- Distribution- Metabolism- Excretion = elimination

** Pharmacodynamic processIt is the study of what a drug does to the body It includes the processes:- Pharmacological effects- Therapeutic effects- Mechanisms of drug actions- Side effects = adverse reactions = unwanted

or untoward effects = toxic effects

** PhrmacogeneticsIndividual variations in responding to drugs** Major objectives:Giving the patient the minimal possible dose

capable of producing the desired effect orrelieving the signs and symptoms of aspecific disease without producing side ortoxic effects

** Branches of pharmacology usually answerall of the following questions:

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

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

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

Chemical nature of drugs:- Neutral ... Steroids- Acidic ... Aspirin, Barbiturates- Basic ... Morphine; AlkaloidsDrug sources:- NaturalPlants (atropine, digoxin), animals (insulin),

human (growth hormone)

- Semisynthetic (human insulin)- Synthetic (agonists; antagonists)Drug nomenclature:- Chemical name e.g. acetyl salicylic acid- Generic name; nonproprietary; approved

name... Aspirin (most widely used inpharmacology)

- Official name... Aspirin BP; Aspirin USP- Trade name; Proprietary; brand name

Remine®; Bufferin®…

Drug absorptionPassage of drug from route of administration

to circulationBioavailability:The fraction of the given dose that gets into

bloodThe bioavailability of an I.V given drug is

100%

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

action- A major site of drug-drug interactionsStrongly bound drugs to blood proteins

remain longer in blood, have longer t1/2 &DOA

** The free form of the drug, is the formwhich is active and crosses membranes

Sites of drug absorption:- Oral mucosa (buccal; sublingual tab.)- Stomach (aspirin)- Intestine (iron; vit. B12)- major site- Lungs (general anesthetics)- Rectum- Skin

Factors affecting absorption:- Drug size- Lipid solubility (major factor)Lipid/water partition coefficient- Degree of ionization or environmental pH:pH = pKa + log [A-]/[HA]pH = pKb + log [BOH]/[B+]

Cont. factors affecting absorption:Polar = ionized = water soluble = active formNonpolar = unionized = lipid soluble =

crosses membranes- Concentration of drug- Surface area of absorption- Blood circulation to absorbing area- Route of administration (I.V the fastest)

Enterohepatic circulationBioequivalency:A comparison between 2 drugs- Chemically similar- Similar bioavailability- Biologically similar- Therapeutically similar

Drug distributionPassage of drugs from blood to different

tissues (site of action)70 Kg man 60% H2O ≈ 42 litersPlasma extracellular fluid intracellular

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

Apparent volume of distribution (AVD):

The volume in which a given drug distributesin different body compartments

AVD = Dose (mg)/C0 (mg/L)

C0 = Concentration of drug in blood at timezero

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

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

Very very high Vd indicates extensive tissuebinding

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

Mechanisms of drug transfer across membranes:- Simple diffusionCrossing through water pores of membranes, no

energy or carrier required, from high to lowconcentration, drugs with low M.W (must be lipidsoluble and concentration gradient is the drivingforce)

D

- Passive diffusion (major mechanism) Crossing through cells or the lipid bilayer, no

energy or carrier required, from high to lowconcentration

D D D

The only requirement for passive diffusion isthat the drug should be lipid soluble

- Facilitated diffusionRequires a carrier, no energy required, from

high to low concentration- Active transportRequires energy ± carrier, could be from low

to high concentration- Endocytosisis Phagocytosis (solid particles) Pinocytosis (fluid particles)

Drug metabolismA change in the chemical structure of the

drug, or addition of a hydrophilic groups toan initially lipophilic drug until it becomessufficiently ionic so as to be easily filteredand excreted by the kidneys

It has nothing to do with the benefit or harmof the drug

Drug metabolism involves 2 major pathways:- Pathway I = Oxidation reduction reactionsAlso known as mixed function oxidase system

and cytochrome P450 system (CYP system)- Pathway II = Conjugation reactions Metylation Acetylation Glucuronide formation

Inactive D

*Active D kidney I

II

I II

II I

Characteristics of an ideal metabolite:- Water soluble- Pharmacologically inactive- Not to be toxicSites of drug metabolism:- Liver (major site)- Intestine- Lungs; brain; kidney; plasma...etc

Factors affecting drug metabolism:- Genetic factors and species differences

(major factor)- Drug-drug interactions- Age (paracetamol vs chloramphenicol)- General health of patients and nutritional

status- Dose and frequency of administration

Drug excretion = eliminationA process by which a drug or it’s metabolites

are eliminated from the bodyMajor sites:- Kidney (most drugs)- LiverKidney function !!!!!

Methods of excretion:- Filtration- Tubular secretion Probenecid PenicillinThe rate of excretion is measured by a

specific constant known as Ke

Ke = Clearance (ml/min)/AVD (ml)Ke unit: min-1 = 1/min

Ke = 0.693/t1/2 (min)

t1/2 = o.693 × AVD/clearance

toxic

Blood I.V I.M Oral therapeutic

Conc. level

ineffective

Time (hr; min)

3hrs 3hrs 3hrs

C0 100 50 25 12.5

Blood Conc. 50% (%) t1/2

Time (hr; min)

Steady state level (chronic administration) PlateauBloodConc.

TimeReached after 5 t1/2 livesLoading dose

Terms:- Indication:Clinical uses of drugs- Contraindications:Situations when not to use drugs- Drug tolerance:↓ response after repeated doses e.g. drugs of

addiction

- Tachyphylaxis:Rapidly developing tolerance- Drug interactions:The effect of one drug on another. Takes

many forms:↑ or ↓ absorption; ↑ or ↓ protein binding; ↑ or

↓ metabolism; ↑ or ↓ excretion; ↑ or ↓toxicity; ↑ or ↓ binding toreceptors… etc

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

- Side effects and drug toxicity:Unwanted, untoward, undesirable, adverse

reactions to a given drug- Idiosynchracy:Abnormal genetically reaction to a given drug

PharmacodynamicsMeans mechanism of action (MOA)Drugs could either act through receptor or

non-receptor mechanisms- Non-receptor mechanisms:Acid-antacids; laxatives; heparin-protamine

sulfate…etc

- Receptor-mediated effects:D + R DR complex responseLock and key theory

D R

Binding of D to R requires that:- Both D and R should be close enough to

each others- The R has to be complementary in it’s

chemical structure to the D- Binding of the D to the R should be

reversible

Binding forces between D & R:- Van der Waals:The weakest bond N…..NThe commonest bond between the D & RClose approximation between the D & R is

requiredThe R chemical structure should be

complementary to the D

- Hydrogen bond:Stronger than Van der WaalsReversibleOccurs when a hydrogen connects 2 oxygens

or 2 nitrogens -O H……O= -N H……N=

- Ionic bond:Stronger than hydrogen bondReversibleOccurs between ions of different charges

- Na+….. Cl-

- Covalent bond:Irreversible bondThe least common bond between the D & its

receptorThe strongest bond; energy is required to

break it downOccurs when the D and the R share a pair of

electrons

Dose response curves:- Graded dose-response curvesVmax

Response (%)

Dose

Vmax

Response (%)

Log dose

Vmax

Response 50

(%)

ED50

Log dose

Vmax

Response 50

(death) (%) LD50

Log dose

- Vmax:Maximum response. Also known as efficacy orintrinsic activity. It is important in

pharmacology- ED50:The dose which produces 50% of response- LD50:The dose which produces death in 50% of

animals

Death is considered the most severe sideeffect to any drug

- Therapeutic index (TI):A measure of the safety of drugs

TI = LD50/ED50

The larger the TI the more safe is the drug

- Potency:A term used whenever we compare the

activity of two drugs producing the sameeffect

Defined as the dose of one drug necessary toproduce a specific response as compared toa second drug producing the same effect

- Affinity:The ability of a drug to form a stable complex

with the receptor

- Quantal dose response curves

# Pt’s

dose

100 effect side effect

# pt’s 50 (%)

ED50 LD50

Log dose

100 effect side effect A B # pt’s 50 TI (A)=100/50= 2

(%) TI (B)=250/50= 5

50 100 250

dose

Types of drug-receptor interactions:1. Drug agonism:Agonist:A drug that interacts with a specific receptor

and produces a responseAddition: Applies whenever two drugs

producing similar response given togetherresult in a final response equals to the sumof the response of each drug (1+1=2)

Synergism: Applies whenever two drugsproducing similar response given togetherresult in a final response greater than thesum of the response of individual drugs(1+1=3 or 5…)

Potentiation: Applies when one drugproducing no response given with anotherproducing a specific response results in anincrease in the final response of the seconddrug (0+1=2 or 5…)

2. Drug antagonism:A pure antagonist is a drug which binds a

specific receptor producing no effect orresponse , but if given with an agonist itreverses the effect of the agonist

Antagonism may take many forms:a. Physiologic antagonism:Sympathetic vs parasympathetic

b. Antagonism by neutralization:Applies whenever two drugs given together

form an inactive complexc. Pharmacologic antagonism: 2 major types1. Competitive antagonism Ag. Ant. Ag. Ant.

Characteristics of competitive antagonism:- Both agonist and antagonist compete

directly for the same receptor or even site- It is reversible- ED50 of agonist ↑ in presence of antagonist- No change in total # of receptors- Dose-response curves are shifted to the right

Ag. Ant. more Ant.

Response (%)

Log dose

2. Noncompetitive antagonism Ag. Ant.

Ag. Ant.

Characteristics of noncompetitive antagonism:- Both agonist and antagonist act on different

sites of a given receptor or even differentreceptors

- It is irreversible- Results in no change in the ED50 of agonist- Total # of receptors ↓- Results in downward shift in the Dose-

response curves

Ag.

Response +Ant. (%) +more Ant.

Log dose