chapter 1 general pharmacology

Compiled by: Birhanu Geta 1

College of Medicine & Health Sciences

Pharmacology for Health Sciences

Compiled by: Birhanu G.(B.Pharm)July, 2015General Pharmacology

General Pharmacolo

gyBirhanu G. ( B.Pharm)


Objectives@ the end of this session students will be able

to:Define what Pharmacology is?Define what meant by drugs?Identify source of drugs.Differentiate Pharmacokinetics and Pharmacodynamics. Explain principles of Pharmacokinetics and Pharmacodynamics.

General Pharmacology


WHAT IS

PHARMACOLOGY?



Derivation Pharmacology =>

Pharmakon = Active Principle/Active Ingredient or equivalent to drug, medicine or poison &

Logia = study. PHARMACOLOGY

means: “THE SCIENCE OF DRUGS”



DEFINITIONPharmacology: Is the study of substances that interact with

living systems through chemical process, especially by binding to regulatory molecules & activating or inhibiting normal body process.

Includes, history, source, properties, compounding, biochemical and physiological effects, PK and PD, therapeutic and other uses, precautions, adverse effects, interactions and contra-indications of drugs.



Drug A French word ‘Drogue’ which means dry herb. Any substance that brings about a change in

biologic function through its chemical action. Alters state in the body: =>can’t create new function but alter existing

function. Are poisons if they used irrationally. Poisons are drugs that have almost exclusively

harmful effects. However, Paracelsus famously stated that "the dose makes the poison,"

“Poisons in small doses are the best medicines; and useful medicines in too large doses are poisonous.

“Every drug is a medicine but every medicine is not a drug!!!”General Pharmacology


ReceptorsSpecialized target macromolecules present

on the cell surface or intracellularly.The biological molecule plays a regulatory

role.Drugs bind with receptors & initiate events

leading to alterations in biochemical activity of a cell, and consequently, the function of an organ.

Some times, the drug may act through non-specific physicochemical mechanisms.– Osmotic properties (bulk laxatives, saline

purgatives, mannitol) – Adsorbents (kaolin, charcoal) General Pharmacology


Basic Areas of Pharmacology Pharmacokinetics (Biodisposition of drugs) Pharmacodynamics

Pharmacokinetics: deals with absorption, distribution, biotransformation & excretion of drugs.

Pharmacodynamics: study of biochemical & physiological effects of drugs & their MOA.

Pharmacotherapeutics: use of drugs in prevention & treatment of disease.

Chemotherapy: effect of drugs upon microorganisms, parasites and neoplastic cells living & multiplying in living organism.

Toxicology: branch of pharmacology which deals with the undesirable effects of chemicals on living systems.

Pharmacogenomics: relationship of individual’s genetic makeup to his/her response to specific drugs.General Pharmacology


History of PharmacologyPrehistoric people recognized beneficial & toxic

effects of many plant & animal materials.Preceding the modern era, there were attempts

to introduce rational methods into medicine. But none were successful owing to the

dominance of systems of thought [without experimentation & observation].

Around end of 17th century, reliance on observation & experimentation began.

About 60yrs ago, controlled clinical trial reintroduced; expansion of research efforts; Drug action & receptor.

Now, the molecular mechanism of action of many drugs is known.General Pharmacology


Application of pharmacologyTo control speed of onset, intensity of the drug's

effect, and duration of action. Hence decide on route of administration, the amount and frequency of each dose, and the dosing intervals.

To identify the possible side effect, and withdrawal symptoms of drugs and take measures to manage.

To avoid adverse effects from drug interaction and contraindicated drugs.

To avoid adverse effects in special populations like geriatrics, paediatrics, pregnant and lactating mothers.

To avoid treatment failure due to tolerance & resistance.

To control misuse of drugs by the patient & health professionals.General Pharmacology


Drugs Drugs mostly interact with a specific molecule

in a biologic system that plays a regulatory role [receptor].

Clinically, drugs used for:–Diagnosis: Barium salts, –Prevention: Vaccines, chemoprophylaxis–Treatment: ART–Cure: Antibiotics–Alteration of physiological processes: Hormones & their derivatives (insulin, GH, contraceptives….)–Global effect: General anesthetics



To interact chemically with its receptor, a drug molecule must have the appropriate:

Size (MW100-1000Dalton), For specificity of action, the ability to

move within the body (e.g., from the site of administration to the site of action).

Electrical charge (bonding), exception Xe.Shape (complementary to that of the

receptor site in the same way that a key is complementary to a lock). –Most of drugs are chiral molecules.

Atomic composition.General Pharmacology


A number of useful or dangerous drugs are inorganic elements, e.g. lithium, iron, & heavy metals.

Many organic drugs are weak acids or bases.– This fact has important implications for the

way they are handled by the body, because pH differences in the various compartments of the body may alter the degree of ionization of such drugs.



Source of DrugsDrugs are obtained from various sources. Drugs may be synthesized within the body

(hormones) or not. i.e. xenobiotics (from the Greek xenos, meaning "stranger").



According to sources they are:- 1.Natural drugs

A. PlantsE.g. . Digoxin from Digitalis purpurea

. Atropine from Atropa belladonna . Quinine from Cinchona officinalis

B. AnimalsE.g.. Insulin from pork/beef . Cod liver oil from Cod fish liver.

C. Minerals: Iron, Iodine, Potassium salts. D. Micro – organisms: Penicillin from

penicillium notatum, Chloramphenicol from Streptomyces venezuelae (Actinomycetes).



2. Synthetic drugs: prepared by chemical synthesis in pharmaceutical laboratories.E.g. Sulphonamides, quinolones, barbiturates.

3. Semi-synthetic drugs: prepared by chemical modification of natural drugs.E.g. . Ampicillin from penicillin G. . Dihydroergotamine from ergotamine.

4. Biosynthetic drugs: prepared by cloning of human DNA in to the bacteria like E.coli.

E.g.. Human insulin (humulin), human GH.



Drug Nomenclature• Existence of many names for each drug causes

lamentable & confusing situation.• A drug has at least three types of names; Chemical name (IUPAC) or scientific name,

Based on molecular structure of the drug Very long, too complex to use in common practice.

International Nonproprietary/generic name, - Given by FDA/WHO while approved, the short hand

version of chemical name. - Recommended in RX. Proprietary/trademark/Brand name, - Given by the pharmaceutical company. - Costly.



Examples: 2-acetoxybenzoic acid Aspirin Jusprin® Ethyl 4-(8-chloro-5,6-dihydro-11 H-benzo[5,6]

cyclohepta[1,2-b] pyridin-11-ylidene)-1-piperidine carboxylate.

Loratadine Claritin®



DOSAGE FORMS (PREPARATIONS)Dosage forms (DFs) are the means by which drug

molecules are delivered to sites of action within the body.

The need for dosage forms:1. Accurate dose.2. Protection e.g. coated tablets, sealed ampules.3. Protection from gastric juice.4. Masking taste and odour.5. Placement of drugs within body tissues.6. Sustained release medication.7. Controlled release medication.8. Optimal drug action.9. Insertion of drugs into body cavities (rectal, vaginal)10.Use of desired vehicle for insoluble drugs.



Types of Dosage formsAccording to route of administration:

OralRectalVaginalParenteralInhaledTopicalOphthalmicOtic



Types of Dosage forms…According to physical form of a drug;1. Solid

a. Tablets – Conventional - Chewable - Sublingual - Extended releaseb. Capsules – Hard gelatin & Soft gelatinc. Powders – Effervesent granules - Insufflations - Dentrifices - Powder for injectionsd. SuppositoriesGeneral Pharmacology

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2. Liquid – Solutions, Suspensions, Emulsions

3. Semisolids – Ointments - Creams - Pastes - Jellies - Pessaries4. Gases (pressurized) - aerosols


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Orally (swallowed)

Through Mucus Membranes– Oral Mucosa (e.g.

sublingual)– Nasal Mucosa (e.g.

insufflated) Topical/Transdermal (through skin)

Rectally (suppository)

According to on set of actionSlow Absorption



Faster Absorption

Parenterally (injection)– Intravenous (IV)– Intramuscular (IM)– Subcutaneous (SC)– Intradermal(ID)-15⁰– Intraperitoneal (IP)

Inhaled (through lungs)

90⁰ 45⁰


Compiled by: Birhanu Geta

Medication Administration– Right Medication– Right Dosage– Right Time– Right Route– Right Patient– Right Documentation

26General Pharmacology

Compiled by: Birhanu Geta

Routes of Drug administrationIs the path by which a drug, fluid,

poison or other substance is brought into contact with the body.

27


Commonly Used Routes of Drug Administration

General Pharmacology Compiled by: Birhanu Geta 28

IV = intravenous; IM = intramuscular; SC = subcutaneous.

Factors governing choice of Route


Drug characteristicsEase of administrationSite of actionOnset of actionDuration of actionQuantity of drug administeredLiver and kidney diseases


Enteral Routes Enteral - drug placed directly in the GI tract:

–sublingual - placed under the tongue–Oral - swallowing (p.o., per os)–Rectal - absorption through the rectum

Oral Route


ADVANTAGES Safe Convenient Economical Usually good

absorption Can be self

administered

DISADVANTAGES Slow absorption

slow action Irritable and unpalatable

drugs Un co-operative &

unconscious pts. Some drugs destroyed First-pass effect

Sublingual Route


ADVANTAGES Economical Quick termination First-pass avoided Drug absorption is quick Can be self administered

DISADVANTAGES Unpalatable & bitter drugs Irritation of oral mucosa Large quantities not given Few drugs are absorbed

Rectal Route


ADVANTAGESUsed in childrenLittle or no first pass effectUsed in vomiting/unconsciuosHigher concentrations rapidly achieved

DISADVANTAGESInconvenientAbsorption is slow and erraticIrritation or inflammation of rectal mucosa can occur

Vaginal Routes Drug may be administered locally in the

vagina in the form of pessaries. E.g. Antifungal vaginal pessaries


First-pass Effect The first-pass effect is the term used for the

hepatic metabolism of a pharmacological agent when it is absorbed from the gut and delivered to the liver via the portal circulation.

The greater the first-pass effect, the less the agent will reach the systemic circulation when the agent is administered orally.


First-pass Effect cont’d…Magnitude of first pass hepatic effect: Extraction ratio (ER)

ER = CL liver/QWhere, Q is hepatic blood flow (usually about 90 L

per hour for 70 kg adult). Systemic drug bioavailability (F) may be

determined from the extent of absorption (f) & the extraction ratio (ER),F = f x (1-ER)

First-pass Effect cont’d…


Systemic Routes


Parenteral

First-pass metabolism can occur with orally administered drugs.

Administration of drugs by the Parenteral Route


Needle insertion for parenteral drug: A. Intradermal

injection @15⁰.B. Subcutaneous

injection @45⁰.C. Intramuscular

injection @90⁰.D. Intravenous

injection

Intravascular (IV)


1. Absorption phase is bypassed (100% BA)2. Precise, accurate and almost immediate

onset of action.3. Large quantities can be given, fairly pain free4. Greater risk of adverse effects

a. High concentration attained rapidly b. Risk of embolism and cannot be recalled

by strategies such as emesis or by binding to activated charcoal

5. IV is the most common parenteral route for drugs that are not absorbed orally.

Intramuscular Route(IM)


Advantages Absorption reasonably

uniform Rapid onset of action for

drugs in aqueous solution. Mild irritants can be given Repository and slow

release preparations First pass avoided Gastric factors can be

avoided

Disadvantages

Only up to 10ml drug given

Local pain and abscess Expensive Infection Nerve damage


Subcutaneous route(SC)1. Slow and constant absorption 2. Absorption is limited by blood flow, affected if

circulatory problems exist 3. Concurrent administration of vasoconstrictor

will slow absorption

Inhalation1. Aerosols (gaseous & volatile agents)-lungs2. Rapid onset of action due to rapid access to

circulationA. Large surface area B. Thin membranes separates alveoli from

circulation C. High blood flow



Inhalation cont’dRespiratory system. Except for IN, risk hypoxia. Intranasal (snorting) Snuff, cocaine may be partly oral

via post-nasal dripping. Fairly fast to brain, local damage to septum. Some of the volatile gases also appear to cross nasal membranes.

Smoke (Solids in air suspension, vapors) absorbed across lung alveoli: Nicotine, opium, THC, freebase and crack cocaine, crystal meth.Particles or vapors dissolve in lung fluids, then diffuse. Longer action than volatile gases. Tissue damage from particles, tars, CO.

Volatile gases: Some anaesthetics (nitrous oxide, ether).

Lung-based transfer may get drug to brain in as little as five seconds.


Topical Mucosal membranes (eye drops, nasal

drops, antiseptic, sunscreen, callous removal etc.)

SkinA. Dermal - rubbing in of oil or ointment

(local action)B. Transdermal - absorption of drug through

skin (systemic action) i. Stable blood levels ii. No first pass metabolism iii. Drug must be potent or patch

becomes to large


Routes of administrationTime of onset Intravenous 30-60 seconds Intraosseous 30-60 seconds Endotracheal 2-3 minutes Inhalation 2-3 minutes Sublingual 3-5 minutes Intramuscular 10-20 minutes Subcutaneous 15-30 minutes Rectal 5-30 minutes Ingestion 30-90 minutes Transdermal (topical) variable (minutes to hours)


Time-release preparations Oral - controlled-release, timed-release,

sustained-release Designed to produce slow, uniform

absorption for 8 hours or longer. Better compliance, maintain effect over

night, eliminate extreme peaks and troughs.


Time-release preparations Depot or reservoir preparations

Parental administration (except IV), may be prolonged by using insoluble salts or suspensions in non-aqueous vehicles.

Example: Implantable contraceptives.

The ROA is determined by: Physical characteristics of the drug, Speed which the drug is absorbed and/or

released, The need to bypass hepatic metabolism and

achieve high conc. at particular sites

ImportantInfo


No single method of drug administration is ideal for all drugs in all circumstances !!!!!!!!!!!!!!!

Very

ImportantInfo!



Pharmacokinetics (The life cycle of a Drug) Pharmacokinetics:– Pharmakon: drug– Kinesis: motion

Action of body on drug/ how body handles drugsPharmacokinetics: ADMEFour pharmacokinetic properties determine the

onset, intensity & duration of drug action.Using knowledge of pharmacokinetic

parameters; clinicians can design optimal drug regimens; including the route of administration, dose, frequency & duration of treatment.General Pharmacology


Absorption Absorption is the process by which a drug

enters the bloodstream without being chemically altered or

The movement of a drug from its site of application into the blood or lymphatic system

How drugs transfer form site of administration?

1. Filtration [aqueous diffusion]-passage of drugs through aqueous pores.

Size should be less than size of pore Has to be water soluble.E.g. Na+, glucose, caffeine.



2. Diffusion: drugs supposed to pass membrane.

Drugs must be lipid soluble.High partition coefficient high absorption.

3. Carrier mediated absorptiona. Facilitated diffusion

- Passive but facilitated.E.g. levodopa & amino acid into brain.

b. Active transport- Use ATP & carrier proteins.- Against the concentration gradient.

E.g. levodopa & methyldopa from the gut.General Pharmacology


4. Phagocytosis & pinocytosis- Process by which large molecules are

engulfed by the cell membrane forming a vesicle & releases them intracellularly. E.g. protein, toxin



Summary of transport across a membrane



Drug absorption• Transfer of a drug from its site of

administration to the bloodstream. • The rate and efficiency of absorption depend

on the route of administration. – For IV delivery, absorption is complete; that

is, the total dose of drug reaches the systemic circulation.

– Drug delivery by other routes may result in only partial absorption and, thus, lower bioavailability.



Factors affecting GI absorptionPH of media & pKa of the drugArea of absorbing surfaceParticle size of the drugFormulation Gut motilityGIT blood flowGastric secretionDrug interaction



A drug must be in solution to be absorbed, since most drugs are either weak acids or weak bases, pH affects their solubility and hence absorption.

Weak bases are absorbed more rapidly from the intestine than stomach.

Small intestine is the major absorption site because:

–It has large surface area (microvilli 200M2)–There is good blood supply (1L

blood/min compared to 150mL/min stomach)–Permeability to drugs is greaterGeneral Pharmacology


Bioavailability (F)• Fraction of administered drug that reaches the

systemic circulation in a chemically unchanged form.– Amount of drug available in the circulation/site

of action– It is expressed in percentage– It is 100% for drugs given IV.

• For example, if 100 mg of a drug is administered orally and 70 mg of this drug are absorbed unchanged, the bioavailability is 0.7 or 70%.Factors affecting bioavailability– Extent of absorption– First pass effectGeneral Pharmacology


Oral Dose

Injected Dose

Plas

ma

Conc

entra

tion

Time

Bioavailability (F)



Drug distributionReversible movement of drug from

bloodstream to interstitium (extracellular fluid) and/or cells.

Factors affecting drug distribution1. Plasma protein binding– Albumin [acidic & hydrophobic drugs]– -glycoprotein [basic drugs]

2. Tissue uptake of drugs/tissue binding-Adipose tissue [DDT]-Bone [TTC]-Liver [chloroquine]-Thyroid gland [iodine]General Pharmacology


3. Barriers –capillary permeability Blood brain barrier (BBB) Placental blood barrier (PBB) Cell membrane

4. Rate of blood flow Brain, Kidney, highly perfused Liver & Lung

5. Plasma concentration



Drug metabolism Enzymatically mediated alteration in drug

structure. Transforms lipophilic drugs into more polar

readily excretable products. Liver - major site for drug metabolism, but

specific drugs may undergo biotransformation in other tissues, such as the kidney and the intestines.

Note: Some agents are initially administered as inactive compounds (pro-drugs) and must be metabolized to their active forms.



InducersThe cytochrome P450 enzymes are an important

target for pharmacokinetic drug interactions. Certain drugs, most notably phenobarbital,

rifampin, and carbamazepine, are capable of increasing the synthesis of one or more CYP isozymes.

This results in increased biotransformations of drugs.

1. Decreased plasma drug concentrations.2. Decreased drug activity if metabolite is

inactive.3. Increased drug activity if metabolite is

active.4. Decreased therapeutic drug effect.General Pharmacology


Inhibitors Inhibition of CYP isozyme activity is also an

important source of drug interactions that leads to serious adverse effects.

The most common form of inhibition is through competition for the same isozyme.

For example, omeprazole is a potent inhibitor of three of the CYP isozymes responsible for warfarin metabolism.

If the two drugs are taken together, plasma concentrations of warfarin increase, which leads to greater inhibition of coagulation and risk of hemorrhage and other serious bleeding reactions.

CYP inhibitors are erythromycin, cimetidine, ketoconazole, and ritonavir, because they each inhibit several CYP isozymes.General Pharmacology


Inhibition of drug metabolism may lead to; - Increased plasma levels over time with long-term

medications. - Prolonged pharmacological drug effect. - Increased drug-induced toxicities.Microsomal enzyme inducersPhenobarbitonePhenytoin Rifampicin CarbamazepineSulphonamides St. John’s Wort Cigarette smoking

Microsomal enzyme inhibitors Isoniazid Disulfiram Cimetidine Allopurinol Chloramphenicol Erythromycin Metronidazole Grape fruit juice



First-Pass Effect: significant metabolic inactivation of some drugs by the liver following oral administration.- Drugs absorbed from the GI tract enter the portal circulation and are carried to the liver before entering the systemic circulation.


http://abdellab.sunderland.ac.uk/Lectures/Parmacology/Pics/anatomy/LiverBile.html


Drug excretionRemoval of a drug from the body occurs via a

number of routes.The major routes of excretion include renal

excretion, hepatobiliary excretion & pulmonary excretion.

The minor routes of excretion are saliva, sweat, tears, breast milk, vaginal fluid & hair.

The rate of excretion influences the duration of action of drugs.

If the drug is excreted slowly, the concentration of drug in the body is maintained and the effects of the drug will continue for longer period.General Pharmacology



Routes of drug excretiona. Renal excretion For water soluble and non volatile drugs.The three principal processes that determine

the urinary excretion of a drug.– Glomerular filtration– Active tubular secretion– Passive tubular reabsorption

The function of glumerular filtration and active tubular secretion is to remove drug out of the body, while tubular reabsorption retain the drug.




b. Hepatobiliary ExcretionThe conjugated drugs are excreted by

hepatocytes in the liver.After excretion of drugs through bile to the

intestine; certain amount of drug is reabsorbed in to the portal vein leading to an entrohepatic cycling which can prolong the action of drug. E.g. Chloramphenicol, estrogen.




c. Gastro intestinal excretionWhen a drug is administered orally, part of

the drug is not absorbed and excreted in the faeces.

The drug which do not undergo enterohepatic cycling after excretion in to the bile are subsequently passed with stool. E.g. Aluminum hydroxide changes the stool

color in to white, Ferrous sulphate darkens it and Rifampicine gives orange red colour to the stool.




d. Pulmonary excretion Many inhalation anesthetics and alcohol are

excreted through the lungs.e. Sweat E.g. Rifampcine, metalloids like arsenic are

excreted in to the sweat.




f. Mammary excretionMany drugs are excreted in to breast milk. Lactating mothers should be cautious about

the intake of these drugs because they may enter in to baby through milk and produce harmful effects in the baby. E.g. Ampicillin, Aspirin, Chlorodizepoxide,

Streptomycin.




PharmacodynamicsPharmacodynamics include:

Mechanism of actions of the drug.How does a drug act in the body?

Effects of the drug: both beneficial & harmful effects.What does a drug do in the body




Pharmacodynamics…Mechanisms of drug action It is of two types:A. Receptor mediated mechanismReceptors- targets of drug action.May present either on the cell surface or

inside the cell. D + R → DR → Biological effect

Where; D=Drug, R=Receptor, DR=Drug Receptor ComplexB. Non-receptor mechanisms Simple physical or chemical reaction.

E.g. Antacids: neutralization reaction.General Pharmacology



Types of Receptors Regulatory proteins

For endogenous regulatory ligands – particularly hormones, growth factors, and neurotransmitters.

E.g. Insulin receptors-insulin Enzymes

Receptors that are inhibited by binding with a drug.

E.g. Cyclooxygenase – Aspirin Transport proteins: Na+/K+ ATPase- Digoxin Structural proteins: Tubulin- colchicine Genetic materials: Rifampcin- RNA polymerase Ion channels: Na, Ca, K, channel blockers.




Models of D-R interaction… Lock & key

Drug acts as key, receptor as lock, combination yields response.

Induced-fit models Dynamic & flexible interaction.



Implications of drug-receptor interaction Drugs can potentially alter rate of any

function in the body. Drugs cannot impart entirely new functions

to cells. Drugs do not create effects, only modify

ongoing ones. Drugs can allow for effects outside of normal

physiological range.



Three aspects of drug receptor function1. Receptors determine the quantitative

relation between drug concentration and response. This is based on receptor’s affinity to bind

and it’s abundance in target cells. 2. Receptors (as complex molecules)

function as regulatory proteins and components of chemical signaling mechanisms that provide targets for important drugs.

3. Receptors determine the therapeutic and toxic effects of drugs in patients.




Dose response relationship Dose: amount of a drug required to

produce desired response in an individual. Dosage: the amount, frequency and

duration of therapy. Potency: measure of how much a drug

is required to elicit a given response. The lower the dose, the more potent is the drug.

Efficacy: the intrinsic ability of the drug to produce an effect at the receptor.

Maximal efficacy: largest effect that a drug can produce.General Pharmacology



Dose response relationship...Drug response depends on:

Affinity of drug for receptor. Intrinsic activity (degree to which a drug is

able to induce intrinsic effects).




Agonism and Antagonism

Agonists facilitate receptor response.

Antagonists inhibit receptor response.

(Direct Ant/agonists)




Types of drug-receptor interactions Agonist drugs: bind to and activate the

receptor which directly or indirectly brings about the effect. Some agonists inhibit their binding

molecules to terminate the action of endogenous agonists.

E.g. slowing the destruction of endogenous acetylcholine by using acetyl cholinesterase inhibitors.

Antagonist drugs: bind to a receptor to prevent binding of other molecules, but lack intrinsic activity. E.g. Atropine decrease acetylcholine effects.General Pharmacology



Types of drug-receptor interactions… Partial agonist drugs: acts as agonist or

antagonist depending on the circumstance, have affinity but have lowered maximal efficacy. E.g. Pindolol can act as an antagonist if a

“full agonist” like Isoproterenol is present. Inverse agonist: is a ligand which produces

an effect opposite to that of the agonist by occupying the same receptor. E.g. metoprolol in some tissues.




Full agonist- A drug with high positive efficacy & produce the system maximal response. Partial agonist- maximal response to the ligand is below the system maximal response. Antagonists- no efficacy or such a low level of efficacy with no visible response. Inverse agonist- A ligand with negative efficacy can reduce the basal response.General Pharmacology


Graded dose–response relationsAs the concentration of a drug increases, its

pharmacologic effect also gradually increases until all the receptors are occupied (the maximum effect).

It is used to determine affinity, potency, efficacy and characteristics of antagonists.




Potency Is relative strength of response for a given

dose. Effective concentration (EC50) is the concentration of

an agonist needed to elicit half of the maximum biological response of the agonist.

The potency of an agonist is inversely related to its EC50 value.

D-R curve shifts left with greater potency.



Efficacy Maximum possible

effect relative to other agents.

Indicated by peak of D-R curve.

Full agonist = 100%

Partial agonist = 50%

Antagonist = 0%

Inverse agonist = -100%General Pharmacology


Quantal(cumulative) dose response r/ship: Is between the dose of the drug and the

proportion of a population that responds to it. For any individual, the effect either occurs or

it does not (‘all’ or ‘none’). Are useful for determining doses to which

most of the population responds; ED50%, TD50%, LD50%, TI(r/ship b/n dose & toxicity) & inter subject variability in drug responses.

They do not predict idiosyncratic reactions and hypersensitivity.




Therapeutic index Median Lethal Dose (LD50): dose which

would be expected to kill one half of a study population.

Median Effective Dose (ED50): dose which produces a desired response in 50% of the test population.

Therapeutic Index: gives a rough idea about the potential effectiveness and safety of the drug in humans. Therapeutic Index (TI) = LD50/ED50The smaller the TI, the less safer the drug is.

Margin of safety=LD1/ED99.General Pharmacology



Therapeutic Index…

ED50 LD50



Factors modifying the dosage & action of drugs

1. Age2. Sex3. Body weight4. Genetics5. Drug tolerance6. Drug intolerance7. Disease states




Drug- Drug interactionsConsequences of Drug- Drug Interactions1. Intensification of effects: increased therapeutic

or adverse effects.Additive Drug Effects (Summation): 1 + 1 = 2. Most frequently seen when two drugs possess similar intrinsic

activity.E.g. sedative-hypnotic type drugs (i.e., barbiturates, alcohol,

benzodiazepines (diazepam, etc.) administered in combination will produce additive effects resulting in over-sedation.

Synergism - the effect of two drugs in combination is greater than the sum of the drugs administered alone (1 + 1 > 2).

E.g. Aminoglycosides with penicillins.Potentiation – one substance alone does not have

effect but when added to another chemical, it becomes effective. (1 + 0 > 1). General Pharmacology



2. Reduction of effects – inhibit drug effects; Either beneficial or detrimental.

Antagonism: it occurs when the effect of one drug is diminished by another drug.(1+1<1).

Types of antagonism; Chemical antagonism or inactivation Physiological (functional) antagonism Pharmacologic or Receptor antagonism Pharmacokinetic/Dispositional antagonism




Basic mechanisms of Drug- Drug interactions Direct chemical or physical interaction - can occur

with drugs mixed together. Pharmacokinetic interaction – can alter all four

processes. Absorption – increase or decrease (e.g., PH, laxative, changes

in blood flow). Distribution – competition for protein binding or changes in

extra cellular PH. Metabolism - induction of drug metabolizing enzymes,

inhibition of metabolizing, and competition of metabolism. Excretion - altered renal excretion (e.g. filtration, reabsorption,

and secretion). Pharmacodynamic interaction

Interactions at same receptor – almost always inhibitory. Interactions resulting from actions at separate sites (if

drugs influence same physiologic process).General Pharmacology



Drug- Food interactions Impact of Food on Drug Absorption – Decreasing rate and/or extent of absorption– Some foods can increase extent of drug

absorption. Impact of Food on Drug metabolism– The grapefruit juice effect (can inhibit

metabolism of certain drugs increased drug levels).

Impact of Food on Drug Toxicity–MAOIs with tyramine– Caffeine with theophylline

Impact of Food on Drug Action– Vitamin K with warfarin.




Adverse drug reactions (ADRs) Any undesired response to a drug. Can range in intensity from annoying to life threatening.Types of adverse drug reactions Side Effects: unavoidable secondary drug effect

produced at therapeutic drugs doses.E.g. 1. Drowsiness that often accompanies the use of

antihistamines 2. Gastric bleeding that can be produced by low therapeutic

doses of aspirin. Toxicities: an adverse drug reaction caused by

excessive levels of drug.E.g. Coma caused by overdose with morphine.

Allergic reactions:– Prior sensitization of the immune system.– Re- exposure to that drug can bring on an allergic response.

E.g. Penicillin allergy General Pharmacology



ADRs... Idiosyncratic effects: an unusual drug

response resulting from a genetic predisposition. Physical dependence: a state in which the

body has adapted to prolonged drug exposure in such a way that if drug use is discontinued abstinence syndrome will result. Develop during long-term use of certain drugs (e.g.

Opoids, barbiturates etc) Carcinogenic effects: ability of certain

mediations /chemicals to cause cancer.Although a number of carcinogenic compounds

have been identified, very few of these are employed therapeutically.

Teratogenic Effects: drug- induced birth defect. General Pharmacology



Any??? 10Q!!!



chapter 1 general pharmacology

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