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Basic Principles of General

Pharmacology

Shashi Bhushan
Scientist C
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Division of Cancer Pharmacology

The term pharmacology comes from the Greek words:
•Pharmakon - drug or medicine
•Logos - the truth about or a rational discussion
…………Truth about medicine

• Pharmacology is the study of how
drugs exert their effects on living
systems.
• More specifically it is the study of
the interactions between a living
organism and drugs that alter normal
biochemical function. 2

History of Pharmacology

Early pharmacology
focused on natural
substances, mainly plant
extracts.

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Modern approach
• Pharmacology is a discipline as a bridge, not only to
connect pharmacy with medicine, but also to link
foundational medicine to clinical medicine

Foundational
FoundationalMedicine
Medicine Clinical
ClinicalMedicine
Medicine

Pharmacy
Pharmacy Pharmacology Medicine
Medicine

Research
Researchof
ofDrugs
Drugs Manufacture
Manufactureof
ofDrugs
Drugs

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g. nerves) Example: treatment of Alzheimer's  Cardiovascular Pharmacology: study of the effects of drugs on heart. spinal cord. vasculature and kidney that participate in cardiovascular function. atenolol  Molecular Pharmacology: study of the biochemical and biophysical characteristics of drug molecules Example: Drug-Receptor Interaction . Subdivisions of Pharmacology  Neuropharmacology: study of the effect of drugs oncomponents of the nervous system (brain. Example: treatment of high blood pressure (hypertension) e.

•Toxicology -Study of harmful effects of drug •Posology.Subdivisions of Pharmacology  Clinical Pharmacology: application of pharmacodynamics and pharmacokinetics to human.……..How medicines are dosed or calculation of dose •Pharmacognosy- Development of medicinal substances obtained from plants .

……………. biochemical and physiology effects of drugs on cellular systems and their mechanisms of action..what the drug does to the body Plasma Site of Dosage Effects Concen. metabolism and excretion of drugs (ADME). Action Pharmacokinetics Pharmacodynamics .. Division of Pharmacology: Two important and interrelated areas:  Pharmacokinetics: Study of the absorption.what the body does to the drug  Pharmacodynamics: Study of the molecular. distribution. …………….

what the body does to the drug • Absorption (A) • Distribution or Disposition (D) • Metabolism (M) • Elimination or Excretion (E) 8 . (I) Pharmacokinetics ……………..

Drug Absorption • Absorption is the process by which a drug enters the bloodstream without being chemically altered • The movement of a drug from its site of application into the blood or lymphatic system • Mathematically it is define in terms of Bioavailability (Rate and extent of absorption). .

Ka (Absorption constant)……….v.: ranges from 0-100% e. Rate of absorptio Area under curve (AUC)……….: 100% • for non i.g. Bioavailability Definition: Rate and extent of absorption i.e. extent of absorp • for i. lidocaine bioavailability is 35% due to destruction in gastric acid and liver metabolism .v.

Lipid diffusion 2. Coabsorption with lipids 4. it must be able to pass through cell membranes (which is a lipid barrier) • Lipid soluble drugs would be ideal to pass through the membrane easily. Facilitated diffusion/active transport . Process of Absorption • In order for a drug to be absorbed. Aqueous diffusion 3. • There are 4 main ways drugs can be absorbed: 1.

e. Lipid diffusion Highly lipid soluble drugs are able to pass across cell membranes quite easily driven by passive diffusion. Levadopa . Aqueous diffusion Drugs which are small and easily dissolved in solution will be able to pass through the cell membrane via aquaporins – special protein channels designed for the movement of water into cells. 4. 2. Coabsorption with lipids Some drugs can be absorbed in conjunction with lipids via micelles formation . digitoxin. ………………….g. Facilitated diffusion/active transport Transport systems which allow the active (require energy) uptake of materials which are structurally similar to the transporter compound. Vitamin A. 3. e.g.Process of Absorption 1.

Factors which influence the rate of absorption – Routes of drug administration – The physicochemical properties of the drug – Dosage forms – Circulation at the site of absorption – Concentration of the drug .

Routes of Drug Administration • The route of administration (ROA) have a profound effect upon the speed and efficiency of drug’s action. • Parentral: Drug delivered in the systematic circulation without crossing intestinal mucosa – Intravascular – Intramuscular – Subcutaneous – Inhalation – Local/ Topical .

Enteral Routes (1) Sublingual .Some drugs are taken as smaller tablets which are held in the mouth or under the tongue.g. e.Drugs which absorbed orally are initially transported to the liver via portal vein. the less the agent will reach the systemic circulation and less drug action . sorbitrate Advantages • Rapid absorption • Drug stability • Avoid first-pass effect : . The greater the first-pass effect.

nausea and vomiting .self. (2) Oral Route (swallowing) • The most common route of drug administration. Drug is given through oral cavity. pain free and easy to take – Absorption .only part of the drug may be absorbed – First-pass effect – Due to Biotransformation – Irritation to gastric mucosa .compared to other parentral routes • Disadvantages – Sometimes inefficient .administered.takes place along the whole length of the GI tract – Economical . • Advantages – Convenient .

pile etc. a drug is mixed with a waxy substance that dissolves or liquefies after it is inserted into the rectum. . • In this form. Easy to terminate exposure 4. (3) Rectal Route • Drugs that are administered rectally as a suppository. Advatages: 1. Unconscious patients and children 2. If patient is nauseous or vomiting 3. Good for drugs affecting the bowel like laxatives.

Parenteral Routes  Direct delivery of drug in to systemic circulation without intestinal mucosa – Intravascular (IV)- placing a drug directly into the blood stream – Intramuscular (IM) - drug injected into skeletal muscle – Subcutaneous - Absorption of drugs from the subcutaneous tissues .

Local/ Topical Route Use of drug for external part of the body like skin.  Mucosal membranes • Eye drops • Antiseptic cream and lotion • Sunscreen lotion • Nasal drops etc. nose etc. Dermal . Transdermal Patches: Nicotine.  Skin a. eye .Oil or ointment for local action b. Hyoscine etc .

On the other hand. e.e.g. Aqueous and lipid solubility · For better absorption a drug must have optimum water and lipid solubility or a optimum partition coefficient. Chemical and enzymatic stability · The drug should be stable in gastric acid and in gut enzymes. are absorbed well · Drugs which are large (often proteins) are absorbed poorly. .W. if it is highly water soluble then it will not cross the biological membrane. or unstable in acid. Penicillin G is highly acid labile. If it is highly lipid soluble it would not dissociate in the circulation i.Factor affecting absorption…… Physico-chemical properties of Molecular weight drug · Drugs with a small M. Ion trapping.

Factor affecting absorption…… pH and lipid solubility: Most drugs are either weak acids or weak bases and can exist in either the ionised (less lipid soluble) or unionised (more lipid soluble) form depending on the pH of the surrounding environment. REMEMBER THAT A DRUG IS ABSORBED BETTER IN THE UNIONISED FORM (Lipophillic drug can cross cell membrane) .

g. Breast milk .  The concentration of ionized aspirin inside the cell continues to rise until it saturates and precipitates as crystals. Prostatic secretions  Aspirin is an acidic drug (pKa=5) and exist in the un- ionised form in stomach (pH 2. which lead to gastric bleeding.Factor affecting absorption…… Ion Trapping Body fluids where a pH difference will favor trapping of highly lipophillic drugs: e.4) where it is ionized and. Aqueous humor (eye) . 22 . it cannot leave the cell. in this form. Vaginal secretions . it can enter the cells of the stomach lining (pH=7.0)  In this form.

 A syrup have fast rate of absorption as compare to tablet  A capsule have fast rate of absorption than tablet  Controlled-release.Factor affecting absorption…… Drug dosage forms  Different dosage forms have different rate and extent of absorption. timed-release. sustained-release dosage form have a uniform absorption and less side effects .

Drug distribution or Disposition .

• Drugs are simultaneously being eliminated and distributed. • Distribution controls drug actions.Dilution in blood. Steps of drug distribution 1.Drug distribution • After absorption drug will distributed throughout the body and it depends on the blood circulation. but distribution is usually faster. Movement into extracellular fluid . .The drug must be able to cross the cell membrane.Drugs need to be able to get out from vascular system.The drug has to reach equilibrium with itself in the blood. efficacy and side effect. Uptake into cells. 2. 3. • Distribution of drugs is rarely uniform.

Adipose tissue has a low blood perfusion so drugs will not be able to reach these places very quickly.A drug will pass through the membrane better if it is unionised (lipophilic).Factors affecting drug distribution • Protein binding.g. . a basic drug will be unionised in a basic environment. e. An acid drug will be unionised in an acid environment. the drug is able to get there faster.More protein binding less distribution • Ability of the drug to cross cell membranes -depend on drug lipid solubility • Extent of blood perfusion . • pH differences across membrane barriers.If a tissue is well perfused.

Metabolism or Bio-transformation of drug 27 .

Occurs in 2 phases: · Phase I reaction · Phase II reaction . Lungs. • Reduces the drugs effect • Often inactivates the drug • Makes the drug more polar so that it can be excreted Site of metabolism: • Occurs mainly in the liver but also occur in other sites like Kidney. GIT and Skin. Drug metabolism • Metabolism or Biotransformation involves the modification of a drug by endogenous metabolic enzymes like CYP-450.

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…………. Cimetidine • Alcohol and smoking induce metabolic enzymes in the liver thus increase the metabolism or reduce the efficacy of some drugs. .Phase-I reactions • The most important phase I reaction is oxidation involving ·A reducing agent (NADPH) · Molecular oxygen · NADPH cytochrome p450 oxidase · Cytochrome p450 • Drugs which inhibit cytochrome p450 will prevent the metabolism of other drugs. which rely on this enzyme e.. • Hence.g. it is important to know whether a person is a smoker or not when prescribing drugs.

UDP glucoronide transferase. Phase II reactions • Phase II reactions are usually the detoxification step.g. • The enzymes involved in phase II reactions are tranferases. catalyses the conjugation of a drug with glucoronide. conjugation. e. • Conjugation usually allows for easier excretion since the drug is converted into a more hydrophilic form. • It combines some reactive group which is added to the phase-I reaction e.g. .

Factors affecting drug metabolism (A) Internal factors: 1· Species : Differences in drug metabolic enzymes level in inter species. while phase II conjugation reactions develop perinatally. Phase I reactions develop very early in the foetus. hepatitis . 3. e.g. Gender differences: There are some differences in alcohol and estrogen metabolism in males and females. 5. cirrhosis. Age: Metabolism of drugs is different in very young and old age. Hormonal effects: A hypothyroid person has a reduced metabolic activity. Alcohol metabolism is vary from person to person due to difference in alcohol dehydrogenase level.g. 2· Genetic polymorphism : Differences in the enzymes of metabolism within intra species (between individuals). 4. 6· Co-existing disease: Diseases of liver will generally reduce its metabolic capabilities e.

. Ethanol may affect the metabolism of diazepam 2.. 3. ... Lifestyle: Smokers can induce the enzymes required in the breakdown of theophyline. Also may affect the plasma proteins binding.g. External factors 1.............Drug – Drug interactions: It cause: • Competition for the same enzyme involved in metabolism • Induction of an enzyme involved in metabolism • Inhibition of an enzyme involved in metabolism e... Dietary factors: A protein deficiency may affect enzyme production..Factors affecting drug metabolism.

Elimination or Excretion of drug .

Elimination of drugs from the body M KIDNEY LIVER A J filtration metabolism O secretion secretion R (reabsorption) M LUNGS OTHERS I N exhalation mother's milk O sweat. R Most important route of drug elimination is via the kidney . saliva etc.

Elimination by the kidney • Drugs which are not metabolised by the liver rely on the kidney as the major way of removal of the drug from the blood. less toxic and able to be filtered through glomerulus. . • The drugs metabolised by liver are more water soluble.

Biliary excretion How does a drug enter the bile? · Transport systems transport the drug from the plasma into the bile against a concentration gradient · Large molecular weight drugs may be subject to this type of transport. .

.After Phase I and II reactions drug will convert in to more water soluble form and excreted in kidney Lungs · Can be used to eliminate gases and volatile anaesthetics Sweat · Drugs which are present in sweat may cause skin sensitivity Milk · Lactating mothers need to be aware that breast milk may contain drugs which are being taken by the mother.Drug elimination………… Liver .

what the drug does to the body ..Pharmacodynamics …………….

40 . • The success of a drug’s response depends on two factors: • Molecular fit • Number of receptor sites it bonds to • The better the fit and the greater number of receptor sites occupied. the stronger the response. How Drugs Work—An Conceptual Overview • Most drugs (free drug) act by forming chemical bonds with specific receptor sites within the body to stimulate and/or inhibit a response. • The interaction of a drug with a receptor is reversible due to interactions via weak bonds (not covalent).

DOSE-RESPONSE CURVE Maximal Effect EFFECT EFFICACY POTENCY ED50 Log [Dose] Therapeutic Index (TI) = TxD50 Safety of drug ∝ TI 41 .

It has intrinsic activity = 1 +++ ++. Agonists and Antagonists AGONIST • A drug is said to be an agonist when it binds to a receptor and causes a response or effect. --- --. +-. +++ Depolarization 42 .

• It has intrinsic activity < 1. 43 .PARTIAL AGONIST • A drug is said to be a partial agonist when it binds to a receptor and causes a partial response.

ANTAGONIST • A drug is said to be an antagonist when it binds to a receptor and prevents (blocks or inhibits) a natural compound or a drug to have an effect on the receptor. Its intrinsic activity is = 0 • They can bind both reversibly and irreversibly 44 . • An antagonist itself has NO activity.

45 . The antagonist inactivates the receptors. B) Irreversible The effect of irreversible antagonists cannot be overcome by more drug (agonist). Competitive Antagonist Similar structure with agonist and compete for the same binding site through two ways • Reversible • Irreversible A) Reversible The effect of reversible antagonists can be overcome by agonist.PHARMACOLOGICAL ANTAGONISTS 1.

g.Non-Competitive Antagonist They don’t have similarity with the agonist and can be bind elsewhere on the receptor site. channel blockers. . e.