Basic Pharmacology

By: Dhshan Hassan Dhshan

Basic Pharmacology By Dhshan Hassan Dhshan

Basic Pharmacology

By: Dhshan Hassan Dhshan

Introduction (General
Pharmacology)

Basic Pharmacology

By: Dhshan Hassan Dhshan

What is Pharmacology? It is the science that deals with chemical substance (drugs) on the function of living system. i.e.: The study of drug - What they are - How they work - what they do Drugs (Therapeutic agent):Any substance other than food can be used in the prevention, diagnosis, or treatment of disease Sources of drugs:-Natural -Synthetic -Semisynthetic -----------------------------------------------------------------------------------------------------------------Pharmacology

Pharmacokinetics

Pharmacodynamics

Pharmacotherapeutics

What the body does to drug ADME

What the drug does to body

The result of drug and body action

-Absorption Mechanism of Uses of Drug Action -Distribution (Therapeutic (Drug receptor -Metabolism effect) interaction) -Elimenation ------------------------------------------------------------------------------------------------------------------

Route of administration
1: Oral rout:
Advantage: 1: The most common. 2: More safe. 3: Non irritant. 4: Easy of Administration. 5: Economic. 6: Potable. Disadvantage:1: Not suitable for: -Emergency -Irritant -Vomiting -Diarrhea 2: Affected by PH. 3: First Pass Effect.(decrease activity and absorption of drug)
Stomach Drug Stomach Drug
3

Liver Intestine

Intestine

Not First Pass Effect

Basic Pharmacology

By: Dhshan Hassan Dhshan

Factors affecting oral absorption:1: Presence of food in the stomach. e.g. -Amino acid compete for the same carrier of l-dopa. -Calcium from milk absorption of Tetracyclin. -Tannic acid and tetracycline absorption of Iron. 2: State of health in the stomach. -presence of disease absorption 3: Gastric Emptying rate. -may be or absorption depend on drugs e.g. -Paracetamol In Emptying rate absorption. -Digoxin In Emptying rate absorption. N.B. Atropine motility of GIT Emptying rate. 4: Motility of GIT. - Motilityin case of diarrhea absorption. 5: PH of GIT. -Acidic drugs absorbed in acidic medium (Stomach). -Basic drugs absorbed in basic medium (Intestine). 6: First pass effect. Absorption. 7:Related to the drug. lipid solubility Absorption.

Blood-Brain Barrier B.B.B

N.B. (Like dissolve like)

-Means polar drug (water soluble drug) not totally absorbed in the cell in tissue due to high amount of lipid content and not pass through B.B.B (Blood Brain Barrier) but lipid Soluble drug highly absorbed and Pass B.B.B.

Blood-Brain Barrier B.B.B

Basic Pharmacology

By: Dhshan Hassan Dhshan

2: Parentral rout (injection):A-Intravenous (IV) injection: Advantage: 1:100% bioavailability (amount of drug reached to blood ) 2: No first pass effect. 3: Suitable for irritant drug. 4: Suitable in emergency. 5: Suitable for Acid labile drugs. Disadvantage: 1: low safety. 2: Must be Sterile. 3: Spreading of infection. 4: Required professional person. 5: Not suitable for oily and Suspended drugs. ----------------B-Intramuscular (IM) injection: Suitable for soln., susp. And oily drugs. Better absorption than SC but less than IV. ----------------C-Subcutaneous (SC) injection: Absorption rate is slower than IV and IM It is suitable for drugs that are non-irritant in aqueous soln. or fine susp. ----------------D-Other injection: e.g. - intacardial - intrabone marrow - intrathecal - intraperitoneal ------------------------------------

3:Mucosal rout:Buccal or Sublingual Nasal Ocular Systemic delivery of Local delivery Local delivery of drug of drug drug Vaginal Rectal Local delivery Systemic and of drug Local delivery of drug ------------------------------------

4: Inhalation:- Systemic delivery of drug

-highly absorbed (high bioavailability) after parental high blood supply. -Many drugs make lung irritants. ------------------------------------

4: Transdermal:- Systemic and Local delivery of drug. -e.g. Nicotine patches.

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Basic Pharmacology

By: Dhshan Hassan Dhshan

Pharmacokinetics
Def.: Effect of the boy on the drug. Consist of 4 process (ADME)

1: Absorption
Def.: the transfer of drug from the site of administration into the blood stream depend on Route of Administration Mechanism of Absorption Passive diffusion (simple diffusion) - From high concn. to low concn. - No needed energy and carrier. -The drug must be lipid soluble and small in Mwt. Factors affecting simple diffusion 1: increase dose concn. Increase absorption. 2: increase Mwt. and size Decrease absorption. 3: increase ionization water soluble drug Decrease absorption. 4: PH at the site of absorption. Special transfer.

1: Facilitate Diffusion. -From high concn. to low concn. with concn. gradient. -Need Carrier and not need energy. e.g. Glucose 2: Active diffusion. -From low concn. to high concn. with concn. gradient. -Need carrier and need energy. e.g. Vit.C

3: Pinocytosis. -Frome low concn. to high concn. with concn. gradient. -Need carrier and need energy. e.g. Vit. B12 intrinsic factor complex.

Basic Pharmacology

By: Dhshan Hassan Dhshan

Factors affecting absorption

1: Patient-Related factors: Route of Administration. I.V.>I.M.>S.C.>Oral>Skin Absorbing surface. Increase Surface increase Absorption Systemic circulation. Shok and heart failure decrease absorption Presence of other drugs. Adrenaline S.C. Vasoconstriction (V.C.) absorption. Specific factors e.g. intrinsic factor for Vit.B12. 2: drug-Related factors: Water and lipid solubility. High lipid solubility Drug high absorption Ionization. Non ionized More lipid soluble high absorption. Valency. Ferrous iron > Ferric iron. Nature. Inorganic (small molecules) > Organic (Big molecules) Pharmaceutical preparation. Solution > Suspension > Tablet -------------------------------------------------------------

Bioavailability
Def.: the amount of administration drug reached to systemic circulation. I.V. = 100% Oral <100% Example: Cyclosporine Bioavailability IV = 100% Bioavailability Oral = 25% Oral dose = 4 x IV dose Factors affecting Bioavailability First pass effect decrease Bioavailability Efflux from introcytes. Physicochemical properties of the drug. (Polarity solubility Particle size) Nature of formulation. (Solution > Suspension > Tablet).
Of drug

Basic Pharmacology

By: Dhshan Hassan Dhshan

2: Distribution
Def.: the transfer of drug from the blood stream into the tissue. Depend on: Blood flow increase increase distribution (lung > liver > Bran) Ability of the drug to pass biological membrane. ( polarity and size of drug) Degree of binding to plasma protein (PP) (increase binding decrease Distribution)

N.B.:

Drug

Plasma Protein (PP)

(Drug

Complex and PP)

Active form inactive from -When the free drug concn. The binding drug converted to free drug to give the same
action. -Amount of free drug can be increase by: 1: Displacement by other drugsReplacement of one drug by another. e.g. Aspirin and warfarin (anticoagulant) is binding in the samesite of PP increase aspirin intake increase free drug (Active drug)of warfarin increase toxicity .
.

2: decrease in albumin or plasma protein liver disease.

Volume of distribution
Def.: the apparent volume of fluid into which an administrated drug is dispersed. Vd (volume of distribution) = Q (Total amount of drug in the body) /Cp (Plasma concn.) : volume of distribution e.g.: - Aspirin Vd =16L / 100Kg. - Digoxin Vd =2290L / 100Kg. N.B.: -If the drug has Vd higher than 42L / 100Kg the drug has low affinity to binding to PP. - If the drug has Vd lower than 42L / 100Kg the drug has high affinity to binding to PP. Cp = Q / Vd
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Basic Pharmacology

By: Dhshan Hassan Dhshan

Half-life (t1/2)
Def.: is the time pass for the plasma concn.. or the amount of drug in the body to be reduced by 50%.
Drug blood concn.

(t1/2)
Max. concn.

50% (t1/2)

Onset time

Elimination time Time

t1/2 can be increase by :

decrease renal blood flow decrease Metabolism rate decrease Protein binding

t1/2 can be decrease by : increase renal blood flow increase Metabolism rate increase Protein binding

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3: Metabolism
Metabolism or Biotransformation usually conversion of drug from non-polar polar more polar Polar Group Metabolism Non lipid soluble Lipid soluble Site of Metabolism. - Hepatic microsomal biotransformation (located in the hepatic smooth endoplasmic reticulum ) -Non Hepatic microsomal biotransformation (located lung, Skin, and kidney)

Responsible for conjugation, and other Oxidation,reduction and hydrolysis. Cant be induced and inhibited. Activity is stable.
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Responsible for Oxidation by Cytocrome P450, Glucuronidation, reduction and hydrolysis. Can be induced and inhibited. Activity is low.

Basic Pharmacology

By: Dhshan Hassan Dhshan

Divided into :-

1: Oxidation e.g. Phenancetin paracetamol 2: Reduction e.g. Chloral hydrate tri-chloro ethanol 3: Hydrolysis e.g. Heroin HAC + Morphine
1: Glucuronidation e.g. Paracetamol 2: Acetylation e.g. Isnoniazide 3: Methylation e.g. Noradrenalin 4: Conjugation e.g. Conjugation with glycine Aspirin

Phase I Phase II

Results of metabolism. Inactivation - Active drug (Adrenalin) Inactive (Vanil mandilic acid (VMA)). Activation - Inactive drug (Imipramine) Active (Desipramine). Maintain activation - Active drug (Phenacetin) Active (Paracetamol). Toxification - Drug (Methyl alcohol) Toxic (Formaldehyde). Factors affecting metabolism. Age: deficiency of liver microsomal enzyme specially in child prolonged action of drug Increase toxicity e.g.Chloramphenicol. Sex differences : metabolism rate of certain drug faster in male than female e.g. diazepam Genetic factor: Absence of specific gene responsible for syntheses of special enzyme essential for normal metabolism. State of health: Presence of disease alter in the normal metabolism. Inhibition of microsomal enzymes: certain drug inhibit the activity of microsomal enzyme leading to prolongation the action of drug increase activity and toxicity of drug e.g. Cemitidine, Chloramphenicol, Omeprazole, Erythromycin and Ketoconazole. Induction of microsomal enzymes:certain drug increase the activity of microsomal enzyme leading to increase metabolism rate decrease activity ( plasma concn. of drug)of drug e.g. Carbamazepine, Phenobarpitone and Imipramine. -------------------------------------------------------------------------------------------------------------------------------------

4: Excretion
Def.: the process which involve excretion of drug out side of the body. Major drug excreted path way by -Urinary excretion -Biliary excretion. Minor drug excreted path way by -Saliva -Skin -Milk -Gastric excretion -Bile salt. If drug acid we used alkaline to increase excretion. If drug alkali we used acid to increase excretion.

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Basic Pharmacology

By: Dhshan Hassan Dhshan

Pharmacodynamics
Def.: the study of the relationship of drug concn. to drug effect.

D + R = DR
- D drug - R Receptor - DRDrug Receptor complex. -Biological effect increase when the drug receptor complex increases. What is a Receptor? -Any biological molecule to which a drug binds and produces Response. - Receptor called Ligand. . Major classes of receptors Ligand-gated ion channels. Voltage-gated ion channels. Enzyme linked receptor (Tyrosine Kinase-Linked Receptor). Endogenous receptor (ligand activated transcription factors). G-protein-coupled receptor.

Ligand-gated ion channels.

Voltage-gated ion channels

Tyrosine Kinase-Linked Receptor

G-protein-coupled receptor

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Basic Pharmacology

By: Dhshan Hassan Dhshan

G-protein-coupled receptor (GPCRs)

G-protein Def.: protein between receptor and effector organs.

GPCRs

Agonist
Receptor

G.p Cell Types:- Gs Stimulatory increase Adenylcyclase increase cAMP (cyclic Adenosine MonoPhosphate ) increase Ca++ influx from Sytoplasmic Reticulam (SR). - Gi Inhibitory decrease Adenylcyclase decrease cAMP decrease Ca++ influx. - Gq Stimulatory increase Phospholipase C (PLC)increase Insitol tri-phosphate (IP3) and increase DAG (Di-Acyl Glycerol). - Go decrease post synaptic Potential decrease vomiting.

Cardiac cell

Blood Vessel

Gs
B-agonist in Cardiac Muscle Mechanism of Gs in Cardiac Muscle Constrictor Drug: Agonist binding to receptor Stimulate receptor stimulate Gs increase A cyclase increase cAMP increase Ca++ from SR increase Ca++ in the Cardiac Muscle Activates myosin light chain kinase Phosphorylates myosin, interacts with actin Cardiac muscle Contraction.

Gq
Vasoconstrictors Drugs Mechanism of Gq in Vasoconstrictors Drugs : Agonist binding to receptor Stimulate receptor stimulate Gq increase PLC PIP2(Phospho Insitol di-phosphate) IP3 + DAG Increase IP3 Increases intracellular Ca++Activates myosin light chain kinase Phosphorylates myosin, interacts with actin Contraction.

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Basic Pharmacology

By: Dhshan Hassan Dhshan

What is a Ligand? Any substance combines with receptor. types of Ligand:-

Ligand has affinity and efficacy to Receptor

Agonist Antagonist

Ligand has affinity and not have efficacy to Receptor

Ligand-receptor interaction
(Lock and Key theory)

Receptor Ligand

--------------------------------------------- Relationship between drug concn. and receptor binding: Increase Concentration of drug [D] increase ability of binding to receptor.

Bmax x [D] B= [D] x Cd

B = Fraction of available receptors bound. Bmax =Maximum binding with receptor. [D] = Concentration of drug. Cd or Kd = dissociation constant.

Bmax B Cd

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Basic Pharmacology

By: Dhshan Hassan Dhshan

Dose Response Curve

Emax: the lowest dose produce maximum response.
ED50

ED50: The dose that produce 50% of Emax.

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Agonist types
B

A : full agonist : Maximum efficacy Maximum Potency B : full agonist : Maximum efficacy Reduced Potency C : Partial agonist : Reduced efficacy Maximum Potency D : Partial agonist : Reduced efficacy Reduced Potency

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Dose
Def.: the amount of drug given to the patient at a time. Types of dose: Therapeutic dose: The average dose that produce therapeutic effect. Maximum tolerated dose: The largest dose of a drug that can be taken safely. Initial dose: The dose used at start of treatment. Maintenance dose: The dose required to maintain the therapeutic effect. Lethal dose or Fetal dose: The dose that produce death.
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Basic Pharmacology

By: Dhshan Hassan Dhshan

Factors affecting the dosage and action of drug. 1: Age, weight and body surface area. Adult dose (20 60 years of age) and weight about 70 kg. Children required small dose. Calculation of child dose from adult dose. Youngs formula : Adult dose X age in years Child dose =
(Age + 12)

Dillings formula : Child dose = Clarks formula : Infant dose =

Adult dose X age in years 20 Adult dose X Wt. in pounds 150

2: Sex: Female need smaller dose than male due to High fat content increase fate in the body slow rate of oxidation decrease metabolism. Effect of sex hormone on liver enzyme. Some drug avoided during Pregnancy, lactation and menstruation. 3: Route of administration: IV < Inhalation < IM < SC < Oral 4: Time of administration: Irritant drugs are better taken after meals e.g. Aspirin. CNS (Central Nervous System) stimulant drugs should be not given at night they may cause insomnia e.g. Ephedrine. 5: Genetic abnormality (Drug Idiosyncrasy) Idiosyncrasy Abnormal reaction to drug due to genetic abnormality. E.g. Primaquine may induce hemolytic anemia in Patient with Glucose-6phosphate dehydrogenase deficiency in red blood cells (Hemolysis)

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Basic Pharmacology

By: Dhshan Hassan Dhshan

6: Hypersusceptibility (Supersensitivity drug intolerance) - The greater response to adrenaline in thyrotoxic patient - Drug intolerance is commonly observed in infant because metabolism and excretion not fully developed

7: Hypersensitivity (Drug allergy) - Antibody-antigen interaction increase release of histamine Symptoms 1 : skin reaction (Skin rash, urtecaria and oedema) 2: Fever 3: Asthmatic attack 4: anaphylactic shock e.g. Penicillin

8: Tolerance Def.: Failure of responsiveness to the usual dose. Types : Congenital Tolerance Racial Ephedrine is not mydriatic in Negroes )) Species Rabbits is tolerated large amount of Belladonna due to Atropinesterase enzyme in rabbit liver and Plasma which rapidly detoxicate atropine. Individual Genetic factors are possibly involved. Acquired Tolerance - Increase the dose to obtain the original effect Cross Tolerance between Nicotine and Lobeline. Tachyphylaxis effect increase gradual decrease e.g. Ephedrine Increase Blood Pressure then decrease. Bacterial resistance to antibiotic. - Mechanism of acquired tolerance (Drug Desensitization) Receptor Medicated Non-Receptor Medicated -loss of receptor Function -Physiological adaptation -Reduction of Receptor No. -reduction of receptor-coupled signaling component -Reduction of drug concn.

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Basic Pharmacology

By: Dhshan Hassan Dhshan

Therapeutic Index
Def.:( Measure of drug safety) it is the ratio of the dose that produces toxicity to the dose that produce effective response in population individual.

LD50 (or TD50) TI = ED50

TI = Therapeutic index LD50 = Drug dose that produces death in 50% of population. TD50 = Drug dose that produces toxic effect in 50% of population. ED50 = Drug dose that produces therapeutic effect in 50% of population. ----------------------------------------------------------------------------------------------------------------

Drug dependence
It usually occurs after administration of CNS acting drugs. Is a phenomena related to tolerance. It involves a certain degree of tissue adaptation. Withdrawal of the drug could produce certain unpleasant symptoms. Types Habituation Addiction - Mild degree of drug dependence. - More serious form of drug dependence. - Psychological dependence. - Psychological and Physical dependence. - When drug stopped develop some - When drug stopped Withdrawal emotional distress for a relative short symptoms reverse the normal period. pharmacological action - e.g. Smoking and Coffee. - e.g. Morphine

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Basic Pharmacology

By: Dhshan Hassan Dhshan

Drug-Drug Interaction
Def.: Drug interact with another drug when presence of both in the body. May be Increase in drug effect. Decrease in drug effect.

When Increase in Drug effect

Addition Algebraic sum of the 2 Drugs effect 1+1=2

Synergism The combination effect more than algebraic sum 1 + 1 = > 2 e.g. Ethyl alc. and barbiturates

Potentiation One of the drug is active and another is inactive 1 + 0 = > 1 e.g. Acetyl alc. and Ether

When Decrease in Drug effect

Antagonism

Chemical antagonism Chemical interaction between 2 drug decrease absorption

Physiological antagonism Decrease physiological function of 2 drugs act on 2 different receptor different effects Competitive

Pharmacological antagonism 2 drugs act on the same receptor but one of them is agonist and the other antagonist
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Acetylcholine and atropine

Non competitive
Acetylcholine and organophosphate