PHARMACOLOGY

PHARMACOLOGY
The science which deals with drugs Origin, structure, preparation, administration, actions, ADME . DRUG: Any molecule used to alter body functions thereby preventing, diagnosing or treating disease (PDT)

Drug Names
1. Chemical name : According to the chemical structure, it is long and rarely used. 2. Official (Approved or Generic) name: The name which is given by the international organization of drug nomenclature. 3. Trade (Proprietary or brand) name: The name which is given by owner (the drug company). Example: 7- Chloro, 3-dihydro benzodiazepine 2- one (Diazepam) Valium, Stesolid, Valipam

Sources of Drugs
1. Plant Alkaloids: Atropine, Pilocarpine and Morphine Glycosides: Digoxin. 2. Mineral: Fe, Ca. 3. Animal: Insulin. 4. Microorganisms: Antibiotics. 5. Synthetic: Aspirin and sulphonamides. 6. Semisynthetic : Ampicillin. 7. Genetic engineering: Recombinant DNA technology, r-insulin, r- erythropoeitin

Routes of Drug Administration

Enteral (through GIT) & Parenteral (out side GIT) Oral Injections IV, IM, SC Buccal Topical Rectal Inhalation

Oral Routes
Tablets, Capsules, Solution, Syrup, Suspension, Elexir. Advantages: Convenient- portable no pain easy to take Cheap no sterilization no expert.

Oral Routes
Disadvantages: Variable bioavailability First pass effect Food can affect absorption Local effect, taste, irritation Effect on flora Unconscious pts.

Buccal/ Sublingual
Advantages: No first pass effect Rapid absorption and effect Drug stability Disadvantages: Inconvenient Small doses only.

Rectal
Suppository or enema. Advantages: Reduced first pass effect - Useful in patients unable to take drugs orally or young children Disadvantages: - Erratic absorption. - Not well accepted

Injections
Intravenous (IV) Bolous and infusion Advantages: Rapid Total dose and large dose Suitable for irritant drugs Disadvantages: Difficulty in finding suitable vein Need expert Risk of toxicity & non recall Expensive

Subcutaneous (SC)
Advantages Self administration insulin - Complete but slow absorption - Absorption delayed and duration of action prolonged by adding vasoconstrictor. Disadvantages Pain - Irritation - Small dose

Intramuscular (IM)
Advantages Larger volume than SC - Depot or sustained release preparation are possible. Disadvantages Pain - Need expert -Erratic absorption as Phenytoin and diazepam.

Inhalation
Local effect Bronchodilator Systemic effect General anesthesia Advantages: - Rapid - No first pass effect Disadvantages: - Irritation - Some particles may be precipitated in mouth or throat

Topical
Local effect Eye drops, Antiseptic solution, Ointment, cream, Lotion, Gargle Systemic effect- Nitroglycerine ointment or patches. High local conc. and effect. Absorption increased by cuts, abrasions and intact skin of infants.

Pharmacokinetics
What the body does to the drug. It deals with: Absorption Distribution

ADME

Metabolism and Excretion of the drug and the mathematical relationships of these parameters

Pharmacodynamics
It is what the drug does to the body. It deals with the pharmacological actions and the mechanisms by which these actions are performed.

Absorption
The passage of drug from site of administration (from out side) to the blood stream. To do so the drug has to pass through cell membranes. Cell membranes are of lipid bilayer and pores. Most drugs are absorbed by Passive diffusion or simple diffusion.

Absorption(cont.)
Absorption by passive diffusion depends on: 1. Concentration gradient Direct proportion 2. Lipid solubility Direct proportion 3. Degree of ionization Indirect proportion

 For acids pKa = pH + log M/I For bases pKb = pH + log I/M Example 1: Aspirin is an acidic drug pKa = 3.4 in the stomach pH = 1.4, so 3.4 = 1.4 + log M/I , log M/I = 2 , M/I = 100 M = 100 I In the duodenum pH 7.4, so 3.4 = 7.4 + log M/I , log M/I = - 4 , M/I = 1/10000 I= 10000 M How does aspirin behave in urine pH = 6.4?

Hasselbalch Henderson Equation

Hasselbalch Henderson Equation(cont.)

Example 2: Ephedrine is a basic drug pKa =9.4 in the stomach pH = 1.4, so 9.4 = 1.4 + log I/M , log I/M = 8 , I/M = 108 I = 108 M In the duodenum pH 7.4, so 9.4 = 7.4 + log I/M , log I/M = 2, I/M = 1/100 I= 100 M How does aspirin behave in urine pH = 6.4?

Question
What is the effect of acidification or alkalinization of urine on excretion of aspirin and ephedrine?

Absorption (cont.)
Facilitated difusion Minority of drugs require carrier mediated transport e.g. Levodopa and Iron

Factors Affecting Rate and degree of Absorption

1. Lipid solubility, degree of ionization & concentration gradient. 2. Surface area. 3. Transit time. 4. Blood flow.

Bioavailability (F)
The fraction of the unchanged unmetabolized drug, which reaches the systemic circulation following administration. IV, F = 100% of the dose i.e. F = 1. F = AUC oral/ AUC IV Different routes and different brands give different bioavailabilities

Factors of Incomplete bioavailability

1. Acid labiality Benzyle penicillin. 2. Incomplete absorption by food or drugs. 3. Metabolism by enzymes in the gut wall or the liver glyceryl trinitrate (First Pass Effect) the metabolism of orally administered drugs by gastrointestinal and hepatic enzymes, resulting in a significant reduction of the amount of unmetabolized drug reaching the systemic circulation.

Distribution
Drug distribution refers to the movement of a drug to and from the blood and various tissues of the body (for example, fat, muscle, and brain tissue) and the relative proportions of drug in the tissues. It is the process by which a drug reversibly leaves the blood stream and enters the extracellular fluid and then the cells of the tissues.

Factors Affecting Distribution

1. Blood flow. 2. Capillary permeability. 3. Binding of drug to plasma proteins and tissues. 4. Hydrophobicity.

Protein Binding
P+D PD P = Plasma protein, D = Free unbound drug PD = Bound drug to protein. Only the the free unbound drug fraction can pass membranes and producing effect, metabolized and excreted. Acid drugs usually bound to albumin. Basic drugs usually bound to 1 acid glycoprotein

Protein Binding(cont.)
Drugs which are highly protein bound: Warfarin Phenylbutazone Diazepam.

Drugs which are highly protein bound: Digoxin Gentamicin Theophylline.

Apparent Volume of Distribution

It is the volume that would be required to contain all the drug in the body at the same concentration as in the plasma. Assuming the body as a single compartment. Vd = Dose/ Cp ---- IV Vd = Fx Dose / Cp ------ Other routes. Low Vd ----- High Cp and low tissue binding , Haemodialysis is useful as in Aspirin and Warfarin and vice versa as in Tricycic antidepressants and Chloroquin

Selective distribution
Iodide Thyroid gland. Thyopentone fat act as a reservior Blood brain barrier (BBB) Keeps some drugs from entering CNS - tight junction in the endothelium, and to pentrate the CNS the drug : Low ionization, Low protein binding, High lipid solubility and of Small molecular size The placental barrier: Protects the fetus, more tight at early monts, same criteria as in BBB

Drug Metabolism
Aims: (Usually) 1. Reducing lipid solubility. 2. Alteration of biological activity. Sites: 1. Liver Most drugs 2. Plasma Succinylcholine 3. GIT mucosa - Contraceptives 4. Synaptic neurones Sympathetic amines.

Pathways of drug metabolism

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Factors Affecting Drug Metabolism

1. Genetic factors Fast and slow metabolizers. As : Isoniazid, Hydralazine. 2. Age, neonates and very old. 3. Pathological factors Liver diseases. 4. Enzyme induction and inhibition:

Microsomal Enzymes

Drug Metabolizing Enzymes

Microsomal
Non Microsomal

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Microsomal Enzymes
Found predominately in the smooth Endoplasmic Reticulum of liver Other areas:
Kidney Lungs Intestinal mucosa

Non-microsomal enzymes
Found in the cytoplasm and mitochondria of hepatic cells Other tissues including plasma

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Microsomal Enzymes
Non-synthetic/ Phase I reactions
Most oxidation and reduction Some hydrolysis

Non-microsomal enzymes
Non-synthetic/ Phase I reactions Most hydrolysis Some oxidation and reduction Synthetic/ Phase II reactions ALL except Glucuronide conjugation

Synthetic/ Phase II reactions

ONLY Glucuronide conjugation

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Microsomal Enzymes

1. Inducible
Drugs, diet, etc.

Non-microsomal enzymes
Not inducible
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