Pharmacology First 2 Lectures PDF

# Pharmacology Pharmacology is the science dealing with drugs. ## Drugs Drugs: are chemical substances that stimulate or inhibit an existing cell function. They are used for treatment, prevention and diagnosis of diseases or modify a physiological process. ## Areas of Pharmacology - **Pharmacokine...

# Pharmacology Pharmacology is the science dealing with drugs. ## Drugs Drugs: are chemical substances that stimulate or inhibit an existing cell function. They are used for treatment, prevention and diagnosis of diseases or modify a physiological process. ## Areas of Pharmacology - **Pharmacokinetics:** It describes what the body does to the drug, which includes Absorption, Distribution, Metabolism & Excretion [ADME]. - **Pharmacodynamics:** It describes what the drug does to the body, which include the study of the pharmacological actions of drugs and their possible mechanisms of action. - **Pharmacotherapeutics:** Study the selection & use of drugs for diagnosis, prevention & treatment of disease. **N.B.:** The main goal of a physician is to give to the patient proper adjusted drug doses to obtain therapeutic levels that produce the desired response with the minimal adverse effects. ## Passage of Drugs Across Cell Membranes The cell membrane is a lipid bilayer interrupted by protein macromolecules in the form of ion channels, carriers and receptors, and contains water filled channels. **Passage of drugs across cell membranes occurs mainly by:** 1. Simple diffusion 2. Carrier mediated. ### Simple Diffusion The chief process involved in absorption & distribution of drugs. Simple diffusion depends on: 1. **Concentration gradient:** drugs pass from one side of the cell membrane to the other along concentration gradient. 2. **Molecular size:** the smaller, the better the absorption. 3. **Lipid solubility and lipid/water partition coefficient:** the more, the better the absorption. * **N.B.:** Lipid/water partition coefficient is the ratio of drug concentration in lipid medium and drug concentration in water medium when it is put in lipid water system. 4. **Degree of ionization:** * The more the ionization, the less the lipid solubility. * Degree of ionization depends on: * pKa of the drug * pH of the medium. 5. **No energy & no carriers are needed.** #### pKa * **pKa** (ionization constant of a drug): It is the pH media at which 50% of the drug is ionized and 50% nonionized e.g. pKa of aspirin 3.5. #### pH of the Medium (MCQ) 1. Most drugs are either weak acids or weak bases. 2. Weak acids are better absorbed in acidic media where it is less ionized and so more lipid soluble. 3. Weak bases are better absorbed in alkaline media where it is less ionized so more lipid soluble. #### Henderson Hasselbalch Equation The degree of ionization is determined by: Henderson Hasselbalch equation (reading only) * **Weak acids:** pKa = pH + log(unionized/ionized) * **Weak bases:** pKa = pH + log(ionized/unionized) **N.B-** Acidic drugs as aspirin will be unionized in acidic medium of stomach -> better absorbed in stomach. When filtered in glomeruli, can be reabsorbed again from renal tubules if urine is acidic, while alkaline urine enhances their excretion. * Weak base drugs as amphetamine will be better absorbed from intestine and acidic urine will enhance their excretion. ### Carrier Mediated Of 2 types: #### Facilitated Diffusion Drugs are transferred across cell membranes: * Along their concentration gradient. * Carrier for substances which are too large or lipid insoluble to diffuse passively * No energy is required. * e.g. glucose uptake by cells. #### Active Transport Drugs are transferred across cell membranes: * Against their concentration gradient * Energy * Carrier * e.g. secretion of penicillin by renal tubules. ## Pharmacokinetics [ADME] ### Absorption Absorption is the transfer of a drug from its site of administration to the systemic circulation. #### Factors Affecting Drug Absorption: very important ##### Factors Related to the Drug: 1. Water and lipid solubility: * Drugs MUST be Water soluble as well as Lipid soluble. * Drugs must be completely dissolved in water to be absorbed. * More lipid solubility → high Lipid/Water partition coefficient → better absorption. 2. Ionization: * Non-ionized → More lipid soluble → Better absorption * Depends on pKa of the drug & pH of the medium. * Quaternary ammonium compounds "Neostigmine" → Ionized → Poor absorption * Tertiary amines "Physostigmine" Non-ionized → Better absorption. 3. Valency: Ferrous iron (Fe2+) > Ferric Iron (Fe3+). 4. Nature: Inorganic (small molecules) > Organic (Big molecules). 5. Pharmaceutical Preparation: * Dosage form: Solution > Suspension > Tablet. * Shape & size of particles and rates of disintegration & dissolution of tables: * Rapid with paracetamol & propranolol BUT slow with digoxin. * Excipient (Filler): CaCO3 & Ca Phosphate * Absorption of Tetracyclines. ##### Factors Related to the Patient: 1. Route of Administration: I.V. and inhalation > I.M. > S.C. > Oral > Skin. 2. Absorbing Surface: * Vascularity: Alveoli > Skeletal muscle > Subcutaneous. * Surface area: Alveoli > Intestine > Stomach (Intestine 1000 X Stomach). * State of health: Diarrhea & mal-absorption * Oral absorption. * Systemic circulation: Shock & Heart failure * Absorption. * Specific factors: Intrinsic factor for Vit B-12. * Absorption of Local anesthetics → Longer duration of action of local anesthetics. * Presence of other drugs: * Adrenaline S.C. → V.C. * Milk (Calcium) * Oral absorption of Tetracyclines (Antibiotic). #### Factors Affecting Oral Absorption: ##### Factors related to the drug: See before ##### Factors related to the patient: 1. Surface area of absorbing surface: * The intestine has surface area 1000 times that of stomach (due to microvilli) and rich blood flow. Thus, absorption from intestine > stomach. 2. State of absorbing surface: Gastritis, malabsorption syndrome * Oral absorption 3. Motility of the gut and rate of dissolution: * Prokinetic drugs increase the gut motility e.g. Metoclopramide * gut motility → ↑ gastric emptying → ↑ absorption of rapidly disintegrated drugs (paracetamol) and ↑ absorption of slowly disintegrated drugs (digoxin). * Atropine inhibits the gut motility → ↓ gastric emptying. * ↓ Absorption of rapidly disintegrated drugs and ↓ absorption of slowly disintegrated ones. 4. pH within the gut: * Weak acids (aspirin) are better absorbed in an acidic media. So better absorbed in stomach. * Weak bases (amphetamine, ephedrine) are better absorbed in an alkaline media of intestine. 5. Specific factors: Intrinsic factor from stomach is essential for Vit B12 absorption. 6. Gut contents: presence of food & other drugs: * Presence of food: * Bad → Food dilutes Drugs & may compete with them for absorption * e.g. aminoacids compete for the same carrier of L-DOPA. * Good → with IRRITANT drugs e.g. aspirin & iron. * Tetracycline and Calcium and iron absorption by chelation. * Cholestyramine & charcoal absorption of many drugs by adsorption. * Grape fruit juice ↓ absorption of drugs by inhibiting P. glycoprotein (which cause reversed transport of drug from gut wall to lumen). * Tea → ↑ iron absorption by its content of tannic acid. #### First Pass Effect: very important Means metabolism of drug in gut wall or liver before reaching systemic circulation. ##### Gut First Pass Effect: 1. Gastric acidity: destroys benzyl penicillin. 2. Digestive enzymes: destroy insulin 3. Mucosal enzymes: destroy chlorpromazine ##### Hepatic First Pass Effect: 1. Drugs extensively metabolized: e.g. Nitroglycerine. * To avoid: change the route of administration: Nitroglycerine SL. 2. Drugs metabolized to a large extent: e.g. propranolol. * To avoid: the oral dose. ### Bioavailability Bioavailability is the fraction of unchanged drugs reaching systemic circulation after any route of administration. * Bioavailability is 100% after IV administration and Variable after oral administration. * Oral bioavailability = (AUC oral / AUC IV) X 100 * Factors affecting oral bioavailability: very important * Amount of drug absorbed: Factors affecting GIT absorption. * First pass metabolism. ### Distribution After absorption from whatever route of administration a drug will distribute according to…