Pharmacodynamics - Part 2 Lecture Notes (20/10/2024) PDF

# Field of Veterinary Medicine ## Veterinary Medicine Program ### Lecture 2: General Pharmacology (Pharmacodynamics - Part 2) #### Dr. Asmaa Elsayyad, Assistant Professor of Pharmacology **Date:** 20/10/2024 ## What are Receptors? - **Def:** Macromolecules form a chemosensitive area on the cell m...

# Field of Veterinary Medicine ## Veterinary Medicine Program ### Lecture 2: General Pharmacology (Pharmacodynamics - Part 2) #### Dr. Asmaa Elsayyad, Assistant Professor of Pharmacology **Date:** 20/10/2024 ## What are Receptors? - **Def:** Macromolecules form a chemosensitive area on the cell membrane or within the cell to which a specific group of drugs or naturally occurring substances (e.g. neurotransmitters and hormones) *called Ligands* can bind. - **Ligands?:** Molecules that combine with the receptors, either endogenous or exogenous (administered drugs). - **Image:** A cartoon of a cell with a key and lock symbol above it. There are arrows to two different areas inside the cells labeled: *Extracellular receptor* and *Intracellular receptor*. ## Terminology - **Affinity? Fit?:** The ability of a drug to fit into a receptor, forming a drug/receptor complex. - **Efficacy? Fit &...?** The ability of drug/receptor complex to induce action. - **Agonist? ... The good guy!:** The drug that fits in a specific receptor forming an agonist-receptor complex with an intrinsic response. - **Antagonist? ... The bad guy!:** The drug that fits in a specific receptor forming an antagonist-receptor complex *without intrinsic response*. (So, it prevents the action of agonist without any effect by itself). - **Image:** A cartoon of two separate cells each with the same four receptors. The first cell is labeled *agonist*, and the agonist is depicted as a green smiling character which activates the receptors. The second cell is labeled *antagonist* and the antagonist does not activate the receptors as depicted by a black frowning character. ## Types of Agonist & Antagonist ### Agonist - Full agonist - Partial agonist ### Antagonist - Competitive antagonist - Non-competitive antagonist - **Image**: A branching diagram depicting the two types of agonist and antagonist along with the subtypes of each using cartoon depictions. ## Full Agonist v. Partial Agonist | **Receptor activation** | **Full Agonist** | **Partial Agonist** | | :------------------------ | :----------------------- | :--------------------------- | | **Response** | Induce maximal response when bind to all/fraction of the receptors | Induce submaximal response when bind to all the receptors (act as both agonist & antagonist) | | **E.g.** | Morphine – Opioid receptors | Buprenorphine – Opioid receptors | ## Types of Antagonist | **MOA** | **Competitive antagonist** |**Non-competitive antagonist** |**Depolarizing Antagonist** | | :------------------------- | :----------------------------------------------------------- | :------------------------------------------------------------------------------------ | :-------------------------------------------------------------------------------------- | | | Competes with the agonist for the same binding site. | Modifies the binding of the agonist to the receptor by binding to another site. | Bind to the same site > initial stimulation followed by inhibition (persistent depolarization). | | **Reversibility** | + (Reversible= displaced by excess agonist) | - (Irreversible) | - (Irreversible) | | **E.g.** | Atropine + Ach - muscarinic receptors | Phenoxybenzamine – alpha receptors; OPC - irreversible anticholinesterase | Succinylcholine – nicotinic receptors; NLD - nicotinic receptors | ## Drug-Receptor-Theories 1. **Occupation theory:** - More number of receptors occupied - The maximal response is reached when all the receptors are occupied. 2. **Rate theory:** - Faster rate of drug-receptor interaction (association & dissociation) - More drug efficacy. 3. **Macromolecular Perturbation theory:** - The drug-receptor combination - Conformational changes of the receptor - **Agonist:** specific perturbation - active (Action) - **Antagonist:** non-specific perturbation - inactive (No action). - **Image:** A cartoon depiction of two receptors, one with a smiling agonist and the other with a frowning antagonist, illustrating specific and nonspecific perturbation. ## Dose and Dosage of Drugs - **Therapeutic (Effective) dose:** The safe amount of a drug that induces the desired effect. - **Minimal effective dose:** The smallest amount that initiates a response. - **Maximal effective dose:** The largest amount safely administered without causing toxicity. - **Maintenance (Ongoing) dose:** The regular amount required to keep the therapeutic blood level by replacing the eliminated amount. - **Toxic dose:** The sufficiently large amount to induce toxic symptoms. - **Lethal dose:** The sufficiently large amount to induce death. - **Dosage (drug regimen):** A set of instructions for how to take a medication (dose, route, frequency, time, duration). - **Image:** A graph, measuring concentration against time, illustrating the different doses and their effects. ## Dose/Response Relationship (DRC) (Plotting of the dose vs response) - **Efficacy (Emax)**: The maximal possible effect induced by a drug regardless of the dose. More efficient drug = higher plateau. Eg. Drug B is more efficient than drug A. - **Potency (ED50)**: The amount of drug required to induce a given response (usually 50% response). More potent drug = lower dose induces the given effect. Eg. Drug A is more potent than drug B. - **Image:** Two graphs illustrating a dose-response curve demonstrating efficacy and potency. ## Therapeutic Index (Window) - It measures the *safety margin* of the drug. - **Therapeutic index (TI) = LD50 / ED50.** - **ED50 (median effective dose):** The dose that induces a therapeutic effect in 50% of the tested lab animals. - **LD50 (median lethal dose):** The dose that kills 50% of the tested lab animals. - The higher the value = the wider the safety margin. - **Image:** A graph illustrating a dose-response curve, demonstrating the therapeutic window and its relationship to the TI. ## Factors Affecting Drug Action and Doses 1. **Age:** - Young & older animals -- ↓dose - Adult animals -- normal therapeutic dose 2. **Body wt.** - Dosage is proportional to body weight (heavier patient -- ↑doses) 3. **Gender:** - Females -- smaller organ size, hormonal difference, pregnancy & lactation > altered dose. 4. **Species:** - Physiological variations (e.g., Emetics -- not used in horses or cattle) - Metabolic variations (e.g., Ivermectin toxicity in cats & dogs) 5. **Route:** - Route may alter action (MgSO4 – orally purgation, locally – decrease swelling, IV – CNS depression) - IV dose = 1/4 oral dose - IM dose = 1/3 oral dose - SC dose = 1/2 oral dose - Rectal dose = 2 oral dose 6. **Time:** - Stomachic – before meals - Digestants – during meals - Irritant drugs – after meals - Hypnotics - before sleep 7. **Pathological state:** - Inflamed intestine, diseased liver or kidney - Immunocompetence (very young or old) ## Intolerance - An extraordinary response to a drug at therapeutic or even sub-therapeutic doses -- ↑risk of toxicity - Genetic deficiency of metabolizing enzymes (poor metabolizer) - e.g., Warfarin --> Hemorrhage. - ↓ the initial dose. - Sudden stopping of some drugs (blockers) after prolonged administration - Rebound action. - E.g., beta blockers --> severe tachycardia & arrhythmia. - Gradual withdrawal ## Tolerance - The unusual resistance to the therapeutic drug dose -- ↑the dose to obtain the initial response. - **A. Congenital** - Without previous exposure to the drug (Genetic disorder--Rapid metabolizer). - ex. Ruminant tolerate barbiturates & rabbits tolerate atropine. - **B. Acquired** - Develops by the constant use of drugs (due to previous exposure). 1. **Cross tolerance:** between two pharmacologically related drugs (e.g., Barbiturates). 2. **Tachyphylaxis (acute tolerance):** Rapid ↓ drug response when used repeatedly at short intervals (e.g., Ephedrine). 3. **Antimicrobial resistance:** micro-organisms can resist antibiotics after previous exposure (e.g., Aminoglycosides). ## How to prevent Tolerance? - **To prevent tolerance:** - Use the lowest effective dose. - Avoid using the drug for prolonged periods. - Drug-free intervals: take breaks from the drug. - Shift to a different medication (e.g. a corticosteroid instead of ephedrine). - **To prevent antimicrobial resistance:** - Only use antibiotics when prescribed. - Administer the full course. - Limit the use of antibiotics as growth promoters. - Follow the withdrawal time. ## Drug Interaction - The action between two or more drugs administered together resulting in an altered response. - **Outside the body (in vitro)** - Occurs during preparing or mixing drugs → *physicochemical incompatibilities* - e.g., oil+ water →*immiscibility* or gentamicin (basic) +penicillin (acidic) →*neutralization*. - **Inside the body (in vivo)** - **A. Pharmacokinetic Interactions:** - **Absorption:** Ca -- tetracycline absorption (insoluble chelate) & Antacids -- ↓absorption of acidic drugs. - **Distribution:** Diuretics -- ↓aminoglycoside distribution (↑toxicity). - **Biotransformation:** Barbiturates -- ↑metabolism of other drugs -- ↓ duration of action. - **Excretion:** Probenecid -- ↓renal excretion of penicillin -- ↑duration of action. - **B. Pharmacodynamic Interactions** - **Addition (1+1= 2):** The combined effect = the sum of the action of two individual drugs of the same action. - e.g. Paracetamol+ caffeine "pain relievers”. - **Synergism (1+1=4):** The combined effect > the sum of the action of two individual drugs of the same action. - e.g. Penicillin+ streptomycin "antibiotics" or Sulfonamides+ trimethoprim "antibacterials". - **Potentiation:** The promotion of a drug's effect by another one with dissimilar properties. - e.g. Probenecid+ Penicillin or Streptomycin+ succinylcholine - **Antagonism:** The opposing effect of a drug to another one when both are administered together. It may be: - **i- Physiological**: e.g., histamine (bronchoconstrictor)+ adrenaline (bronchodilator). - **ii- Chemical**: e.g., Protamine+ heparin → inactive product. - **iii- Pharmacological**: Competitive (e.g. Tubocurarine+ Ach -- cholinergic receptors) or Depolarizing (e.g. succinylcholine + Ach -- cholinergic receptors) ## Drug Cumulation - The tendency of drugs to cumulate in the body due to: - **1. Slow metabolism or excretion (rate of administration > elimination).** - **2. Binding to tissue or plasma proteins (E.g. Digoxin in heart muscle) → the bound part is inactive → slowly released & eliminated → prolonged effect & ↑toxicity.** - The full therapeutic response-- summation of doses (increase the initial dose then temporal cessation then resuming). - **Image:** A cartoon depiction of a drug attaching to a protein and another depiction of the drug moving through the body including the plasma and tissues. # Thank You - **El Tur Campus:** Sahely Road - **Ras Suder Campus:** Obour Street - **Sharm El Sheikh Campus:** El Nour District - **Website:** www.ksiu.edu.eg - **Email:** [email protected]