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Pharmacology

Pharmacology. By Prof. Dr. Amany Ibrahim El-Brairy Professor of Pharmacology H107. Why we study Pharmacology?. Drug information : knowledge, skills, and attitude Rationale and safe prescribing in dental practice throughout the dental graduate career Self and continuous learner.

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Pharmacology

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  1. Pharmacology By Prof. Dr. Amany Ibrahim El-Brairy Professor of Pharmacology H107

  2. Why we study Pharmacology? • Drug information : knowledge, skills, and attitude • Rationale and safe prescribing in dental practice throughout the dental graduate career • Self and continuous learner

  3. The following scheme is used in discussion of a drug Name Of The Drug 1- Definition 2-Pharmacokinetics = What the BODY does to the DRUG = A. D. M. E. a- Absorption: Oral and/or Other b- Distribution: Binding to plasma proteins, Blood Brain Barrie & Placental barrier. c- Metabolism: Hepatic and/or other d- Excretion: Renal and/or other e.g. Milk

  4. 3- Pharmacodynamics = What the DRUG does to the BODY a- Mechanism of action b- Pharmacological actions: - Desirable = Therapeutic effects = Uses - Undesirable = Adverse effects = Side effects and toxicity 4- Pharmacotherapeutics: a- Therapeutic uses = Indications b- Dosage 5- Side effects and toxicity: a- Manifestations b- Management 6- Contraindications 7-Drug interactions.

  5. Types of drug names Chemical: e.g. acetyl salicylic acid. Generic (scientific): e.g. aspirin. Commercial (Trade): e.g. Rivo, Aspocid, Rhonal..etc.

  6. PHARMACOKINETIC What the Body dose to the Drug? Absorption, Distribution, Metabolism , Excretion ADME

  7. Absorption Reabsorption Bound Drug Free Drug Metabolite/s Distribution Site of Action Site of storage Excretion Metabolism

  8. The study of pharmacokinetics is important to: 1- Design a proper dosage schedule (dose, route, frequency of administration) 2- Determine the drug’s bioavailability.

  9. * Bioavailability: 1- The fraction (%) of administered drug that reaches the systemic circulation in an unchanged form. 2- Bioavailability is 100% after I.V. & most variable after oral administration

  10. Absorption Rate & Efficiency = Bioavailability Oral Systemic Circulation I.V. GIT pH & Enzymes Liver Oral I.V.

  11. Bioavailability of a Route = Area under the curve (AUC) of the route x100 Area under the curve (AUC) of I.V. route

  12. Trans-membrane Movement of DrugsPassage of Drugs Across Biological Membranes Cell membrane is formed mainly of bimolecular LIPID sheet, interrupted by protein macromolecules (receptors, carriers, etc.), water-filled pores & ion channels Lipid Protein Water Ions

  13. * TypesofPassage of drugs A) Passive Transfer: 1- Simple Diffusion: a- Mostly across the LIPID phase of cell membrane. b- Water & water-soluble small M.W. drugs pass across the water-filled pores. * Characteristics: 1- Along concentration gradient. 2- NO carrier. 3- NO energy. Lipid No Carrier No Energy

  14. Factors & Forces: 1-Gradient(Concentration of drugs ) Higher gradient = Higher rate of passage across the membrane. 2-Molecular weight & size: The smaller is the faster.

  15. *Passive Diffusion (cont.) 3-Solubility in water is a must. 4-Oil (lipid) / Water (O/W) partition coefficient. The higher is the better. A 10 g B 9 2 / / 1 8 9 1/4 Oil H2O

  16. *Passive Diffusion (cont.) 5-Ionization: • It depends upon pH of the medium & pKa of the drug (pH at which 50% of drug is ionized) • Low Ionization = High lipid solubility = Better passage. • Drugs are non-ionized when they are present in a similar medium (Acidic drugs in acid medium and basic drugs in alkaline medium).

  17. * Effect of pH on Oral Absorption & Renal Excretion of Drugs : - For weak base and acid drugs: a- The unionized (non-polar) form is lipid soluble and easily absorbed. b- Ionized (polar) form of drugs is lipid insoluble and not easily absorbed but easily excreted. • Weak acid drugs are more unionized in acid & more ionized in alkaline media. • Weak base drugs are more unionized in alkaline & more ionized in acid media.

  18. When drugs are present in a reverse medium → Ionized → not lipid soluble → not absorbed → Excreted. • Aspirin is better absorbed in acid medium e.g. Stomach. • Alkalinization of urine by sodium acetate, or citrate  its urinary excretion. • Ephedrine is better absorbed in alkaline medium e.g. Intestine. • Acidification of urine by ammonium chloride  its urinary excretion.

  19. 2-Filtration: Passage of drugs through Capillary endothelium & Glomeruli * Characteristics: • Along hydrostatic and osmotic gradients • No carrier • No energy Circulation

  20. 2-Filtration )cont.) * Factors & Forces: 1- Molecular weight 2- Not bound to plasma proteins 3- Hydrostatic and osmotic gradients 4- Blood flow

  21. B) Special Transfer: 1- Facilitated Diffusion: Along concentration gradient Needs Carrier Site for Saturation No energy Example: Glucose uptake Carrier No Energy

  22. B) Special Transfer (cont.) 2- Active Transport: Against concentration gradient Needs Carrier Site for Saturation & Competition (Interaction) Energy & Enzymes Example: Na+/K+ pump & Renal tubular excretion of penicillins Carrier Energy

  23. B) Special Transfer (cont.) 3- Pinocytosis (Cell Drinking): Energy dependent Example: Absorption of Vit B12 + Intrinsic factor by terminal ileum

  24. I- Absorption • Transfer of drugs from their site of administration to the systemic circulation

  25. *Factors Affecting Absorption: A) Factors Related to the Patient 1-Route of Administration: I.V. > I.M. > S.C. > Oral > Skin 2-Absorbing Surface: a-Vascularity: Alveoli > Skeletal muscle > Subcutaneous b-Surface area: Alveoli > Intestine > Stomach c-State of health: Diarrhea & mal-absorption inhibitOral absorption

  26. 3-Systemic circulation: Shock & Heart failureAbsorption 4-Specific factors: Intrinsic factor for Vit B-12 5-Presence of other drugs & food: • a-Adrenaline S.C. V.C. Absorption of Local anestheticsLong duration of action • b-Milk (Calcium)   Oral absorption of Tetracyclines (Antibiotic)

  27. B) 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. Drugs insoluble in water e.g. Barium chloride (BaCl2) are NOT absorbed. More lipid solubility High Lipid/Water partition coefficientBetter absorption

  28. 2-Ionization: Non-ionized drugs are more lipid soluble Better absorption Depends on pKa of the drug & pH of the medium. Tertiary amines Non-ionizedBetter absorption. Streptomycin has high pKa Always ionizedNot absorbed SulfaguanidineNot ionized yetnot lipid solublePoor absorption

  29. 3- Valency: Ferrous iron (Fe2+) is better absorbed than Ferric Iron (Fe3+). 4- Nature: Inorganic (small molecules) > Organic (Big molecules) 5- Pharmaceutical Preparation: a- Dosage form: Solution > Suspension >Tablet b- Shape & size of particles and rates of disintegration & dissolution of tables: Rapid with paracetamol & propranolol Slow with digoxin c- Excepient (Filler)e.g. CaCO3 & Ca Phosphate  Absorption of Tetracyclines.

  30. Routes of Administration • Enteral 1- Buccal e.g. Sublingual 2- Oral 3- Rectal • Others 1- Parenteral e.g. Injection 2- Inhalation 3- Topical

  31. Effect Of Administered Drug: 1-Systemic (General): If drug is absorbed and distributed 2-Local (Topical): If drug is not absorbed nor distributed

  32. Enteral Route • 1-Sublingual  Absorbed directly Systemic circulation Good Bioavailability • 2-Oral  Stomach & Intestine  pH changes & enzymes  Portal circulation  Liver metabolism  Systemic circulation Most variable Bioavailability • 3-Rectal (Suppository)  a-Upper rectum  Portal circulation  Liver metabolism  Systemic circulation b-Lower rectum  Systemic circulation

  33. 1- Oral Route Characteristics: 1- Suitable: a- Small amount or volume b- Palatable: If bad taste  - Dilute with milk or fruit juice - Use sugar coated or effervescent form b- Non-irritant: If Mild irritant  - Take after meal - Use enteric coated form: Covered with acid resistant coat

  34. Advantages: Convenient (Safe, easy & economic) Disadvantages: 1-NOT in emergency  Delayed onset 2-NOT in uncooperative patients e.g. coma, insane or very young 3-NOT in vomiting or severe diarrhea 4-NOT in very irritant drugs e.g. Emetine HCl 5-NOT in unabsorbed drugs when systemic effect is wanted 6-NOT for drugs with extensive First Pass Effect (Metabolism): a-pH changes: Benzyl penicillin is destroyed by gastric acidity b-Digestive enzymes: Insulin c-Hepatic enzymes: Nitroglycerin

  35. D) Factors Affecting Oral Absorption: 1- StateofHealth of G.I.T. Mucosa e.g. Mal-absorption Syndrome. 2- Specific Factors e.g. Intrinsic Factor for Vit B12 Absorption. 3- Gastric Emptying: a- Metoclopramide (Primperan, Anti-emetic) Emptying  -  Absorption of Paracetamol (Rapid rates of Disintegration & Dissolution). -  Absorption of Digoxin (Slow rate of Disintegration & Dissolution) b- Atropine  Emptying  The REVERSE Effects. 4- Gut Motility: Marked alterations (e.g. Morphine)  Absorption.

  36. 5- pH a- Gastric Acidity  Absorption of Salicylates & Barbiturates b- Intestinal Alkalinity  Absorption of Ephedrine & Amphetamine. 6- Presence of FOOD & Other DRUGS: a- Bad  Food dilutes Drugs & may compete with them for absorption e.g. amino-acids compete for the same carrier of L-DOPA b- Good  with IRRITANT drugs e.g. aspirin & iron. c- Milk (Ca2+) & Anti-acids  Interfere with Tetracycline absorption. d- Tea (Tannic Acid) & Tetracycline  Iron absorption. e- Cholestyramine & Activated Charcoal  Absorption of Most Drugs.

  37. 7- First Pass Effect (Pre-Systemic Metabolism):  Bioavailability a- Gut First Pass Effect: - Gastric Acidity: Benzyl Penicillin. - Digestive Enzymes: Insulin & Pituitary hormones - Mucosal enzymes: Tyramine, L-DOPA, -Methyldopa &Chlorpromazine - Flora: Histamine c- Hepatic First Pass Effect: - Extensive: Nitroglycerine, Lidocaine & Natural sex hormones. - Partial: Propranolol & Morphine. - Minimal: Atenolol, Nadolol & Barbitone. d- How to OVERCOME Hepatic First Pass Metabolism? - Increase the oral dose of the drug e.g. Morphine & Propranolol - Use other routes (NOT ORAL) e.g. Sublingual “Nitroglycerine”. 8- Factors related to the DRUGe.g. Lipid Solubility.

  38. 2-Sublingual (Pellet or Linguat) *Example: Isoprenaline & Nitroglycerine. *Advantages: 1- Easy. 2- Escape gut and hepatic first pass effect  Good bioavailability. 3- Rapid onset. 4- Proper control of dose by either spitting or swallowing excess of the drug.

  39. 3-Rectal: 1- Solid (Suppository): Drug (Aminophylline) in a cone of gelatin or cocoa butter. 2- Fluid (Enema): a- Evacuant (Cleansing) enema e.g. for constipation: -Large volume (1 liter) -High head pressure -Mild irritant (chamomile) b- Retention enema e.g. Nutrient: -Small volume (1/4 liter) -Low head pressure -Non-irritant

  40. B) Advantages: a- Escape gut & hepatic first pass effects b- Useful in patients with vomiting c- Useful in uncooperative patients e.g. coma & young children d- Useful in mild irritant drugs e.g. aspirin and aminophylline e- Useful in large volume drugs

  41. Parenteral RoutesAll drugs must be STERILE and PYROGEN-FREE A)Subcutaneous Pellet Implantation: Sterile pellet under the skin  Fibrosis  Slow absorption  Long duration e.g. some hormones (Contraceptives). B)Intradermal Injection (I.D.): e.g. Sensitivity tests & Vaccinations.

  42. C)Subcutaneous Injection (S.C.): 1-Drugs should be: a- Non-irritant (If irritant or oily  Inflammation) b- Aqueous Solution or fine suspension. 2-Absorption can by Enhanced by: a- Use a solution b- Massage of injection area c- Application of heat d- Add hyaluronidase enzyme 3-Absorption can be Slowed by: a- Use a suspension b- Application of cold c- Add adrenaline (V.C.) to local anesthetics d- Add gelatin to heparin

  43. D) Intramuscular (I.M.): 1- Drugs can be: Solution, suspension, oily, non-irritant or mild irritant. 2- Better absorption than S.C. 3- Some drugs (Diazepam & Phenytoin)  Bound to muscle proteins  Irregular absorption.

  44. E) Intravenous (I.V.): • Either SLOW bolus injection or Infusion (Drip) method. • Water solution ONLY. • Advantages: Useful in Emergencies a- 100% bioavailability b- Immediate onset c- High plasma concentration d- Useful for Irritant & Large volume drugs

  45. Disadvantages: MOST DANGEROUS ROUTE a- If Allergy  Anaphylactic shock b- If Very Irritant  Thrombophlebitis c- If Extravasation of irritant drug  Severe pain and inflammation d- If Rapid I.V.  Velocity reaction  Cardiac problems (Aminophylline) e- Pyrogenic reaction by phospho-lipo-protein of microorganisms f- Transmission of diseases e.g. Viral Hepatitis C & AIDS.

  46. F) Other Injections: 1- Intra cardiac e.g. Adrenaline in cardiac resuscitation 2- Intra-umblical = I.V. in new born e.g. Lobeline in neonatal asphyxia 3-Intra-bone marrow = I.V. 4- Intra-arterial e.g. Angiography and cancer chemotherapy 5- Intra-peritoneal as substitute for Hemodialysis 6- Intra-thecal (CSF) e.g. spinal anesthesia, antibiotics in meningitis & Radiography 7- Intra-articular e.g. Steroids in osteoarthritis 8- Intra-cameral (Into aqueous humor)

  47. Inhalation - Inhaled drugs may be in the form of: a-Gas e.g. Oxygen & Nitrous oxide b-Vapor of Volatile liquid e.g. Halothane (General anesthesia) c-Solution e.g. Salbutamol (B2-agonist in Bronchial asthma) d-Powder e.g. Di-sodium-cromoglycate (Mast cell stabilizer in Bronchial asthma)

  48. - Excellent absorption because of: a-Wide surface area b-High vascularity c-Thin porous membrane of the alveoli

  49. Topical e.g. Skin & M.M. 1-Usually Local effect. However highly lipid soluble drugs can be absorbed from the skin. 2-Skin absorption can be enhanced by: a-Iontophoresis by the aid of galvanic electric current e.g. Methacholine in P.V.D. b-Inunction by the aid of rough rubbing. c-Transdermal Drug Delivery System (TDDS) e.g. Skin patch of nitroglycerine - Prolonged blood level with minimal fluctuations - Better patient compliance - Avoid gut & hepatic first pass effect

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