Pharmacology I SGS 242 PDF

OCTOBER UNIVERSITY FOR MODERN SCIENCES AND ARTS FACULTY OF DENTISTRY PHARMACOLOGY I SGS 242 Prof. Dr. Amany I. El-Brairy Prof. Dr. Abdelfattah H. Marrie The best of British higher education in the best environment  Pharmacology...

OCTOBER UNIVERSITY FOR MODERN SCIENCES AND ARTS FACULTY OF DENTISTRY PHARMACOLOGY I SGS 242 Prof. Dr. Amany I. El-Brairy Prof. Dr. Abdelfattah H. Marrie The best of British higher education in the best environment  Pharmacology I For Dentistry Students SGS 242 Amany I. El-Brairy Abdelfattah H. Marrie  Contents Subject Page 1- Introduction i 2- Objectives of the course ii 3- General Pharmacology 1 4- Autonomic Nervous System 24 5- Blood 44 6- Skeletal muscle 54 7- Central Nervous System 58 8- General Anesthesia 78 9- Local Anesthesia 84 10- Bibliography 89  Introduction Pharmacology, a discipline bridging basic and clinical science, is now increasingly directed toward developing new drugs and therapeutic agents based on sound mechanistic principles. For example, coincident with the explosion of information in the molecular biology, biochemistry, and physiology of receptors and signaling mechanisms; the neurobiology of transmitters; and the immunochemistry of monoclonal antibodies and lymphokines, the aim of pharmacology is to develop new drugs and therapeutic agents of greater selectivity than previously thought possible. Classical physiological responses to drugs and fundamental studies of disease processes in clinical medicine also continue to contribute important insights for drug development. Accordingly, in this book, appropriate, balanced emphasis is placed on both basic and clinical mechanistic aspects with the goal of providing the student with a sound fundamental understanding of the discipline, within a text of reasonable size, to better prepare for future self-learning in pharmacology. i  Objectives of Pharmacology Course For Dentistry Students At the end of this course, each student should be able to: Demonstrate an understanding of the terminology used to describe basic pharmacologic principles and drug classification. Describe the basic pharmacokinetic principles governing uptake, distribution, metabolism and elimination of drugs and apply these principles in the therapeutic management of patients. Describe and explain pharmacodynamic concepts of drug-receptor interaction to accurately predict drug responses at all levels of biological organization. Interpret pharmacological data such as dose-response curves in the context of optimizing drug therapy. Differentiate between terms such as efficacy, potency and therapeutic index as they relate to drug therapy. Demonstrate an understanding of the basic mechanisms of drug- induced toxicity and drug-drug interactions and develop appropriate approaches to their management. Demonstrate an understanding of the basic mechanisms involved in modification of drug responses by disease, genetic background, sex and age. Apply the above concepts to all major drug groups in the development of the most effective and safe treatment regimen for patients presenting with a variety of therapeutic problems. Describe the effects exerted by drugs on cells, tissues, organ systems, and patients and be able to explain the mechanisms underlying these effects at various levels of biological organization. Demonstrate his/her development of a professional set of attitudes concerning drug therapy. Utilize appropriate resource materials (i.e. textbooks, literature & colleagues) to supplement their basic fund of knowledge in developing a rational and safe therapeutic approach for patients. ii  General Pharmacology  General Pharmacology PHARMACOLOGY NB) 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 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. Types of drug names Chemical: e.g. acetyl salicylic acid. Generic (scientific): e.g. aspirin. Commercial (Trade): e.g. Rivo, Aspocid, Rhonal..etc. General 1 General  PHARMACOKINETICS (What the Body dose to the Drug?) Absorption, Distribution, Metabolism & Excretion (ADME) Absorption Systemic Bound Drug Circulation Excretion Distribution: Free Drug 1-Site of action Metabolites 2-Site of Storage Metabolism The study of pharmacokinetics is important to design a proper dosage schedule (Dose, route, frequency of administration) and to determine the drug’s bioavailability. * 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. Oral I.V. G.I.T. Hepatic Systemic pH Metabolism Circulation Digestion Area under the curve (AUC) of the route 3- Bioavailability of a Route = X 100 Area under the curve (AUC) of I.V. route Plasma Conc. Plasma Conc. I.V. Oral AUC AUC Time Time General 2 General  Trans-membrane Movement of Drugs Passage of Drugs Across Biological Membranes. * Types of Passage of drugs: Lipid A) Passive Transfer : Protein 1- Simple Diffusion: Water 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. * Factors & Forces: 1-Gradient (Concentration of drugs & Electric of ions): Higher gradient = Higher rate of passage across the membrane. A B 2-Molecular weight & size: The smaller is the faster. Lipid 9 2 3-Solubility in water is a must. / / 4-Oil (lipid) / Water (O/W) partition coefficient. The higher is the better. Water 1 8 5-Ionization: 9 x It depends upon pH of the medium & pKa of the drug. (pKa = Dissociation constant of 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). When drugs are present in a reverse medium → Ionized → not lipid soluble → not absorbed → Excreted. Weak acid drugs e.g. Aspirin and Barbiturates are better absorbed in acid medium e.g. Stomach. Alkalinization of urine by sodium or potassium acetate, bicarbonate, benzoate or citrate → ↑ Their urinary excretion. Weak base drugs e.g. Ephedrine & Amphetamine are better absorbed in alkaline medium e.g. Intestine. Acidification of urine by ammonium chloride or ascorbic acid → ↑ Their urinary excretion. * Effect of pH on Oral Absorption & Renal Excretion of Drugs : 1- 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. 2- According to Henderson-Hasselbalch equation : a- For weak acids : pKa = pH + Log UNionized / Ionized drug. Weak acid drugs are more unionized in acid & more ionized in alkaline media. b- For weak bases: pKa = pH + Log Ionized / UNionized drug. Weak base drugs are more unionized in alkaline & more ionized in acid media. General 3 General  2- Filtration: Passage of drugs through capillary endothelium & Glomeruli * Characteristics: 1- Along hydrostatic and osmotic gradients No carrier Systemic Circulation No energy * Factors & Forces: 1- Molecular weight 2- Not bound to plasma proteins 3- Hydrostatic and osmotic gradients 4- Blood flow B) Special Transfer: Cell Membrane 1- Facilitated Diffusion: + Carrier No Energy Along concentration gradient Needs Carrier → Site for Saturation & Competition (Interaction) No energy Example: Glucose uptake Cell Membrane + Carrier 2- Active Transport: + Energy Against concentration gradient Needs Carrier → Site for Saturation & Competition (Interaction) Energy & Enzymes Example: Na+/K+ pump & Renal tubular excretion of penicillins 3- Pinocytosis (Cell Drinking): Energy dependent Example: Absorption of Vit B12 + Intrinsic factor by terminal ileum Characteristics Simple Diffusion Facilitated Diffusion Active Transport 1- Gradient: Along Along Against 2- Carrier: NO Yes Yes 3- Saturation & NO Yes Yes competition: 4- Energy: NO NO Yes 5- Example: Lipid soluble drugs Glucose Na+/K+ pump General 4 General  I- Absorption l Transfer of drugs from their site of administration to the systemic circulation *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 → ↓↓ Oral absorption 3-Systemic circulation: Shock & Heart failure → ↓↓ Absorption 4-Specific factors: Intrinsic factor for Vit B-12 5-Presence of other drugs: a-Adrenaline S.C. → V.C. → ↓↓ Absorption of Local anesthetics → Long duration of action b-Milk (Calcium) → ↓↓ Oral absorption of Tetracyclines (Antibiotic) 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 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. 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 BUT slow with digoxin c- Excepient (Filler)e.g. CaCO3 & Ca Phosphate → ↓ Absorption of Tetracyclines. General 5 General  Routes of Administration Enteral Others 1- Buccal e.g. Sublingual 1- Parenteral e.g. Injection 2- Oral 2- Inhalation 3- Rectal 3- Topical NB) Effect Of Administered Drug: 1-Systemic (General): If drug is absorbed and distributed 2-Local (Topical): If drug is not absorbed nor distributed Enteral Route 1-Sublingual → Absorbed directly →Systemic circulation → Good Bioavailability. S.L. 9 2-Oral → Stomach & Intestine → pH changes & enzymes → Portal circulation → Liver metabolism → Systemic circulation → Most variable Bioavailability. Oral → GIT & Liver →? 3-Rectal (Suppository) → a-Upper rectum → Portal circulation → Liver metabolism → Systemic circulation Rectal b-Lower rectum Systemic circulation 1- Oral Route A) Characteristics: 1- Suitable: a- Small amount or volume NB) Enteric Coated Tablet b- Palatable: If bad taste → e.g. Na Salicylate - Dilute with milk or fruit juice Acid resistant - Use sugar coated or effervescent form Drug coat e.g. c- Non-irritant: If Mild irritant → Shellac - Take after meal - Use enteric coated form: Covered with acid resistant coat 2- Stable: pH changes, digestive enzymes & hepatic enzymes. 3- Absorbable if used for systemic effect B) Advantages: Convenient (Safe, easy & economic) C) 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 (Anti-amebic) 5-NOT in unabsorbed drugs when systemic effect is wanted (Streptomycin in TB) 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 (Anti-anginal) General 6 General  D) Factors Affecting Oral Absorption: 1- State of Health 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. 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. 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, α-Methyldopa & Chlorpromazine - Flora: Histamine b- Hepatic First Pass Effect: - Extensive: Nitroglycerine, Lidocaine & Natural sex hormones. - Partial: Propranolol & Morphine. - Minimal: Atenolol, Nadolol & Barbitone. 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 DRUG e.g. Lipid Solubility. w w w w w w w w w w w w w w w w w w 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. General 7 General  3- Rectal: A) Either: 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 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 c c c c c c c c c c c c c c c Parenteral Routes All 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. C)Subcutaneous Injection (S.C.): 1-Drugs should be: a- Non-irritant b- Aqueous Solution or fine suspension. If irritant or oily → Inflammation 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 General 8 General  D) Intramuscular (I.M.): 1- Drugs can be either: 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. E) Intravenous (I.V.): Either SLOW bolus injection or Infusion (Drip) method. Water solution ONLY. Advantages: a- 100% bioavailability Useful in Emergencies b- Immediate onset c- High plasma concentration d- Useful for Irritant & Large volume drugs 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. 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) **************************** Inhalation 1- 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) 2- Excellent absorption because of: a-Wide surface area b-High vascularity c-Thin porous membrane of the alveoli General 9 General  Topical e.g. Skin 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 3-Usually skin absorption is not wanted and harmful: a-Estrogen hormone in females → Cancer breast. b-Cortisone in infants → Moon face. c-Insecticides → Toxicity. h h h h h h h h h h h h h h h Distribution NB) Patterns Of Distribution: Total Body Fluid Extra-cellular Intra-cellular Intra-vascular Interstitial Cells 1- Free fraction Bound Fraction 2- High M.W. (Poly) & Bound → xxx 3- Low M.W. BUT NOT lipid soluble xxx 4- Low M.W. & Lipid Soluble A) Binding To Plasma Proteins: A fraction of Most drugs binds Reversibly to plasma proteins Mainly albumin. The Bound fraction of the drug → NOT Active, NOT Filtered, NOT Metabolized & NOT Excreted → Depot Form. More binding = More Depot = Longer duration. The Free fraction of the drug → Active, Metabolized & Excreted. There is equilibrium between the bound & the free fractions of the drug. Drugs extensively bound to plasma proteins e.g. Thiopentone (I.V. Anesthesia) & Diazoxide (Arterio-dilator) have to be injected rather Rapidly I.V. Drugs have specific binding sites on plasma proteins = Non-functioning receptors → Site for competition & drug interactions. Site for Drug Interactions: Aspirin (NSAID), Phenytoin & Sulfa drugs displace: 1- Oral Anti-coagulants e.g. Warfarin → Hemorrhage. 2- Oral Hypoglycemics e.g. Tolbutamide → Hypoglycemia. 3- Bilirubin in neonates → Jaundice & Kernictrus. General 10 General  B) Patterns Of Distribution: 1- Intra-vascular (Single Compartment): Drug is retained in the blood compartment. Drugs that can NOT filtrate through capillary endothelium. Examples High MW > 500 e.g. Polypeptides (Plasma proteins & Drugs bound to plasma proteins) & Polysaccharides (Heparin & Dextrans). 2- Extra-cellular (Two compartments = Intra-vascular + Interstitial): Drugs that can filtrate (Small MW) but can NOT pass cell membrane (Not lipid soluble). Ionized form of drugs (Neostigmine), Mannitol, Na+, Cl- & SO4. 3- All over the body (Multi-compartment = Intra + Extra-cellular): Drugs that can filtrate (Small MW) & Can pass cell membrane (Lipid soluble). Non-ionized form of drugd (Physostigmine), Alcohol, Aspirin & Barbiturates. 4- Tissue Reservoirs: a- Hair: Arsenic b- Thyroid: Iodine c- Heart: Digitalis d- Liver: Vit B12 & Chloroquine e- Fat: Thiopentone f- Bone: Ca2+ 5- Blood Brain Barriers: Lipid cellular barrier composed of Brain Capillary Endothelium (Which lacks the water channels) and the adjacent Glial tissue. Only lipid soluble Non-ionized drugs can pass B.B.B. along their concentration gradient. Inflammation (Meningitis) increases permeability of B.B.B. Penicillins can pass inflamed meninges but NOT normal ones. 6- Placental Barrier: Lipid cellular barrier composed of Epithelium of Fetal Villi & Capillary endothelium. Rich in enzymatic activity e.g. M.A.O. Drugs that pass placental barrier may cause: - During pregnancy → Teratogenicity e.g. Thalidomide & Tetracyclines - During Labor → Neonatal asphyxia e.g. Morphine & Barbiturates. General 11 General  Metabolism (Biotransformation) Chemical alteration of the drug AIMING to convert: Drugs (Active, Non-ionized & Lipid soluble) → Metabolites (Inactive, Ionized & water soluble) → Easily excreted in urine & bile. * Types of Metabolism: A) Phase-I (Non-Synthetic) → Oxidation, Reduction & Hydrolysis 1- Oxidation: - Phenacetin (Active) → Paracetamol (Active) 2- Reduction: - Chloral hydrate (Active) → Tri-chloro-ethanol (More active) 3- Hydrolysis: - Di-acetyl-morphine (Heroin) → Acetic acid + Morphine (Active) NB) Result of Phase-I Metabolism: 1- Inactivation: Active Drug → Inactive Metabolite - Adrenaline & Noradrenaline → Vanil Mandilic Acid (VMA) 2- Activation: Inactive Drug (Prodrug) → Active metabolite - Imipramine (Inactive) → Desipramine (Active) 3- Maintain Activation: Active Drug → Active Metabolite - Diazepam (Active) → Nor-diazepam (Active) 4- Toxification: Drug → Toxic metabolite - Methyl alcohol → Formaldehyde → Blindness B) Phase-II (Synthetic, Conjugation): - Usually leads to inactivation - May lead to activation e.g. Morphine → Morphine-6-Glucoronoid (More active) - Types: 1- Glucuronic acid : e.g. Aspirin, Paracetamol, Morphine & Chloramphenicol. 2- Acetic acid (Acetylation): e.g. Isoniazide, Sulfonamides & Hydralazine. 3- Methylation : e.g. Noradrenaline (→ Active Adrenaline) & Histamine. 4- Glycine: e.g. Aspirin General 12 General  * Site Of Biotransformation: 1- Organs: a- Liver (Hepatic) is the main site for biotransformation b- Lung → Nicotine, Prostaglandins & Angiotensin (ACE). c- Kidney → Vitamin D d- G.I.T. & Gut flora → Tyramine & Histamine e- Skin → Vitamin D f- Plasma (Cholinesterase) → Succinylcholine 2- Cellular Enzymes: Microsomal Non-Microsomal 1- Site: Smooth endoplasmic reticulum Cytoplasm, Mitochondria, etc. 2- Organs: Mainly Hepatic All organs 3- Phase-I: Oxidation / Reduction Oxidation/Reduction & Hydrolysis (Cytochrome P-450) 4- Phase-II: Glucuronidation ONLY All Except Glucuronic acid 5-Induction: Inducible NOT inducible * Factors Affecting Hepatic Microsomal Enzymes: A) Hepatic Microsomal Enzyme Inducers (Activators): Examples: Phenytoin, Carbamazepine, Rifampicin, Testosterone, Cortisol & Tobacco smoking. They ↑ Metabolism of other drugs e.g. Oral anti-coagulants, Oral hypoglycemics & Oral contraceptives → ↓ Their duration of action. They ↑ Their own metabolism (Auto-induction) → Tolerance. B) Hepatic Microsomal Enzyme Inhibitors: Specific: Grapefruit, Estrogen, Cimetidine, Chloramphenicol, Erythromycin & Ciprofloxacin. Non-specific (General): a- Hepato-toxic drugs: Carbon monoxide, Carbon tetrachloride & Ozone. b- Drugs ↓ Hepatic blood flow: β-Blockers (Propranolol) & H2-Blockers (Cimetidine) C) Age: H.M.E. Activity is inhibited in extremities of age. Premature neonate can NOT conjugate chloramphenicol → Fatal Grey Baby Syndrome. D) Liver disease, Starvation & Cancer → ↓ H.M.E. Activity E) Genetic Abnormality (Idiosyncrasy): Favism & Abnormal Pseudo-Ch.E. General 13 General  Excretion A) Renal: Non-volatile drugs and metabolites are excreted in the urine. The clearance of some drugs depends mainly on renal excretion (Little or no metabolism) e.g. Atenolol, Nadolol, Barbitone & Gallamine → Caution in Renal patients. Renal excretion is the result of glomerular filtration and active tubular secretion & reabsorption. Passive Glomerular filtration for water soluble Non-bound drugs with M.W. < 500 e.g. Mannitol. Active Tubular Excretion (Saturable & Site for competition & Drug Interaction): Weak acid drugs e.g. Penicillin, Frusemide, Uric acid & Probenecid. Weak base drugs e.g. Digoxin & Quinidine Changes in urinary pH → Affect excretion of weak Acid & Base drugs: a- Alkalinization of urine (Na or K Acetate, Bicarbonate or Citrate) → ↑ Renal excretion of weak Acid drugs e.g. Aspirin & Phenobarbitone b- Acidification of Urine (NH4Cl or Ascorbic acid “Vit C”) → ↑ Renal excretion of weak Base drugs e.g. Ephedrine & Amphetamine. B) Lung → Gases (CO2) & Volatile Liquids (Halothane) C) Alimentary Tract: 1- Saliva (pH = 8): a- Drugs: Morphine & Aspirin b- Elements: Iodide & Mercury. 2- Stomach ; e.g. Morphine. 3- Bile → Intestine → Either: a- Excreted in large intestine b- Reabsorbed → Entero-Hepatic Circulation e.g. Morphine, Indomethacin, Sulindac, Digitoxin, Rifampicin, Thyroxin & Phenolphthalein. c- Some anti-microbials are excreted in bile in an active form e.g. Ampicillin & Rifampicin → Useful in treatment of Cholecystitis & Typhoid carrier. 4- Large Intestine: Either via the bile or unabsorbed oral drugs. D) Skin Glands: 1- Sweat : e.g. Vit B-1, Hg, As & Rifampicin → Red discoloration of sweat. 2- Milk : May affect suckling baby e.g. Morphine, nicotine, Purgatives, Tetracyclines & Chloramphenicol. General 14 General  PHARMACODYNAMICS (What the DRUG does to the BODY) ⇒ This science deals with Mechanism & pharmacological Actions of drugs. ⇒Drugs are chemical substances that modify increase or decease already present cell function but do not create a new one. However, genetic engineering and gene therapy may change this concept. * Types of Drug Action: 1- Local or Topical Action: NO Absorption from site of administration → NO Distribution → NO Systemic actions. The drug acts at site of application. Examples: Most of eye & ear drops, intra-articular injections & skin ointment. 2- Systemic or General Action: The drug is absorbed and distributed from site of administration. Examples: Oral aspirin, Subcutaneous (SC) adrenaline & Sublingual (SL) isoprenaline. 3- Reflex or Remote Action: The drug acts at a site to provoke an effect away from its site of action. Examples : SC Camphor → Irritation → Reflex ↑ Respiratory center = Reflex Analeptic. * Mechanism of Drug Action: 1- Physical: a- Adsorption: Kaolin & Activated charcoal in diarrhea. b- Osmotic: MgSO4 as a purgative. c- Demulcent: Liquorice as an anti-tussive. d- Astringent: Tannic acid mouth wash in gingivitis 2- Chemical: a- Neutralization: - NaHCO3 (Antacid) + HCl (Gastric acid) in treatment of hyperacidity. b- Chelation: Organic compound + Heavy metal → Non-toxic easy excreted complex. - Dimercaprol (British Anti-Lewisite or BAL) for Mercury (Hg) 3- Interference with Cell Division: Anti-cancer drugs e.g. Nitrogen mustard. 4- Interference with Metabolic Pathway: Sulfonamides compete with PABA in bacteria → ↓ Synthesis of folic acid. 5- Inhibition of Enzymes: Physostigmine (↓ Cholinesterase) & Aspirin (↓ Cyclooxygenase, COX). General 15 General  6- Action on Ion Channel: Local anesthetics block Sodium (Na+) channels. Calcium channel blockers (CCB) e.g. Verapamil block L-type of voltage gated calcium channels of heart & blood vessels. Some pharmacologists consider ion channels as an especial type of receptors. 7- Action on Receptors: A Receptor is a chemo-sensitive & chemo-selective cellular macromolecule that reacts specifically with a Ligand (drug, transmitter or hormone) to produce a biological response: Affinity (Ka) Efficacy or Drug + Receptor Drug/Receptor Complex Response (Kd) Intrinsic Activity NB) 1- Affinity = Ability of a drug to fit onto a receptor to form Drug/Receptor complex. 2- Efficacy or Intrinsic Activity = Ability of D/R complex to evoke a response. 3- Ka = Association constant with the receptor 4- Kd = Dissociation constant from the receptor * Dose – Response Curve of Drugs: It represent the relation between Log Dose and Response (Effect) of a drug. It is useful to: B 1- Know the Effects (responses): Minimal effect (Emin), Emax A Response (Effect) Maximal Effect (Emax) & Submaximal effects C e.g. 50% effect (E50) 2- Know Doses that produce Minimal effect (EDmin), E50 Maximal effect (EDmax) & Submaximal effect e.g. 50% effect (ED50) 3- Compare drugs: Emin a- Efficacy (‫ → )اﻟﻔﺎﻋﻠﻴﺔ‬Compare Emax (B>A>C) b- Potency (‫ →)اﻟﻘﻮة‬Compare the doses that ED50 produce the same Submaximal effect (A>B>C) Log Dose (conc.) 4- Determine the type of a blocker whether a- Competitive → Parallel shift to right (↓ Potency) with same Emax (Same efficacy) b- Non-competitive → Non-parallel shift to right (↓ Potency) with decreased Emax (↓ Efficacy) General 16 General  * Types of Ligands A) Stimulants = Agonists: These drugs stimulate the receptors directly and produce their effects by their own. They should have: 1- Affinity. 2- High intrinsic activity or efficacy to stimulate the receptors. 3- Rapid rates of association (Ka) & dissociation (Kd). Examples: Adrenaline (α &β), A.Ch. (M & N) & Morphine (μ &κ). B) Blockers: These drugs produce their effects indirectly by blocking the receptors and blocking the actions of internal chemical transmitters and/or hormones. They are: 1- Antagonists: They should have: a- Affinity. b- No = Zero efficacy → No dose/response curve c- Slow dissociation from receptors. They block the action of agonists. Examples: Prazosin, propranolol, atropine & naloxone. A 2- Partial Agonists = Dualists: They should have: Response a- Affinity. b- Low intrinsic activity = Weak efficacy B → Less maximum response (Emax) than agonists. c- Moderate rates of association & dissociation. They produce initial stimulation then block of the receptor Log Dose If used alone → Weak stimulation of the receptor → Weak response A = Full agonist B = Dualist If used in presence of an agonist → Block the action of the agonist. Examples: Ergotamine (α + 5-HT), Oxprenolol (β), Nicotine (NN) & Succinylcholine (NM). * Types of Block: A B A) Competitive Block: Response - Antagonists bind REVERSIBLY with the receptors. - Antagonists can be DISPLACED by excess agonists → Surmountable -They produce PARALLEL shift of the curve to the RIGHT → ↓ Potency. - They produce NO effect on the maximum response (E-max) = Same Efficacy. Log Dose Examples: Propranolol, atropine & naloxone. A = Agonist alone B = Agonist + Competitive blocker General 17 General  B) Non-Competitive Block: - Antagonist is NOT displaced by agonist → Non-surmountable A Response - Non-Parallel shift of cure to the Right = ↓ Potency. B - Decrease maximum response (E-max) = ↓ Efficacy. - Types of Non-Competitive Block : a- REVERSIBLE : - The antagonist binds REVERSIBLY to the receptor. Log Dose - The block ends by the Metabolism of the blocker. A = Agonist alone - Usually of Short duration of action. B = Agonist + Non-competitive blocker - Examples : succinylcholine. b- IRREVERSIBLE : - The antagonist binds COVALENTLY to the receptor. - The block ends by Resynthesis of new receptors. - Usually of Long duration of action. - Examples: organophosphorus compounds. NB) * Types of Ligands: Characteristics Stimulant Blocker = Agonist Antagonist Partial Agonist = Dualist 1- Affinity +++ +++ +++ 2- Efficacy +++ No = Zero Moderate 3- Ka & Kd Rapid Slow Moderate 4- Effect Stimulation Block Stimulation then Block NB) * Types of Block: Competitive Non-Competitive 1- Blocker is displaced by excess agonist 1- Blocker is not displaced by excess agonist = Surmountable = Non-surmountable 2- Parallel shift of curve to right → ↓ Potency 2- Non-parallel shift of curve to the right → ↓ Potency 3- Same Emax = Same Efficacy 3- Decreased Emax → ↓ Efficacy 4- Example: Atropine & Propranolol 4- Types: Reversible & Irreversible Reversible Irreversible 1- Block ends by metabolism 1- Block ends by resynthesis of of the blocker new receptors 2- Short acting 2- Long acting 3- Example: Succinylcholine 3- Example: Phenoxybenzamine NB) Chronic Use of Drugs Affects the No. & Sensitivity of Receptors: Long use of Agonists → ↓ No. & Sensitivity of Receptors → Down Regulation. Long use of Antagonists or drugs that ↓ transmission → ↑ No. & Sensitivity of Receptors → Up Regulation. General 18 General  Doses of Drugs (Posology) 1- Therapeutic Dose: Average dose calculated for an Adult, Male, 20-60 year old & 70 Kg body weight. 2- Initial Dos; Initial large dose aiming to reach the therapeutic plasma concentration 3- Maintenance Dose: Small daily dose required to replace eliminated drug from the body to maintain the achieved therapeutic plasma concentration. 4- Maximal Tolerated Dose; Highest dose without toxic effects. 5- Lethal or Fatal Dose: Dose that kill the patient or an experimental animal 6- Therapeutic Index: Ratio = LD50 / ED50 - LD50 = Lethal dose in 50% of animals - ED50 = Effective dose in 50% of animals A good guide to determine & compare SAFETY of drugs The Higher the therapeutic index → The Safer the drug * ** * * * * ** * * ** ** * * * Factors Affecting The Dose & Action of Drugs 1- Biological Variations 2- Age 3- Weight & Surface area 4- Sex 5- Route & Time of administration 6- Cummulation 7- Psychology 8- Pathology 9- Idiosyncrasy 10- Allergy 11- Supersensitivity 12- Tolerance 13- Drug interactions 1- Biological Variations: There are individual variations in the response to the same dose of a drug (Range of doses). Start by minimal effective dose then increase the dose gradually as needed. 2- Age: → Decrease the dose in extremities of age a- Geriatrics (Elderly > 60 years): They have exhausted drug-elimination mechanisms (metabolism & excretion). Use 2/3 or 3/4 of the adult dose. b-Pediatrics (Young < 20 years): They have immature drug-elimination mechanisms (metabolism & excretion). Calculate the dose by: - Infant (< 1 year) dose (Clark’s Formula) = Adult dose X (Weight of infant in Pounds/150) - Child (1 – 12 year) dose (Young’s Formula) = Adult dose X [Age in years / (Age + 12)] or (Dilling’s Formula) = Adult Dose X (Age in Years / 20) 3- Body Weight & Surface Area: Skeletal muscle weight is more important than fat or edema. Surface area is more accurate in calculating doses for children & infants. General 19 General  4- Sex: Males need higher doses than females: - Males have bulky muscle tissue & Androgens (HME Inducers) - Females have bulky fat tissue & Estrogen (HME Inhibitor) Some drugs are contraindicated in females during physiological periods: - Menstruation: Aspirin & Cathartics increase amount of bleeding - Pregnancy: Sex hormones& Phenytoin are teratogens - Labor: Barbiturates & Morphine might lead to neonatal asphyxia - Lactation: Drugs excreted in milk e.g. Purgatives, Tetracyclines & Chloramphenicol 5- Route & Time Of Administration: Affect the dose: usually I.V. dose < Oral dose Affect the effect: After meal → No effect Orally → Empty stomach → 4 g → Cholagogue Mg SO4 15 g → Saline purgative I.V. → ↓ CNS, ↓ Smooth muscle, ↓ Skeletal muscle & ↓ Cardiac muscle Retention Enema → Dehydrating agent e.g. in brain edema If drug is irritant → Use after meals If drug is sedative → Use at bed time 6- Cumulation: Occurs with zero-order kinetics when the rate of intake > rate of elimination. Examples: Digitalis, Aspirin L.D., Phenytoin L.D. & Ethanol L.D. To avoid cumulation decreases either the dose or frequency of administration. 7- Psychological Effect: Some patients improve by psychological (suggestion) rather than pharmacological effect of the drug (placebo effect). Placebo (Dummy medication) is an inert substance (lactose, starch, etc.) used in a dosage form (tablet, capsule, etc). Useful in: a- Treatment of patients by psychological suggestion b- As a comparison when testing new drugs 8- Pathological Condition: Some drugs act ONLY in presence of disease: o Aspirin acts as an antipyretic ONLY in fever o Digitalis acts as a diuretic ONLY in heart failure Pathology may cause supersensitivity: o Adrenaline in thyrotoxicosis o β-Blockers in bronchial asthma Pathology may affect drug kinetics: Achlorhydria → ↓ Intrinsic factor → ↓ Absorption of Vit B-12 → Pernicious anemia. General 20 General  9- Allergy (Hypersensitivity): Due to antigen / antibody reaction. → Abnormal response 10- Idiosyncrasy (Pharmacogenetics) : Presence of genetic abnormality → Abnormal response 11- Supersensitivity (Intolerance) → ↓ Dose of the drug 12- Tolerance : Repeated administration of a drug might lead to decreased response → ↑ Dose of the drug 13- Drug interactions → Summation, Synergism, Antagonism & Reversal. p p p p p p p p p p p p p Dosage Forms According to the ROUTE of administration: Enteral Others 1- Buccal e.g. Sublingual 1- Parenteral e.g. Injection 2- Oral 2- Inhalation 3- Rectal 3- Topical I- Buccal Dosage Forms: Drugs are put in the mouth and they are NOT swallowed → Either local or systemic effects. 1- Sublingual pellet → Systemic effect. 2- Buccal Spray: Spray under the tongue → Systemic effect e.g. Nitroglycerine 3- Lozenge: Tablet, usually big, to be dissolved slowly in mouth. 4- Mouth paint: Usually contains antiseptic and local analgesic. 5- Mouth wash and gargle General 21 General  II- Oral Dosage Forms: ♦ Drugs are taken via the mouth and swallowed → Either Local or Systemic effects. ♦ Either Solid forms or Liquid forms A) Solid Oral Dosage Forms: 1- Powder: Contained in a bottle or packet e.g. Oral Rehydration. 2- Effervescent granules in a bottle of packet: To mask bad taste of the drug and ensure its complete dissolution e.g. Aspirin. 3- Tablets: Drugs are compressed in a discoid form a- Simple b- Sugar coated: To mask bad taste c- Enteric coated: Covered by acid resistant coat e.g. Shellac or Keratin → Dissolve in alkaline pH of intestine → Release of contents → Useful for drugs that are irritant to stomach (Sodium salicylate) or drugs destroyed by gastric acidity. d- Sustained release (SR) = Controlled release (CR) = Timed release (TR) = Retard: Drugs are enclosed in coats with different dissolution rates in GIT → Slow uniform release and absorption of drug → Long duration of action with less variability in plasma concentration → Less frequent intake of drug → Better patient compliance. 4- Capsules: Drugs are put in gelatin containers either soft (for liquids) or hard (for powder and granules). a- Hard gelatin capsule containing either powder or granules. b- Enteric coated capsule. c- Sustained Release Capsule. d- Soft capsule containing liquid e.g. Oil. B) Liquid Oral Dosage Forms: Either in Aqueous vehicle or Alcoholic vehicle. 1- Aqueous Preparations: a- Decoction: Raw material e.g. plant leaves are boiled in water. b- Infusion: Soak raw material in cold or hot water. c- Solution: Drugs are completely dissolved in water. d- Mucilage: Gum in water, useful as suspending and emulsifying agent. e- Suspension: Insoluble powder suspended in water by the use of emulsifying agent e.g. gum. Shake well be fore use. f- Emulsion: Fixed oil dispersed in water by the use of emulsifying agent e.g. gum. Shake well before use. g- Aromatic water: Volatile oil in water. h- Mixture: More than one active ingredient in the preparation. i- Syrup: Sweetened, flavored and colored preparation. 2- Alcoholic Preparations: a- Tincture: Extraction of active ingredient in alcohol. b- Spirit: Volatile oil in alcohol. c- Elixir: Sweetened, flavored and colored hydroalcoholic preparation that contains 25% alcohol. General 22 General  III- Rectal Dosage Forms: 1- Solid = Suppository. 2- Liquid = Enema either Evacuant or Retention. IV- Parenteral Dosage Forms: A) Subcutaneous Pellet Implantation. B) Injection: In the form of solution, suspension, oil or powder for reconstruction. May be contained in 1- Ampoule : For single use. 2- Vial: Small bottle for either single or multiple use. 3- Bottle: Big container for IV solutions. V- Inhalation Dosage Forms: 1- Gas in cylinders: Oxygen, carbogen & Nitrous oxide. 2- Volatile liquid: Halothane. 3- Solution aerosol: Spray, atomizer or Nebulizer e.g. Salbutamol. 4- Finely micronized powder: Spinhaler e.g. Cromoglycate. VI- Topical Dosage Forms: A) Skin: 1-Ointment: Fatty base immiscible with water for dry lesions. 2- Cream: The base is miscible with water, suitable for oozing lesions. 3- Lotion: Aqueous base applied withOUT rubbing. 4- Liniment: Applied on skin with rough rubbing e.g. camphor as counter-irritant. 5- Dusting powder: Either protective e.g. talcum powder or medicated. 6- Paint: e.g. Tincture iodine 7- Spray. 8- Collodion: Nitrated cellulose + Colophony resin dissolved in Ether + Alcohol → Apply to skin → Ether and Alcohol evaporate leaving thin flexible layer. 9- Transdermal Delivery System (TDS): Aiming for absorption of drug from the skin to produce systemic effect: a- Transdermal patch: Nitroglycerine, nicotine, hyoscine & clonidine. b- Cream and Ointment: Nitroglycerine. c- Iontophoresis: by the use of galvanic electric current e.g. Methacholine. B) Eye: Drops, ointment, lotion & Oculosert (thin film containing the drug put in conjunctival sac). C) Ear: Drops and ointment. D) Nose: Drops, spray & inhalers. E) Vagina: Tablet (simple or foaming), Ovule (pessary = suppository), douche & cream. General 23 General Autonomic Nervous System  Autonomic Nervous System Nervous Systems Central Nervous System (CNS) Peripheral Nervous System (PNS) Sensory Motor Voluntary Involuntary (Somatic) (Autonomic, Visceral, Vegetative) Sympathetic Parasympathetic Somatic Autonomic 1- Actions Voluntary Involuntary 2- Supply Skeletal muscles Cardiac & smooth muscle, and Exocrine 3- Relay NO Ganglia glands 4- Single innervation Ganglia Innervations Dual (Double) Innervation (Symp. + Para.) * Types of Autonomic Nerves → Sympathetic & Parasympathetic Brain Para. A.Ch. A.Ch. M MR NN Spinal Cord (NN) Symp. A.Ch. NN NA α β A.Ch. NN A.Ch. Sweat & VD Sk.m. M Sk.m. Somatic A.Ch. NM A.N.S. 24 A.N.S.  Autonomic Nervous Syste Parasympathetic Sympathetic Actions: Usually Antagonistic But Both ↑ Atrial Conductivity & ↑Salivation a- Type Usually Localized Usually Generalized b- Aim: Conserve energy & Discharge excreta Stress (Fight & Fright) c- Pupil: Constricted → Miosis Dilated → Mydriasis d- Salivation: ↑ Profuse Watery ↑ Viscid e- Bronchi: Constricted Broncho-dilatation f- Heart: ↓ All properties BUT ↑ Atrial conductivity ↑ All properties ↓ Cardiac Output (C.O.P.) ↑ C.O.P. g- Bl.p.: ↓ Hypotension ↑ Hypertension h- G.I.T.: ↑ Wall & ↓ Sphincters → Defecation ↓ Wall & ↑ Sphincters i- U.B.: ↑ Wall & ↓ Sphincters → Urination ↓ Wall & ↑ Sphincters j- Sex organs: Erection Ejaculation * Chemical Transmitters: Chemical substances released from stimulated nerve ending (terminal or varicosity) in response to nerve action potential → Bind with specific receptors on effector organs. A receptor is a chemo-sensitive macromolecule that combine selectively with a ligand (Chemical transmitter or hormone or drug) → Complex → Effect (response). Nerve fibers and receptors are named after the chemical transmitters: 1- A.Ch. → Cholinergic nerve & Cholinergic receptor = Cholinoceptor. 2- Noradrenaline (N.A.) → Adrenergic nerve & Adrenergic receptor = Adrenoceptor. 3- Other transmitters e.g. A.T.P. → Non-Adrenergic Non-Cholinergic (NANC) → They act as co-transmitters or neuro-modulators. A.N.S. 25 A.N.S.  Adrenergic Receptors (Adrenoceptors) * Types: Types Alpha (α) & Beta (β). Subtypes α1, α2, β1, β2 & β3. Site: C.N.S. (Central), on Nerve ending (Presynaptic) & on effector organ (Postsynaptic) α α α C.N.S. Nerve Ending Effector organ β β β Central Presynaptic Postsynaptic I- Alpha-1 Receptors: Sites: Mainly Post-synaptic on effector organs. Actions: a- Contraction of pilomotor muscle → erection of hair. b- ↑ Contraction of dilator pupillae muscle → Active Mydriasis. c- Generalized V.C. specially skin, m.m. & renal. → ↑ Total Peripheral Resistance (TPR) → Hypertension. d- ↑ Viscid salivation. e- Spasm of G.I.T. & U.B. sphincters. f- Ejaculation & contraction of prostatic capsule. g- Contraction of pregnant uterus. h- Facilitate Neuro-Muscular transmission. Specific Agonists: 1- Phenylephrine: Used in hypotension & added to local anesthetics 2- Naphazoline (Prisoline) & Xylometazoline (Otrivin) used as Nasal dencongestant Specific Antagonist e.g. Prazosin → V.D. → used in hypertension and peripheral vascular disease. II- Alpha-2 Receptors: Sites: Central (CNS), Presynaptic (Nerve ending) & Postsynaptic (Effector organ). Actions: a- ↓ C.N.S. → Sedation b- ↓ Sympathetic tone c- Kidney → ↓ Release of Renin. Selective Agonists e.g. Clonidine & α-Methyl N.A. used in hypertension. Selective Antagonist e.g. Yohimbine. A.N.S. 26 A.N.S.  Beta (β) Adrenoceptors Subtypes β1,β2 & β3. Central, Presynaptic & Postsynaptic. I- Presynaptic β → ↑ Release of Noradrenaline. II- Postsynaptic β1-Adrenoceptors: Actions: a- ↑ C.N.S. → Anxiety CN b- ↑ Heart → ↑ C.O.P. c- Kidney → ↑ rennin d- ↑ Lipolysis → ↑ F.F.A. Selective agonists e.g. Dobutamine used in heart failure. Selective antagonists e.g. Atenolol III- Postsynaptic β3: Actions: ↑ Lipolysis & ↑ Thermogenesis. Selective Agonist → Octopamine. IV- Postsynaptic β2: Actions: a- Generalized V.D. specially skeletal muscles. b- Broncho-dilatation. O2 Glucose c- ↑ Glycogenolysis in liver & skeletal muscle. d- ↑ Release of insulin. V.D. e- ↑ K+ uptake by skeletal muscle. f- Relax G.I.T., U.B. & uterus. + K+ Insulin g- Skeletal muscle twitches. Selective agonist e.g. Sk.m. Salbutamol (Ventoline) & Salmeterol (Serevent) used in bronchial asthma Selective antagonist e.g. Butoxamine. A.N.S. 27 A.N.S.  I Sympathomimetics Drugs that stimulate adrenoceptors and produce actions similar to sympathetic nerve stimulation A- Adrenaline (Epinephrine) Natural sympathomimetic catecholamine present in A-cells of adrenal medulla (80% of its secretion) and some neurons in CNS. Unstable, if exposed to air or light → Oxidized → Adrenochrome Red in color & very TOXIC. Adrenaline is put in dark-glass ampoules. Unstable in aqueous and alkaline media. Add acid as a preservative. Stable in blood as it contains reducing agents e.g. Glutathione & Ascorbic acid. *Pharmacokinetics: Absorption: a-NOT effective Orally → V.C. of gut mucosa & Metabolized by gut & liver enzymes. b-Routes of Administration: -S.C. → V.C. → Slow absorption → Long duration & less toxicity. -Inhalation in bronchial asthma -Eye drops in Glaucoma -Intracardiac in cardiac resuscitation -I.M. → V.D. → Rapid absorption → Short Duration & Toxicity (OBSOLETE) -I.V. → Severe hypertension & Arrhythmia → Very dangerous (OBSOLETE) Distribution: Catecholamines do NOT pass B.B.B. Fate: a-Major part (80%) → Metabolized by M.A.O. & C.O.M.T. → V.M.A. b-Neuronal uptake (18%) c-Excreted unchanged in urine (2%). *Pharmacodynamics: Adrenaline stimulates directly ALL types & subtypes of adrenoceptors (α1, α2, β1, β2 & β3). A) Local Actions: 1-Skin → α → S.C. → V.C. 2-Mucous membranes e.g. Gum → α → V.C. → Decongestion & Haemostatic. 3-Eye → α → Decongestion & ↓ I.O.P. (↓ Synthesis of aqueous humor) → No mydriasis (V.C. & destruction by alkalinity of tears) 4-Inhalation → Bronchi → β2 → Bronchodilatation → α → V.C. & decongestion of bronchial mucosa A.N.S. 28 A.N.S.  B) Systemic Actions: 1-C.N.S.: Very mild stimulation → Anxiety. 2-Eye: Systemically → α1 → ↑ D.P.M. → Active mydriasis. 3-C.V.S.: a-Heart (Mainly β1): ↑ ALL Cardiac properties → ↑ C.O.P. ↑ Cardiac work → ↑ Oxygen needs → May cause angina pectoris ↑ Excitability & Automaticity → May cause arrhythmia b-Blood Vessels: Skin, mucous membrane & Renal → Mainly α → VC Skeletal muscle, coronary & mesenteric → Mainly β2 → V.D. c-Blood Pressure: Hypertension 4-Respiratory System → β2 → Bronchodilatation. 5-G. I. T.: α → Viscid salivation α + β → Spasm of sphincters & Relax wall of G.I.T. 6- Urinary Bladder: α & β → Spasm of sphincter & Relax wall. 7-Uterus: Variable but relaxes pregnant human uterus (B2) 8-Skeletal Muscle: β2 → V.D., ↑ Glycogenolysis, ↑ K+ uptake & Tremors Anti-fatigue effect α → Facilitate N-M transmission 9-Anti-Allergic effect: Physiological antagonist of histamine (2 agonists, 2 receptors, 2 opposing actions) Mast cell stabilization → ↓ Release of allergotoxins e.g. histamine. 10-Endocrine: ↑ Hypothalamo-Pituitary-Adrenal axis → Release of Cortisol 11-Metabolic: a-Hyperglycemia: Liver (β2) → ↑ Glycogenolysis b- ↑ Skeletal muscle glycogenolysis (β2) → ↑ Lactic acid c- ↑ Lipolysis (β1 & β3) → ↑ Free fatty acids Liver Blood Sk.m. d- Calorigenic effect & ↑ Oxygen consumption e- ↑ Blood coagulation due to activation of factor V K+ α1 K + β2 K+ f- Initial Hyperkalemia (α1 → ↑ Release of K+ from the liver) → Followed by Hypokalemia (β2 → ↑ Uptake of K+ by skeletal muscle) A.N.S. 29 A.N.S.  *Therapeutic Uses = Indications: 1- Added to local anesthetics (Except cocaine) → S.C. → α → V.C. → ↓ Absorption of local anesthesia → ↑ Duration, ↓ Systemic toxicity & ↓ Bleeding. NB) Cocaine is a sympathomimetic (↓ Uptake-1 → ↑ Noradrenaline → α → V.C.) 2- Haemostatic: After tooth extraction and Nasal pack in epistaxis. 3-Eye drops in Glaucoma 4-Cardiac arrest → Intracardiac adrenaline → Cardiac resuscitation 5-Acute bronchial asthma (S.C. or Inhalation) 6-Acute allergy: Angio-edema & anaphylactic shock (Adrenaline is life-saving). 7-Acute hypoglycemia *Dosage: 1-S.C.: ½ ml of 1/1000 solution = ½ mg 2-Inhalation: 1/100 solution 3-Eye drops: 2% solution *Adverse Effects of Adrenaline: 1-C.N.S.: Anxiety and headache. 2-Eye: Local adrenaline → Irritation & pigmentation 3-α → V.C. → Gangrene if injected around finger or toe, hypertension & cerebral hemorrhage. (Prevention and treatment by α-blockers e.g. Prazosin) 4- β1 → Heart → Tachycardia, palpitation, angina & arrhythmia. (Prevention & treatment by β1-blockers e.g. Atenolol). 5- β2 → Skeletal muscle tremors *Contraindications: 1- Arround finger & toes and in circumcision. 2- Hypertension 3- Hemorrhagic shock (Cause of death is renal V.C.) 4- Angina pectoris 5- Cardiac arrhythmia. 6-Thyrotoxicosis * Drug Interactions 1- Digitalis → Arrhythmia 2- General Anesthesia e.g. Halothane → Arrhythmia 3- Non-selective β-blockers e.g. Propranolol → Unopposed α → Severe Hypertension & Hyperkalemia. A.N.S. 30 A.N.S.  Adrenaline (Epinephrine) Pharmacodynamics Pharmacotherapeutics Adverse Effects Contraindications & Drug Interactions A) Local Actions: 1-Skin → SC → α → VC 1-Add to local anesthesia 1-Gangrene of fingers 1-Around finger, toe & circumcision 2-M.M. → α → VC 2-Decongestion & haemostatic 2-Hypertension 2-Hypertension 3-Eye → α → Decongestion. ↓ IOP 3-Open angle glaucoma 3-Cerebral hemorrhage 3-Hemorrhagic shock & NO mydriasis Dipivefrin is better 4-Irritate eye 4-Inhalation → β2 → Bronchodilatation 4-Lowei’s test → Diagnose acute pancreatitis B) Systemic Actions: 5-Acute bronchial asthma 1-CNS → Mild stimulation → Anxiety 5-Anxiety & headache 2-Eye → Active mydriasis 3-C.V.S.: 6-Cardiac resuscitation 6-Tachycardia, 4-Tachycardia, angina & arrhythmia a-Heart → β1 → Cardiac stimulation → + ve Ino, +ve Chrono, Palpitation, Angina & 5- With digitalis or General anesthesia +ve Dromo → ↑ COP, ↑ work & ↑ O2-consumption Arrhythmia e.g. Halothane ↑ Excitability & ↑ Automaticity b-BV: Skin & mm → α → VC , Sk.m. → β2 → VD → ↓ TPR 6-In Supersensitivity e.g. Thyrotoxicosis c-Hypertension (↑ SBP & ↓ DBP) 4-Bronchodilatation (β2) 5-G.I.T.: Relax wall (α + β) & spasm of sphincters (α) 7-Contraction ring of uterus 6-Urinary Bladder: Relax wall (β) & spasm of sphincter (α) 7-Uterus: Relax pregnant uterus (β2) 8-Acute allergy 8-Facilitate N-M transmission (α) & Tremors (β2) 7-Sk.m. tremors 9-Antiallergic: Physiological antagonist of histamine 10- ↑ Hypothalamo-Pituitary- Adrenal → ↑ Cortisol 9-Acute hypoglycemia 11-Metabolic: a-Hyperglycemia (α + β) *Dosage Forms: b-Hyperlipidemia (β1 + β3) 1-S.C. 2-Inhalattion c-Hyperkalemia the (α) → Hypokalemia (β2) 3- I.C. 4-Eye drops A.N.S. 31 A.N.S.  B- Noradrenaline (Norepinephrine) (Levophed, Levarterenol) Natural sympathomimetic catecholamine. Chemical transmitter at postganglionic sympathetic, Adrenal medulla (20% secretions), Pheochromocytoma (90%) & C.N.S. Unstable (Like adrenaline) → Adrenochrome. *Pharmacokinetics: NOT Orally, NOT pass BBB, Uptake & Metabolism by MAO & COMPT → VMA. Administered by I.V. Infusion. *Pharmacodynamics: Direct sympathomimetic MAINLY Non-selective α1 & α2 and some β1 & β3 NO β2 1-CNS: Mild stimulation → Anxiety 2-Eye: Decongestion & ↓ IOP 3-CVS: a- Blood vessels → α → Generalized V.C. b- HYPERTENSION c- Reflex BRADYCARDIA: Hypertension → Reflex vagal stimulation (Mask weak β1 effect). This reflex bradycardia can be blocked by Atropine. d- β1 → ↑ Excitability & automaticity → May cause arrhythmia 4-Respiratory: No bronchodilatation 5-G.I.T. & Urinary Bladder: Relax wall & spasm of sphincters 6-Uterus: Contract pregnant uterus → Abortion 7-Metabolism: Hyperglycemia & Hyperlipidemia *Therapeutic Uses: 1- Acute hypotension. 2-Added to local anesthesia (Except cocaine) *Adverse Effects: 1-Gangrene if injected around finger or toe 2-Hypertension → Cerebral hemorrhage 3-Bradycardia & arrhythmia 4-Abortion 5-If extra-vasation → Gangrene 6-If sudden stop → Severe hypotension A.N.S. 32 A.N.S.  *Contraindications & Drug Interactions of Noradrenaline: 1-Around finger or toe, hypertension & hemorrhagic shock 3-Coronary heart disease, arrhythmia, digitalis & general anesthesia e.g. halothane 3-Pregnancy 4-Extravasation & Sudden stop ========================== C- Dopamine (Intropin) Natural sympathomimetic catecholamine Chemical transmitter in C.N.S. & periphery *Pharmacokinetics: 1- Not Orally, Not BBB, Uptake & Metabolism by MAO & COMT. 2- Administered by I.V. Infusion. *Pharmacodynamics: 1-Small dose → ↑ D-receptors → V.D. (RENAL + mesenteric, coronary & cerebral) 2-Moderate Dose → ↑ D & β1 → VD + Inotropic effect → ↑ COP. 3-Large dose → α1 → V.C. *Therapeutic Uses of Dopamine: 1-SHOCK (Hemorrhagic, Cardiogenic & Septic = Endotoxic): 2-Resistant heart failure *Adverse Effects of Dopamine: 1-Large dose (Rapid infusion) → Tachycardia, angina, arrhythmia & hypertension. 2-Nausea and vomiting. ================= A.N.S. 33 A.N.S.  NB) Sympathomimetics: Catecholamine Non-Catechol 1-Stability Not Stable Stable Indirect 2-Passage Not Pass Pass NA 3-Orally Not Orally Orally 4-B.B.B, Not B.B.B. Pass 5-Met. Rapid Slow or No MAO 6-Duration Short Long Dual R Direct Effector organ 1 2 3 4 Tachyphylaxis Direct Indirect 1-Potency Potent Weaker 2-Onset of action: Rapid Slower 3-Sympathectomy or depletion of stores Supersensitivity Abolish 4-Redeated administration Normal response Tachyphylaxis D- Ephedrine+ Sympathomimetic Non-catecholamine alkaloid *Pharmacokinetics: Absorbed Orally, mucous membranes & parenterally Distributed ALL over the body & passes B.B.B. Not metabolized, it may ↓ M.A.O. Excreted unchanged in urine → Acidification of urine → ↑ Its excretion *Pharmacodynamics: Dual (Mixed) Sympathomimetic, acts MAINLY indirect Actions are similar to adrenaline BUT: 1- Weaker, Slower, Longer & Tachyphylaxis as sympathomimetic. 2- More Potent as C.N.S. Stimulant, but weaker than amphetamine. E- Amphetamine+ Synthetic sympathomimetic Non-catecholamine alkaloid Acts mainly as INDIRECT Similar to Ephedrine BUT More CNS stimulant & produces ADDICTION. A.N.S. 34 A.N.S.  II- Beta - Blockers Actions Uses Adverse Effects & Contraindications 1- Heart (β1): -ve Inotropic Hypertrophic obstructive cardiomyopathy Heart failure -ve Chronotropic Tachycardia e.g. Thyrotoxicosis Bradycardia NOT with Verapamil -ve Dromotropic Atrial tachyarrhythmia → Protect ventricles Heart block ↓ COP ↓ Cardiac work & O2 consumption Angina of Effort Variant (Prinzmetal) angina ↓ Excitability & ↓ Automaticity Arrhythmia 2- Blood vessels (β2): ↓ V.D. → Unopposed α → V.C. P.V.D. 3- Anti-hypertensive: Hypertension Hypotension ↓ Sympathetic outflow from CNS ↓ COP + α-blockers in Pheochromocytoma Alone in Pheochromocytoma ↓ Renin ↓ Noradrenaline release Reset Baroreceptors ↑ PG 4- ↓ I.O.P.: Glaucoma (Timolol) Practolol → Muco-Cutaneous-Ocular syndrome 5- Bronchi (β2) → Bronchospasm Bronchial asthma 6- Metabolism: ↓ β2 → ↓ Glycogenolysis With insulin → Severe hypoglycemia ↓ β2 → ↓ Hypokalemia Hyperkalemia ↓ β1 & β3 → ↓ Lipolysis ↑ Triglycerides & ↓ H.D.L. 7- I.S.A. (Some β-Blockers) = Dualist 8- C.N.S. (Lipophilic β-Blockers) Migraine headache (Propranolol) Sedation ↓ Anxiety Anxiety & Panic syndrome ↓ Tremors Familial tremors 9- Na+ Channel Block (Some β-Blockers): Sudden stop → Rebound β stimulation Membrane stabilizer = Local anesthetic → Angina, arrhythmia and hypertension. Direct Myocardial Depressant A.N.S. 35 A.N.S.  *Members of β-Blockers: A) Non-Selective β-Blockers e.g. Propranolol (Inderal) ♦ Block BOTH β1 & β2 receptors ♦ Lung → Bronchospasm → Contraindicated in Bronchial asthma (B.A.) ♦ Liver → ↓ Hepatic blood flow & ↓ Glycogenolysis → C.I. in Diabetes mellitus (D.M.) ♦ Limbs → ↓ Blood flow → C.I. in P.V.D. e.g. Raynaud’s disease ♦ Coronary → C.I. Variant (Prinzmetal) angina (V.A.) B) Cardio-selective β1-Blockers: ♦ Allowed in small dose with caution in Variant Angina, Bronchial asthma, Diabetes mellitus & Peripheral vascular diseases. ♦ Examples: Atenolol (Tenormin) Metoprolol (Betaloc) & Bisoprolol (Concor): C) α + β - Blockers e.g. Labetalol (Trandate) and Carvedilol (Dilatrend) *************************************** III- Central Sympathoplegic Drugs: * Mechanism of Action: 1- α2-Agonists: α-Methyl-Dopa & Clonidine→ ↓ Sympathetic outflow But→ Sedation 2- Imidazoline I1-Agonists: Moxonidine → ↓ Sympathetic outflow & Less sedation. 3- Reserpine → ↓ V.M.C. But More sedation. 1- α-Methyl Dopa (Aldomet): *Mechanism: 1- Prodrug: α-Methyl dopa DecarboxylaseÆ α-Methyl Dopamine β-Hydroxylase Æ α-Methyl Noradrenaline → α2-Agonist → a- Central → ↓ Sympathetic outflow from C.N.S. = Main Mechanism b- Presynaptic → ↓ Release of Noradrenaline. c- Kidney → ↓ Release of Renin. 2- Inhibits the synthesis of Catecholamines & Serotonin. *Advantages: Maintains R.B.F. *Disadvantages: a- Allergy (Hypersensitivity): Hemolytic anemia (+ve Coombs' test) & Hepatotoxicity. b- CNS: Sedation, Depression & Parkinsonism. c- Bradycardia & Postural Hypotension. d- Fluid retention. e- Dry mouth & Constipation. f- Endocrine → ↑ Prolactin → Galactorrhea, Gynecomastia & Impotence. *Used in Hypertension especially: a- High renin. b- Renal insufficiency. c- Pregnancy. A.N.S. 36 A.N.S.  2- Clonidine: *Mechanism: a- α2-Agonist → Central ↓ Sympathetic, Presynaptic ↓ Noradrenaline & Kidney ↓ Renin. b- Imidazoline I1-Agonist → Central ↓ Sympathetic tone. * Advantages: Maintains RBF. * Disadvantages: a- If used in Large Dose or IV → Initial Hypertension. b- Sudden Stop → Severe HYPERTENSION. Treat by either reuse Clonidine or give α-blocker + β-Blocker. c- Similar to methyl-dopa: - Sedation & Depression. - Dry Mouth (Xerostomia). - Bradycardia. - Constipation. - Impotence. * Used in Hypertension specially: a- High renin. b- Renal insufficiency. ************************************* The Parasympathetic System I- Parasympathomimetics (Cholinomimetics, Muscarinic-Receptor Agonists) These are drugs that stimulate Muscarinic “Peripheral Cholinergic” Receptors (MR or PCR) either directly or indirectly: Effector Organ ♦ Direct Parasympathomimetic MR ♦ Indirect Parasympathomimetic = Anti-Ch.E. → ↑ Endogenous A.Ch. Choline Esters ♦ Direct parasympathomimetics ♦ Contain Choline → Quaternary ammonium compound+ (- N+-)→ Highly ionized → Low lipid solubility → Not pass B.B.B. & distributed extracellularly A.N.S. 37 A.N.S.  1- Acetylcholine (A.Ch.) Natural Direct parasympathomimetic choline ester. It is the chemical transmitter at: 1- All post-ganglionic parasympathetic - Muscarinic 2- Post-ganglionic sympathetic to thermo-regulatory sweat glands - Blocked by and V.D. fibers of Sk.m. Atropine 3- All autonomic ganglia (Symp. & Para.) - Nicotinic-Nerve (NN) 4- Adrenal medulla - Blocked by Ganglion Blockers 5- Neuro-Muscular Junction - Nicotinic-Muscle (NM) Motor End Plate of Sk.m. - Blocked by N-M blocker e.g. Curare 6-C.N.S.: Brain (M mainly e.g. Basal ganglia) & Spinal cord (NN mainly e.g. Renshaw Cells) *Pharmacokinetics of A.Ch.: 1- Choline is a quaternary ammonium+ - N+ - → Low lipid solubility 2- Not absorbed orally, Do not pass BBB, Distributed Extracellularly 3- Metabolized by Choline esterase enzymes. * Mechanism of Ac`tion of A.Ch.: A.Ch. Stimulates Directly Muscarinic & Nicotinic cholinergic receptors. * Actions of A.Ch.: A) Muscarinic Actions: Miosis & Hypotension 1- Eye: Miosis & ↓ Intra-ocular pressure & V.D. → Hypotension 3- Respiratory System → Bronchospasm & ↑ Secretions 3- G. I. T. → ↑ Salivation & other secretions, ↑ Peristalsis & Relax sphincters 4- Urinary Bladder → Spasm of wall & relaxes sphincter 5- Uterus → Contraction of Non-pregnant uterus 6- ↑ All exocrine glands including thermoregulatory sweating B) Nicotinic Actions: Twitches & Hypertension 1- ↑ NM → Skeletal muscle twitches 2- ↑ NN → ↑ All ganglia & Adrenal medulla * Therapeutic Uses of A.Ch.: NOT used Clinically 1- Ineffective Orally 2- Short Duration 3- Non-Selective A.N.S. 38 A.N.S.  2- Cholinomimetic Alkaloids Pilocarpine ♦ Direct Parasympathomimetics ♦Not esters → Not metabolized by Ch.E. enzymes ♦Natural Tertiary amine ( - N - ) alkaloid of plant origin (Pilocarpus leaflet) * Pharmacokinetics: 1- Absorbed orally 2- Distributed all over the body & passes B.B.B. 3- NOT metabolized by Ch.E., also does not ↓ Ch.E. 4- Excreted in urine * Pharmacodynamics: ♦ Direct stimulation of Muscarinic receptors mainly + nicotinic ♦ Selective on Eye & Exocrine secretions * Therapeutic Uses: 1- Sialagogue → ↑ Salivary secretion → Treat Xerostomia 2- Miotic eye drops → Miosis + ↓ I.O.P. + ↑ Lacrimation withOUT twitches used in Treatment of Glaucoma 3- Promote growth of hair (Tonoscalpine Hair lotion). ********************************** 3- Anti-Cholinesterases ♦ Indirect Parasympathomimetics → ↓ Ch.E. → Accumulation of endogenous A.Ch. → ↑ MR & NR → Endogenous A.Ch.-like actions. A) Reversible Anti-Ch.E.: e.g. Physostigmine and Neostigmine B) Irreversible Anti-Ch.E.: e.g. Organophosphorus Compounds Their effect ends by resynthesis of new Ch.E. enzymes A.N.S. 39 A.N.S.  Reversible Anti-Choline-Esterases Physostigmine (Eserine) Neostigmine (Prostigmine) 1- Nature: 1-Natural Tertiary amine alkaloid ( - N - ) 1- Synthetic Quaternary ammonium of plant origin (Calabar beans) compound ( - N+ - ) 2- Kinetics: 2-a- Absorbed Orally 2-a- Irregularly absorbed orally b- Passes B.B.B. b- Do NOT pass B.B.B. c- Rapid metabolism by Ch.E. c- Slowly metabolized by Ch.E. d- Short duration d- Longer duration of action 3- Dynamics: 3- Reversible Anti-Ch.E. → Endogenous A.Ch. Like → ↑ MR & ↑ NR a- More specific on Eye → a- More specific on GIT & UB Miosis + ↓ IOP + Twitches ↑ Wall & ↓ Sphincters b- C.N.S. Stimulation b- Direct Sk.m. Stimulant effect 4- Uses: 4-a- Eye drops in glaucoma. 4- a- Myasthenia Gravis: b- I.V. in Atropine poisoning b- Curare poisoning (I.V.) NB) In (a & b) add Atropine to block the unwanted muscarinic actions c- Paralytic ileus (S.C. & I.M.) d- Retention of urine (S.C. & I.M.) e- P.A.T. (S.C. & I.M.) 5- Toxicity: 5-a- Exaggerated A.Ch. like actions 5-a- Exaggerated A.Ch. like actions b- CNS stimulation → Convulsion b- No convulsions 6- Management 6-a- Atropine 6- Atropine of Toxicity: b- Anticonvulsants e.g. Diazepam No need for anticonvulsants Irreversible Anti.Ch.E. Organophosphorus Compounds Examples: Parathion (Insecticide), Sarin (War Gase) & Metrifonate (Anti-Bilharzial). Poisoning → Exaggerated A.Ch. like actions (Muscarinic & Nicotinic ) + Convulsions. Cause of Death: Respiratory failure (Bronchospasm + Secretions + Paralysis of respiratory muscles + R.C. inhibition). Treatment of poisoning: a- Care of respiration b- Atropine A.N.S. 40 A.N.S.  II- Parasympatholytics These are drugs that compete with A.Ch. for the muscarinic receptors They include: Atropine, Hyoscine & Atropine substitutes Atropine *Pharmacokinetics: 1- Well absorbed orally, mucous membranes & parenterally Cell 2- Distributed all over the body (intra & extra-cellularly) & passes B.B.B. 3- Partially metabolized in liver (70%) CNS 4- Excreted in urine partially unchanged (30%) Acidification of urine → ↑ Its urinary excretion 70% 30% ↑ in Acid urine * Pharmacodynamics: A) Local Actions: 1-Eye: Mydriasis & ↑ Intraocular pressure 2- Skin & mucous membranes → Local Anodyne (Analgesic) action B) Systemic Parasympatholytic Actions: Atropine blocks ALL types of muscarinic receptors 1- C.V.S.: a- Heart: Tachycardia b- Blood vessels: Large dose especially in children → Atropine Flush of face & chest c- Blood pressure: Small therapeutic dose → Minimal effect 2- Respiratory Tract: Bronchodilatation & dry bronchial secretions (Ipratropium is better). 3- G. I. T.: a- ↓ Salivary secretion → Dry mouth = Xerostomia b- ↓ Gastric HCl (Pirenzepine is more selective) c- Relax wall → Antispasmodic (Propantheline is more selective) d- Spasm of sphincters → Constipation 4- Urinary Bladder: Relax wall and Spasm of sphincters → Retention of urine (Emepronium is more selective) 5- Skin: ↓ Sweat → Anhidrosis → Dry, red & hot skin 6- ↓ ALL secretions Except milk, bile & urine A.N.S. 41 A.N.S.  C) C.N.S. Actions of Atropine: Mainly C.N.S. Stimulant → Restlessness, excitation, hallucination & mania. Medulla: ↑ R.C. (Analeptic) and ↓ Vomiting center (Anti-emetic) ↓ Basal Ganglia → Anti-Parkinsonian (Benztropine is more selective) *Therapeutic Uses of Atropine: Dose: 0.3 – 0.6 mg Orally & Parenterally 1- Antidote for Parasympathomimetic poisoning e.g. Oragophosphorus 2- Mydriatic in Iritis & Corneal ulcer 3- Bradycardia & Heart block 4- Bronchial asthma (Ipratropium) 5- Peptic ulcer (Pirenzepine) 6- Colic e.g. Intestinal, Biliary & Renal. (Propantheline) 7- Diarrhea 8- Nocturnal enuresis & Urinary incontinence (Emepronium) 9- Hyperhidrosis 10- Preanesthetic medication (Hyoscine): a- ↑ R.C. → Prevent respiratory depressant effect of Anesthesia & Morphine b- ↓ Salivary & Bronchial secretion → Prevent Aspiration pneumonia c- Protect the heart form the depressant effect anesthesia e.g. Halothane 11- Vomiting & Motion sickness (Hyoscine) 12- Parkinsonism (Benztropine) * Adverse Effects & Toxicity of Atropine: A) Manifestations: 1- Toxic psychosis → Hallucination, mania → convulsions → Coma 2- Parasympatholytic manifestations: a- Mydriasis, photophobia, blurring of vision & glaucoma b- Dry, red & hot skin c- Dry mouth d- Tachycardia e- Distention, constipation & retention of urine 3- Allergy B) Management of Atropine Poisoning: 1- Physostigmine (I.M. or I.V.) to correct peripheral & central manifestations 2- If psychosis → Diazepam 3- If Hyperthermia → Ice bags & cold bathes 4- If oral poisoning → Stomach wash 5- If respiratory failure →Artificial respiration. A.N.S. 42 A.N.S.  * Contraindications of Atropine: 1- Fever ***2- Glaucoma 3- Bronchial asthma 4- Tachycardia 5- Constipation & paralytic ileus ***6- Enlarged prostate (Benign Prostatic Hyperplasia) 7- After neostigmine in curare poisoning → Severe initial bradycardia 8- Allergy to Atropine Hyoscine (Scopolamine) o Natural Parasympatholytic tertiary amine alkaloid of plant origin o Pharmacology similar to atropine BUT: 1- Shorter duration of action 2- Parasympatholytic actions are Stronger on Eye & Secretions But Weaker on G.I.T. & Heart → No tachycardia 3- C.N.S.: a- Mainly Depressant → Sedation & Hypnosis (Dreamless sleep, ↓ R.E.M.) But if used alone in presence of pain → Hyperalgesia, Excitation & Delirium b- Amnesia to recent events c- Euphoria d- ↓ Vomiting center → Anti-Motion sickness e- ↓ Basal ganglia → Anti-Parkinsonian f- ↑ R.C. g- Large dose → Excitation → Central anticholinergic syndrome * Therapeutic Uses of Hyoscine: 1- Preanesthetic medication → Better than Atropine a- C.N.S. Depressant → Sedation, Hypnosis & amnesia → ↓ Dose of Anesthesia b- More ↑ R.C. & More Antisecretory c- No tachycardia → Safer in Thyrotoxic patients 2- Prophylaxis of Motion sickness (Air sickness) A.N.S. 43 A.N.S. Blood  Blood * Blood Coagulation: Thromboplastins + Platelets + Ca2+ Fibrinogen Prothrombin Thrombin Fibrin Control Of Bleeding A) Local Hemostatics = Styptics: 1- Physical Methods: Pressure, Cold & Cautary. 2- Vaso-constrictors: Adrenaline nasal pack in Epistaxis. 3- Astringents: Tannic acid & Alum → Precipitate blood proteins. 4- Local Coagulants: a- Thromboplastin: - Coagulen (Topical & I.M.) : Mammalian tissue Thromboplastin. - Russell’s Viper Venom (Topical use ONLY). b- Thrombin. Fibrinogen c- Fibrin Glue: Fibrinogen + Thrombin d- Human fibrin foam. Thrombin e- Absorbable Gelatin Sponge. - Topical can be applied dry or moistened with normal saline - Avoid use in presence of infection f- Oxycel (Oxidized Cellulose): - Surgical tissue with sticky surface → Mechanical block & clot formation. - Not absorbed → Not left in wounds. B) Systemic Coagulants: 1- Fresh blood transfusion → Restore volume & supply coagulation factors. 2- If due to capillary fragility: a- Vitamin C (Ascorbic acid) + Vitamin P (Rutin) → Treat Scurvy. b- Ethamsylate (dicynone) Orally & injection. 3- If due to Hemophilia: a- Anti-hemophilic globulin (Factor VIII) b- Arginin Vasopressin & Danazol → ↑ Factor VIII synthesis. c- Tranexamic acid (Anti-fibrinolytic). 4- If due to Thrombolytic (Fibrinolytic) therapy → Use Anti-Fibrinolytics e.g. Aminocaproic acid & Tranexamic acid. 5- If due to Anticoagulant therapy: a- If Heparin- → Use Protamine+ sulfate → Chemical neutralization. b- If Oral Anticoagulant e.g. Warfarin → Use Vitamin K (Phytomenadione). Blood 44 Blood  * Vitamin K: 1- Quinone derivative. Vit- K Reductase 2- Vitamin K (Quinone, K) Active Reduced Form (Dihydroquinone, K2H). 2- Essential for hepatic synthesis of activated (Carboxylated) coagulation factors II (Prothrombin), VII, IX & X. CO2 + O2 Inactive Decaroxylated Coagulation Factors Active Carboxylated Coagulation Factors (Prothrombin, VII, IX & X) (Prothrombin, VII, IX & X) Active Reduced Vit K (Dihydroquinone, K2H) Inactive Vitamin K-Epoxide (KO) Epoxide Reducatse + NADPH # Warfarin 3- Therapeutic Uses: Hemorrhage due to Hypoprothrombinemia → a- ↓ Synthesis of Vit K by intestinal flora → Oral broad-spectrum antibiotics. b- ↓ Absorption of Vit K → Liquid paraffin, Obstructive jaundice & Mal-absorption. c- ↓ Hepatic utilization of Vit K → Hepato-cellular damage. d- Drug induced hypoprothrombinemia → Oral anticoagulants & Salicylates. 4- Preparations of Vitamin K: a- Phytomenadione (Vit K-1): - Natural, of Plant origin. - Fat soluble → Needs bile for absorption. b- Menaquinone (Vit K-2): - Natural, synthesized by intestinal flora. - Fat soluble → Needs bile for absorption. c- Menadione (Vit K-3): Synthetic , Fat soluble. d- Menadiol Na Diphosphate (Vit K-4): Synthetic , Water soluble → No need for bile. Displaces bilirubin in neonates → Jaundice & Kernictrus. m m m m m m m m m m m m m m Control Of Thrombo-Embolic Disorders 1- Inhibitors of Platelet Aggregation e.g. Aspirin → Prevent arterial thrombosis. 2- Thrombolytics (Fibrinolytics) e.g. Streptokinase → Dissolve already formed thrombus. 3- Anti-coagulants → Prevent thrombus formation & extension of present thrombi. Blood 45 Blood  Anti-Coagulants 1- Drugs That REMOVE Ionic Calcium: a- By Precipitation: Na+ or K+ Oxalate → Used In-Vitro Only e.g. Test tubes. b- By deionization → Combine with Calcium without precipitation → Chelation → Na+ Citrate 3.8% & Na+ Edetate → Used In-Vitro Only e.g. Blood transfusion. 2- Oral Anti-Coagulants: Effective In-Vivo Only. a- Coumarines: Warfarin & Dicoumarol. b- Indanediones: Phenindione & Diphenadione. 3- Injectable Anti-Coagulants: a- Thrombin Inhibitors = Anti-Thrombin: - Direct Anti-Thrombin: Hirudin & Hirulog. - Indirect Anti-Thrombin: Heparins (High & Low Molecular Weight Heparins) b- Thrombin-Like → Fibrinogen Depletors → Ancrod. ***************************** Heparin * Source: Present naturally with Histamine in Mast cells & Basophils in lung, liver & intestine. Obtained from bovine lung & porcine intestinal mucosa. * Chemistry: Sulfated muco-polysaccharide. Strong acid → Carries strong electronegative charges → Poly-anionic. * Pharmacokinetics: Not absorbed orally. Used either I.V. or S.C. NEVER I.M. → Hematoma. Distributed Intra-vascularly. Dose NOT pass B.B.B. or Placental Barriers → Allowed in pregnancy. 95% Bound to plasma proteins. Partially metabolized by Hepatic Heparinase enzyme → Uroheparin. Excreted in urine partially as Heparin (20%) & Mainly as Uroheparin (80%). Not excreted in Milk → Does Not Affect suckling baby. I.V. → Immediate onset of action & Short duration (4 - 6 hours). * Pharmacodynamics: A) Anti-coagulant BOTH In-Vivo & In-Vitro: Heparin acts on Preformed activated coagulation factors e.g. Thrombin. Its electronegative charges are essential for its activity. Mechanism of Action: Inactivation of preformed coagulation factors It combines to & Activates Anti-Thrombin III → Neutralization of activated factors IIa (Thrombin), IXa, Xa (Mainly) & XIIa. B) Lipemia Clearing effect via activation of Lipoprotein lipase enzyme. Blood 46 Blood  * Doses of Heparin: 1 mg Heparin = 100 Units. Routes of Administration: a- I.V. bolus injection: 10’000 U initially then 5000-10’000 u / 4 – 6 Hours. b- I.V. Infusion: 10’000 U initially then 1000-1500 U (10-15 U/kg) / Hour. c- Deep S.C. (Abdominal wall) small dose Heparin: 5000 / 8 - 12 hours. Control of Dose: a- Coagulation time = Whole Blood Clotting Time (WBCT) = Normally 4-8 minutes → Prolonged 2 – 2.5 times. b- Activated Partial Thromboplastin Time (APTT) = Normally 26 – 33 seconds → Prolonged 2 – 2.5 times. * Heparin Antagonists: a- Protamine Sulfate → Strong Base → Chemical Neutralization of Heparin. 1 mg Protamine SO4 1% solution for each 1 mg (100 U) Heparin. Excess Protamine SO4 → Bleeding. b- Fresh blood transfusion. * Adverse Effects of Heparin: 1- Hemorrhage. 2- Hypersensitivity. 3- Prolonged use of full dose → Transient Alopecia & Osteoporosis. 4- Thrombocytopenia, of 2 types: a- Mild & transient due to heparin-induced platelet aggregation. b- Severe & persistent due to heparin-induced Anti-platelet Antibodies. ¾ Low Molecular Weight Heparin (LMWH ): ƒ Examples: Enoxaparin (Clexane), Dalteparin (Fragmin) & Rivaparin ƒ Small fraction of unfractionated heparin (MW = 5000 – 8000) → High affinity to Anti-Thrombin III → Strong Inhibitor of activated factor Xa. ƒ Advantages: a- Minimal effect on platelet aggregation or lipo-protein lipase activity. b- Minimal bleeding tendency. b- Long t ½ → S.C. or I.V. od or bid. c- Easy calculation of dose → No need for laboratory monitoring. ¾ Hirudin & Hirulog: ƒ Obtained from Medicinal leech. Now synthesized by rDNA technology → Lepirudin I.V. infusion. ƒ Direct & selective Thrombin inhibitors. ƒ Not dependent on Anti-thrombin III & Not antagonized by platelet factor. ƒ Useful in patients allergic to heparin or develop thrombocytopenia. Blood 47 Blood  ¾ Ancrod: ƒ An enzyme of Ancrod snake venom. ƒ Thrombin like But → Abnormal fibrin → Rapid fibrinolysis & uptake by R.E.S. → Depletion of Fibrinogen. ƒ Side effects → Hemorrhage & Hypersensitivity. ƒ Anti-dote: Fibrinogen & Anti-venom. Warfa