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General pharma

Short intro to general pharma for BDS students.
Apologies if I missed out on something.

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General pharma

  1. 1. Hiba Hamid PHARMACOLOGY CHAPTER 1 GENERAL PHARMACOLOGY Definitions: Pharmacology: Defined as the study of biochemical and physiologic aspects of drug effects, including absorption, distribution, metabolism, elimination, toxicity, and specific mechanisms of drug action. Pharmacokinetics: The way in which body handles the drug. Includes absorption, distribution, metabolism and elimination of the drug. Pharmacodynamics: Effects of drug on the body. Includes drug receptor concept (mechanism of action of drug), and dose response relationships (biochemical and physiological effects of drug). Medical pharmacology: Science of materials used to prevent, diagnose, and treat disease. Toxicology: Deals with undesirable effects of chemicals in biologic systems. Pharmacy: Deals with preparation, dispensing, and proper utilization of drugs. Pharmacognosy: Deals with biological, biochemical, and economic features of natural drugs and their constituents. Drug: Any small molecule that, when introduced into the body, alters the body’s function by interactions at the molecular level. Prodrugs: Compound that on administration into the body, must undergo chemical conversion by metabolic processes before becoming an active pharmacological agent. 1
  2. 2. Hiba Hamid Pharmacopoeia: Book containing a list of products used in medicine. Examples: 1. USP= United States Pharmacopoeia 2. BP= British Pharmacopoeia Routes of drug administration of drugs: A. Enteral (alimentary) routes: 1. Oral 2. Sublingual/Buccal 3. Rectal B. Parenteral (extra-alimentary) routes: 1. Intravenous: drug introduced into a subcutaneous vein 2. Intramuscular: drug introduced into a muscle (e.g. deltoid or gluteus maximus) 3. Subcutaneous: drug injected below the skin 4. Intraperitoneal: drug introduced in the peritoneal cavity 5. Intra-arterial: drug introduced into an artery 6. Intra-thecal: drug introduced through theca of spinal cord into subarachnoid space 7. Transdermal: drug applied across dermis of skin 8. Topical: drug applied over skin or mucous membrane 9. Inhalational: drug introduced into the respiratory tract 10. Intracardiac: drug injected directly into heart 11. Intra-articular: drug injected into joint cavity 12. Bone marrow injection: drug injected into bone marrow (e.g. sternum in adult and tibia in children) Oral route: Advantages: 1. Most convenient, most economical, most commonly used route 2. Can be used for local as well as systemic actions of drugs 3. Safest route 4. Convenient dosage forms that do not require sterile techniques 5. Delivery into circulation slow so that rapid, high blood conc. are avoided and untoward effects are less 6. Largest surface area for absorption 7. Drugs that cause irritation on parenteral administration can be given 8. Larger dose can be given 2
  3. 3. Hiba Hamid Disadvantages: 1. Rate of absorption variable 2. Irritation of mucosal surface can occur 3. Compliance of patient is ensured 4. First pass effect (i.e. extensive hepatic metabolism of drug before it reaches its site of action) 5. Cannot be used in comatose pts. or in pts. with emergency 6. Poorly lipid soluble drugs (e.g. Neostigmine) are not absorbed 7. Drugs destroyed by digestive enzymes (e.g. insulin, pituitary hormones) or by gastric acidity (e.g. benzyl penicillin) cannot be given 8. Certain GIT pathologies interfere with absorption of drugs, e.g. gastritis, peptic ulcer, vomiting, and diarrhea 9. Drugs that undergo enterohepatic circulation (e.g. epinephrine) are destroyed 10. Some drugs are not absorbed from GIT (e.g. streptomycin); thus given parenterally Sublingual route: Advantages: 1. Rapid absorption 2. Excess drug can be removed from mouth 3. First pass effect avoided 4. Can be used in emergency conditions, e.g. nitroglycerin in angina attack Disadvantages: 1. Drugs that cause vasoconstriction of sublingual mucosa can’t be given 2. Large doses cannot be administered 3. Repeated administration damages oral mucosa 4. Irritation of oral mucosa can occur Rectal route: Advantages: 1. Used when oral administration is impractical, e.g. coma 2. Drugs irritant to stomach can’t be given 3. Can be used in uncooperative pts. and in children 4. Can be used in unconscious pts. or in vomiting 5. First pass effect partially avoided Disadvantages: 1. Absorption is imperfect 2. Cannot be used frequently 3. Patient feels embarrassed and might not prefer administration at times 3
  4. 4. Hiba Hamid Parenteral route: Advantages: 1. Rapid response, thus can be used in emergency situations 2. Comatose or uncooperative pts. 3. Dose can be accurately delivered 4. First pass effect is avoided 5. Drugs irritant to GIT can be given Disadvantages: 1. Rapid absorption leads to increased untoward effects 2. Sterile formulation and aseptic technique are required 3. Local irritation at the site of injection may occur ABSORPTION OF DRUG Passage of drug from site of administration into the blood stream Mechanisms of drug absorption from GIT 1. Passive diffusion 2. Facilitated diffusion 3. Active transport 4. Endocytosis and exocytosis Factors that modify drug absorption: A. Factors related to the drug: 1. Lipid-water partition coefficient: directly proportional to absorption 2. Degree of ionization: inversely proportional to absorption 3. Chemical nature of molecules 4. Dosage form: solutions are better absorbed than suspensions B. Factors related to the patient: 1. Route of administration: absorption is poor from intact skin, good from mucous membrane, and complete from parenteral sites 2. Area and vascularity of absorbing surface: directly proportional to absorption 3. State of health of absorbing surface 4. Rate of general circulation: influences rate of transport of drug 5. Specific factors: e.g. “intrinsic factor” for absorption of vit. B12 Factors influencing absorption of a drug: 1. Effect of pH on drug absorption a) Most drugs are either weak acids or weak bases. 4
  5. 5. Hiba Hamid 2. 3. 4. 5. b) Acidic drugs (HA) release a proton (H+), causing a charged anion (A-) to form: HA ↔ H+ + Ac) Weak bases (BH+) can also release an H+. However, the protonated form of the basic drug is usually charged, and the loss of a proton produces the uncharged base (B): BH+ ↔ B + H+ d) Drugs pass readily through membranes if they are uncharged e) Thus, for weak acids, the uncharged protonated HA can permeate through membranes, and A- cannot. f) For weak bases, the uncharged form, B, penetrates through cell membrane, but the protonated BH+ does not. Blood flow to absorption site a) Because blood flow to intestines is greater than flow to stomach, absorption from intestine is favoured over that from the stomach. b) Shock severely reduces the blood flow to cutaneous tissues, thereby minimizing absorption from SC administration. Total surface area available for absorption a) Intestines have a large surface area for absorption because of the surface rich brush borders containing microvilli. Contact time at the absorption surface a) If a drug moves through the GIT very quickly, as in diarrhea, it is not well absorbed b) Anything that delays the transport of the drug from the stomach to the intestine delays the rate of absorption. c) Parasympathetic input increases the rate of gastric emptying d) Sympathetic input, prompted during exercise or stressful conditions, as well as anticholinergics, delays gastric emptying. e) Presence of food in the stomach both dilutes the drug and slows gastric emptying. Therefore, a drug taken with a meal is generally absorbed slowly. Expression of P-glycoprotein a) Is a multi-drug transmembrane transporter protein responsible for transporting various molecules, including drugs, across cell membranes. b) Expressed throughout the body c) Its functions include: i. In the liver: transporting drugs into bile for elimination ii. In kidneys: pumping drugs into urine for excretion iii. In the placenta: transporting drugs back into the maternal blood, thereby reducing fetal exposure to drugs iv. In the intestines: transporting drugs into the intestinal lumen and reducing drug absorption into the blood v. In the brain capillaries: pumping drugs back into blood, limiting drug access to the brain. 5
  6. 6. Hiba Hamid d) In areas of high expression, P-glycoprotein reduces drug absorption e) Also associated with multi-drug resistance. Bioavailability: The fraction (or percentage) of the administered dose of drug that reaches the systemic circulation. The route by which a drug is administered, as well as the chemical and physical properties of the agent, affects its bioavailability. Factors that influence bioavailability: In contrast to IV administration of a drug which confers 100% bioavailability, oral administration of a drug involves first pass metabolism. This biotransformation of the drug determines the amount of agent reaching the circulation and at what rate. 1. First pass hepatic metabolism a) When drug absorbed across GIT, it enters portal circulation before entering systemic circulation b) If drug is rapidly metabolized in the liver or gut wall during this initial passage, amount of unchanged drug that reaches the systemic circulation is decreased c) Drugs exhibiting high first pass metabolism should be given in sufficient quantities to ensure that enough of the active drug reaches the target concentration 2. Solubility of the drug a) Very hydrophilic molecules are poorly absorbed because of their inability to cross lipid-rich cell membranes. b) Drugs extremely hydrophobic are also poorly absorbed because they are totally insoluble in body fluids, therefore, cannot gain access to the surface of cells c) For a drug to be readily absorbed, it must be largely hydrophobic, yet have some solubility in aqueous solutions. This is one reason why many drugs are either weak acids or weak bases. 3. Chemical instability a) Some drugs, like penicillin G, are unstable in the pH of gastric contents. b) Other drugs, like insulin, are destroyed in the GIT by degradative enzymes. 4. Nature of drug formulation a) Drug absorption may be altered by factors unrelated to the chemistry of the drug b) Particle size, salt form, crystal polymorphism, enteric coatings, and presence of excipients (such as binders and dispersing agents), can influence ease of dissolution, therefore altering the rate of absorption. 6
  7. 7. Hiba Hamid Binding of drugs to plasma proteins 1. Upon entering blood, some drugs bind nonspecifically and reversibly to plasma proteins, e.g. albumin and globulin 2. An equilibrium is produced between the bound and free drug 3. Bound drug: a) Cannot leave vascular space b) Is not metabolized c) Is not eliminated d) Is inactive pharmacologically e) Forms a storage depot from which small proportion of active drug is freed constantly 4. Free drug: a) Exerts pharmacological effects b) Is metabolized by liver microsomal enzymes c) Is eliminated by kidneys DISTRIBUTION OF DRUGS Process by which drug reversibly leaves the bloodstream and enters the interstitium (extracellular fluid) and then the cells of the tissues. Delivery of the drug from the plasma to the interstitium depends mainly on:  Cardiac output  Regional blood flow  Capillary permeability  Tissue volume  Degree of binding of the drug to plasma and tissue proteins  Relative hydrophobicity of the drug Volume of distribution: Total Body Water 42 liters Intracellular volume Extracellular volume 28 liters 14 liters Interstitial volume 10 liters Plasma volume 4 liters 7
  8. 8. Hiba Hamid Apparent volume of distribution  The apparent volume of distribution, Vd, can be thought of as the fluid volume that is required to contain the entire drug in the body at the same concentration measured in the plasma  Calculated by dividing the dose that ultimately gets into the systemic circulation by the plasma concentration at time zero (C0): 𝐴𝑚𝑜𝑢𝑛𝑡 𝑜𝑓 𝑑𝑟𝑢𝑔 𝑖𝑛 𝑡ℎ𝑒 𝑏𝑜𝑑𝑦 𝑉𝑜𝑙𝑢𝑚𝑒 𝑜𝑓 𝑑𝑖𝑠𝑡𝑟𝑖𝑏𝑢𝑡𝑖𝑜𝑛 = 𝑃𝑙𝑎𝑠𝑚𝑎 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑑𝑟𝑢𝑔 𝑎𝑡 𝑡𝑖𝑚𝑒 𝑧𝑒𝑟𝑜  A drug rarely associates with only one of the water compartments of the body  Vast majority of the drug distributes into several compartments, avidly binding to cellular components like lipids, proteins, and nucleic acids. Effect of Vd on drug half-life  A large volume of distribution has an important effect on the half-life of a drug, because drug elimination depends on the amount of drug delivered to the liver or kidney (or other organs where metabolism occurs) per unit of time.  Delivery of drugs to organs of elimination depends not only on blood flow, but also on fraction of drug in the plasma.  If Vd is large, most of the drug is present in the extraplasmic space and is unavailable to excretory organs.  Any factor that increases Vd leads to increase in half-life and extends the duration of action of the drug. Drug clearance:  Ratio of rate of elimination of a drug to the concentration of the drug in the plasma or blood.  Drug eliminated with first order kinetics, clearance is a constant; i.e. ratio of rate of elimination to plasma concentration is same regardless of plasma concentration  Drug eliminated with zero order kinetics, clearance is not a constant. Half-life:  Time required for the amount of drug in the body or blood to fall by 50%.  For drugs eliminated by first order kinetics, this number is a constant regardless of the concentration. Loading dose: Dose which is administered to quickly achieve the desired concentration of drug in the body. Maintenance dose: It is the dose which is administered to replenish the amount of drug which is eliminated in intervals between two doses, so that a steady concentration of drug is maintained in the plasma. 8
  9. 9. Hiba Hamid Therapeutic window:  It is safe range between the minimum therapeutic concentration and the minimum toxic concentration of a drug.  Minimum effective concentration usually determines the desired trough levels of a drug given intermittently.  Minimum toxic concentration determines the permissible peak plasma concentration. METABOLISM OF DRUGS  Metabolism of a drug sometimes terminates its action, at other times it enhances it. First pass effect / pre-systemic elimination  The elimination of drug that occurs after administration but before it enters the systemic circulation (e.g. during passage through the gut wall, portal circulation, or liver for an orally administered drug).  Drug metabolism occurs primarily in the liver. A. Drug metabolism as a mechanism of termination of action of the drug The actions of many drugs (e.g. sympathomimetics, phenothiazines) is terminated before they are excreted by being metabolized to biologically inactive derivatives. B. Drug metabolism as a mechanism of drug activation Prodrugs (e.g. levodopa, minoxidil) are inactive as administered, metabolized in the body to become active. Many drugs are active when administered and have active metabolites (e.g. morphine, some benzodiazepines) C. Drug elimination without metabolism Some drugs (e.g. lithium, among others) are not modified by the body; they continue to act until they are excreted. Phase I reactions  Reactions that convert the parent drug to a more polar (water-soluble) or more reactive product by unmasking or inserting a polar functional group such as —OH, —SH, or —NH2.  Include the following reactions:  Oxidation (by cytochrome P450 group of enzymes, also called mixed function oxidases)  Reduction  Deamination  Hydrolysis  These enzymes found in high concentrations in the smooth endoplasmic reticulum of the liver. 9
  10. 10. Hiba Hamid Phase II reactions  Reactions that increase water solubility by conjugation of the drug molecule with a polar moiety such as glucuronate, acetate, or sulfate.  Synthetic reactions that involve addition (conjugation) of subgroups to —OH, —SH, and —NH2 functions on the drug molecule.  Reactions include:  Glucuronidation  Acetylation  Glutathione conjugation  Glycine conjugation  Sulfation  Methylation Factors affecting biotransformation rate  Chemical properties of the drug: molecular weight and ionic charge  Route of administration: oral route causes first-pass effect  Genetic factors: e.g. acetylation of isoniazid is under genetic control  Diet: starvation depletes glycine and alters glycine conjugation  Dosage: toxic doses depletes enzymes  Age: liver cannot detoxify chloramphenicol in neonates  Gender: young males are prone to sedation from barbiturates than females are.  Diseases: liver disease decreases metabolism and kidney disease decreases excretion of drug. ELIMINATION OF DRUGS  The phase of drug inactivation or removal from the body by metabolism or excretion.  Major organs for excretion of drug from body are:  Kidneys  Glomerular filtration  Active tubular secretion  Passive tubular reabsorption  Liver  Polar metabolites of drugs that are poorly absorbed from bile, are excreted through bile.  Some drugs undergo enterohepatic circulation  GIT  When high conc. of drugs are present in blood, they are transferred from blood into GIT lumen by passive diffusion, e.g. morphine  Lungs  Mainly gaseous anesthetics are excreted into expired air 10
  11. 11. Hiba Hamid  Minor routes  Tears  Sweat  Saliva  Breast milk Drug clearance by kidney A. Glomerular filtration 1. Free drug (not bound to albumin) flows through capillary slits into Bowman’s space as part of the glomerular filtrate. 2. Lipid solubility and pH do not influence the passage of the drugs into the glomerular filtrate 3. Varying the glomerular filtration rate and plasma binding of the drugs may affect this process B. Proximal tubular secretion 1. Secretion primarily occurs in the proximal tubules by two energy-requiring active transport systems; one for anions (e.g. for deprotonated forms of weak acids) and one for cations (e.g. for protonated forms of weak bases) 2. Each of these transport systems show low specificity and can transport many compounds. 3. As a result, competition between drugs for these carriers can occur within each transport system 4. Premature infants and neonates have an incompletely developed tubular secretory mechanism, thus retaining certain drugs in the glomerular filtrate C. Distal tubular reabsorption 1. As drug moves toward DCT, its conc. in the filtrate increases and exceeds that of the perivascular space 2. If uncharged, the drug may diffuse out of the nephric lumen back into the systemic circulation 3. Manipulating the pH of the urine to increase the ionized form of the drug in the lumen may be done to minimize the amount of back-diffusion, and, hence, increase the clearance of the drug 4. Weak acids better excreted in alkaline urine. Weak bases better excreted in acidic urine. This process is called “ion trapping”. 5. For example, a patient presenting with phenobarbital (weak acid) overdose can be given bicarbonate, which alkalinizes urine, keeps the drug ionized, thereby decreasing its reabsorption. 6. If overdose is with a weak base, like amphetamine, acidification of urine with NH4Cl leads to protonation of the drug (it becomes charged), leading to its excretion enhancement 11
  12. 12. Hiba Hamid First order elimination  Rate of elimination is proportional to the concentration (i.e. higher the concentration, greater the amount of drug eliminated per unit time).  As a result, drug’s concentration in the plasma decreases exponentially with time  Most drugs in clinical use exhibit first order elimination. Zero order elimination  Rate of elimination is constant regardless of concentration  As a result, the concentration of these drugs in plasma decrease in a linear fashion over time. 12