Pharmacology - General Pharmacology (PDF)

Pharmacology General Pharmacology The word "pharmacology" is derived from the words pharmakon. which means "drug", which means "science." Pharmacology is the science of the study of substances that interact with living systems through chemical processes, especially by binding to regul...

Pharmacology General Pharmacology The word "pharmacology" is derived from the words pharmakon. which means "drug", which means "science." Pharmacology is the science of the study of substances that interact with living systems through chemical processes, especially by binding to regulatory molecules and activating or inhibiting normal body processes A. Branches of pharmacology Pharmacology comprises two main branches: 1) pharmacokinetics and 2) pharmacodynamics. 1. Pharmacokinetics (what body does to drug): It involves movement of drug and includes study of absorption, distribution, metabolism, and excretion of drugs. The study of what happens to the drug in the body is called pharmacokinetics. For example, chlorpromazine is absorbed at a faster rate by the parenteral route than the oral route; it binds with plasma and tissue protein and it is metabolized into the liver and is excreted in 15 to 30 hours. 2. Pharmacodynamics (what drug does to body): 1 is a quantitative study of the biological and therapeutic e ect of drug. For example, curare (a plant extract used by tribals as arrow poison) is a nondepolarizing blocker which rapidly produces muscle weakness and nally leads to skeletal muscle paralysis. B. Other branches 1. Pharmacotherapeutics: It is a branch of medicine which deals with clinical application of the pharmacokinetic a n d pharmacodynamic knowledge of the drug, in nding a cure of diseases or relief of symptoms. It includes use of drugs in the treatment, diagnosis, or prevention of a disease or use in alteration of physiological functions for the bene t of the recipient. 2. Toxicology: It is a science of poisons. Poisons are substances that are harmful and dangerous or show fatal symptoms in animals and human beings; many drugs in large dose act as poisons, for example, aspirin in less dose acts as an anticoagulant by inhibiting thromboxane A2; thus, it is useful for heart patients but in high dose causes ulceration and can lead to fatal bleeding. 3. Chemotherapy: It is concerned with the e ect of drug upon microorganisms and parasites, living and multiplying in living organisms. It is now also useful for the treatment of cancer by targeting cancerous cells. fi fi ff fi ff  4. Pharmacognosy: It deals with the study of the sources of drugs derived from plants and animal origin. 5. Pharmacy : It is the art and science of compounding or preparing suitable dosage forms for administration of drugs in man and animals and dispensing drugs. It also includes identi cation. selection, collection, puri cation, isolation, standardization, and quality control o f medicinal substances. Sources of Drugs: Drugs are obtained mainly from plants, animals, microbes, and mineral sources. Nowadays, a majority of therapeutically used drugs are produced from synthetic or semisynthetic products. 1. Animal sources: Insulin, heparin, thyroid extract, and antitoxic sera (for example, antisnake venom). 2. Minerals: Liquid para n, ferrous sulfate, magnesium sulfate, magnesium trisilicate, kaolin, etc. 3. Microorganisms-bacteria and fungi: Penicillin, streptomycin, erythromycin 4. Human beings: These products are obtained from human beings. For example, immunoglobulins from blood, growth hormone from the pituitary gland, placental extract from placenta. 5. Synthetic compounds: Analgesics, antimicrobials, hypnoties, anticancer drugs, ete. 6. Genetic engineering: Human insulin, growth hormone, ete. 7. Hybridoma technique: Monoclonal antibodies, etc. E. Drug nomenclature/naming of drugs Drug nomenclature is a system of names that puts drugs into classi cation, as of anatomic structures, molecular entities, or organisms. The three broad name classi cations of drugs are as follows: Chemical/molecular/scientificname International nonproprietary/generic/approved name Proprietary/brand/trade name fi ffi fi fi fi Pharmacokinetics: what the body does to a drug Four pharmacokinetic properties determine the onset, intensity, and duration of drug action (Figure): Absorption: First, absorption from the site of administration permits entry of the drug (either directly or indirectly) into plasma. Distribution: Second, the drug may reversibly leave the bloodstream and distribute into the interstitial and intracellular uids. Metabolism: Third, the drug may be biotransformed through metabolism by the liver or other tissues. Elimination: Finally, the drug and its metabolites are eliminated from the body in urine, bile, or feces. Using knowledge of pharmacokinetic parameters, clinicians can design optimal drug regimens, including the route of administration, dose, frequency, and duration of treatment. Schematic representation of drug absorption, distribution, metabolism, and elimination. fl ROUTES OF DRUG ADMINISTRATION The route of administration is determined by the properties of the drug (for example, water or lipid solubility, and ionization) and by the therapeutic objectives (for example, the need for a rapid onset, the need for long term treatment, or restriction of delivery to a local site). Major routes of drug administration include enteral, parenteral, and topical, among others ­ A. Enteral Enteral administration (administering a drug by mouth) is the most common, convenient, and economical method of drug administration. The drug may be swallowed, allowing oral delivery, or it may be placed under the tongue (sublingual) or between the gums and check (buccal), facilitating direct absorption into the bloodstream 1. Oral: Oral administration provides many advantages and is the most convenient dosage form. Oral drugs are easily self- administered, and toxicities and/or overdose of oral drugs may be overcome with antidotes, such as activated charcoal. However, the pathways involved in oral drug absorption are the most complicated, and the low gastric pH inactivates some drugs. A wide range of oral preparations is available including enteric- coated and extended-release preparations a. Enteric-coated preparations: An enteric coating is a chemical envelope that protects the drug from stomach acid, delivering it instead to the less acidic intestine, where the coating dissolves and releases the drug. Enteric coating is useful for certain drugs (for example, erythromycin and omeprazole) that are acid labile for drugs that are irritating to the stomach (for example, aspirin) b. Extended-release preparations: Extended-release (abbreviated SR, CR, ER, XR, XL, etc.) medications have special coatings ingredients that control drug release, thereby allowing for slower absorption and prolonged duration of action For example, the half-life of oral morphine is 2 to 4 hours, and it must be administered six times daily to provide continuous pain relief. However, only two doses are needed when extended-release tablets are used. 2. Sublingual/buccal: The sublingual route involves placement of drug under the tongue. The buccal route involves placement of drug between the cheek and gum. Both the sublingual and buccal routes of absorption have several advantages, including ease of administration, rapid absorption, bypass of the harsh gastrointestinal (GI) environment, and avoidance of rst-pass metabolism (see discussion of rst-pass metabolism B. Parenteral The parenteral route introduces drugs directly into the systemic circulation. Parenteral administration is used for drugs that are poorly absorbed from the GI tract (for example, heparin) or unstable in the GI tract (for example, insulin). Parenteral administration is also used for patients unable to take oral medications (unconscious patients) and if require a rapid onset of action. 1. Intravenous (IV): IV injection is the most common parenteral route. It is useful for drugs that are not absorbed orally, such as Gentamysine 2. Intramuscular (IM): Drugs administered IM can be in aqueous solutions, which are absorbed rapidly, or in specialized depot preparations, which are absorbed slowly. fi fi  3. Subcutaneous (SC): Like IM injection, SC injection provides absorption via simple di usion and is slower than the IV route. SC injection minimizes the risks of hemolysis or thrombosis associated with IV injection and may provide constant, slow, and sustained e ects. 4. Intradermal (ID): The intradermal (ID) route involves injection into the dermis, the more vascular layer of skin under the epidermis. Agents for diagnostic determination and desensitization are usually administered by this route. C. Other 1. Oral inhalation and nasal preparations: Both the oral inhalation and nasal routes of administration provide rapid delivery of drug across the large surface area of mucous membranes of the respiratory tract and pulmonary epithelium. 2. Intrathecal / intraventricular : The blood - brain barrier typically delays or prevents the absorption of drugs into the central nervous system (CNS). When local, rapid e ects are needed, it is necessary to introduce drugs directly into the cerebrospinal uid. 3. Topical: Topical application is used when a local e ect of the drug is desired, for example, skin, eye, ear, nose, vaginal, and urethral. 4. Transdermal : This route o f administration achieves systemic e ects by application of drugs to the skin, usually via a transdermal Patch 5. Rectal: Because 50% of the drainage of the rectal region bypasses the portal circulation, the biotransformation of drugs by the liver is minimized with rectal administration. Absorption: is the transfer of a drug from the site of administration to the bloodstream. The rate and extent of absorption depend on: 1. Chemical characteristics of the drug. 2. Dosage form. ((solid/liquid/gas o r aqueous solution, suspension, or oil). 3. Route of administration (which in uences bioavailability). Routes of administration other than intravenous may result in partial absorption and lower bioavailability. A. Determinants of absorption The general determinants of the absorption rate of drugs include the following: 1. Routes of drug administration 2. Dissolution into aqueous uids at the absorption site 3. Lipid solubility 4. Concentration gradient 5. Blood ow at the absorption site 6. Surface area of the absorption site ff fl ff fl ff fl ff fl ff  B. Mechanisms of absorption of drugs from the Gl tract Depending on their chemical properties, drugs may be absorbed from the Gl tract by: 1. Passive di usion. 2. Facilitated di usion. 3. Active transport. 4. Endocytosis. 1. Passive di usion: The drug moves from an area region of high concentration to one of lower concentration Passive di usion does not involve a carrier. Not saturable. No need energy. The vast majority of drugs are absorbed by this mechanism. Water-soluble drugs penetrate the cell membrane through aqueous channels or pores, whereas lipid-soluble drugs readily move across most biologic membranes due to solubility in the membrane lipid bilayers ff ff ff ff  2. Facilitated di usion: Other agents can enter the cell through space specialized transmembrane carrier proteins that facilitate the Cell membrane passage of large molecules. This process: not require energy. Saturated of carrier. 3. Active transport: Moving drugs against a concentration gradient, from a region of low drug concentration to one of higher concentration. Speci c carrier proteins that span the membrane. Energy-dependent. Driven by the hydrolysis of adenosine triphosphate (ATP). The process is saturable. fi ff  4. Endocytosis and exocytosis: This type of absorption is used to transport drugs exceptionally large size across the cell membrane. Endocytosis involves engulfment of a drug by the cell membrane and transport into the cell by pinching o the drug- lled vesicle Exocytosis is the reverse of endocytosis. Many cells use exocytosis to secrete substances out of the cell through a similar process of vesicle formation., whereas certain neurotransmitters (for example, norepinephrine) are stored in intracellular vesicles in the nerve terminal and released by exocytosis. C. Factors in uencing absorption 1. E ect of pH on drug absorption: Most drugs are either weak acids or weak bases. Acidic drugs (HA) release a H+ causing a charge anion (A-). Weak base (BH+) release a H+, the protonated from of basic drugs is usually charged, and loss of proton produces the uncharged base (B). ff fl ff fi pH = - Log [ H + ] ‫اللوغارتم السالب لتركيز أيون الهايدروجني‬ pH for medium = un constant pKa = - Log Ka ‫اللوغارتم السالب لثابت التأين‬ pKa for drug = constant The distribution of a drug between its ionized and nonionized forms depends on the pH and pKa of the drug Drug weak base in pH (medium) acidic like in stomach, ionized form greater than unionized low absorption. Drug Weak base in pH (medium) alkaline like in intestine, unionized form greater than ionized high absorption. Determination of how much drug will be found on either side of membrane. The relationship of pKa and the ratio of acid - base concentration to pH is expressed by the (Henderson- Hasselbalch) equation This equation is useful in determination how much drug will be found on either side of a membrane that separate two compartment that di er in pH for example: Stomach = pH 1.0 - 1.5 Blood p l a s m a = pH 7.4 ff  2. Blood ow to the absorption site: The intestines receive much more blood ow than the stomach, so absorption from the intestine is favored over the stomach. 3. Total surface area available for absorption: With a surface rich in brush borders containing microvilli, the intestine has a surface are a about 1000-fold that of the stomach, making absorption of the drug across the intestine more e cient. 4. Contact time at the absorption surface: If a drug moves through the Gl tract very quickly, as can happen with severe diarrhea, it is not well absorbed. (The presence of food in the stomach) 5. P-glycoprotein: P-glycoprotein is a transmembrane transporter protein responsible for transporting various molecules, including drugs, across cell membranes. That is, it "pumps" drugs out of cells. Thus, in areas of high P-glycoprotein reduces drug absorption. In addition to transporting many drugs out of cells. Bioavailability Bioavailability is the rate and extent to which an administered drug reaches the systemic circulation. (chemically unchanged form). For example, if 100 mg of a drug is administered orally and 70 mg is absorbed unchanged, the bioavailability is 0.7 or 70%. Determining bioavailability is important for calculating drug dosages for intravenous routes of administration. Determination of bioavailability: Bioavailability is determined by comparing plasma levels of a drug after oral administration with plasma levels achieved by IV administration. After IV administration, 100% of the drug rapidly enters the circulation. When the drug is given orally, only part of the administered dose appears in the plasma. By plotting plasma concentrations of the drug versus time, the area under the curve (AUC) can be measured fl ffi fl Factors that in uence bioavailability: 1. First - pass hepatic metabolism: When drug is absorbed across the GI tract. It enters the portal circulation before entering the systemic circulation. If the is rapidly metabolized by the liver, the amount of unchanged reach to systemic circulation is decreased (lidocaine, propranolol). 2. Solubility of the drugs: Hydrophilic drug are poorly absorbed because of their inability to cross the lipid - rich cell membrane. 3. Chemical instability: Some drug such as penicillin G, are unstable in the pH of the gastric contents, insulin are destroyed in the GI tract by digestive enzymes. 4. Nature of the drug formulation: Drug absorption may be altered by factors unrelated to the chemistry of the drug. For example, particle size, salt form, enteric coatings, and the presence of excipients can in uence the ease of dissolution and, therefore, alter the rate of absorption. fl fl