GENERAL PHARMACOLGY

GENERAL PHARMACOLGY. MELAKU T. (B.pharm, Msc pharmacology).

Outline. Introduction Definitions of pharmacology and related terms Source of drugs Naming of drugs Pharmaceutical dosage forms Fate of administered drugs.

DEFINITIONS. Pharmacology is the study of substances that interact with living systems through chemical process, especially by binding to regulatory molecules and activating or inhibiting normal body process. Blend of two Greek words, “Pharmakon” to mean drug or medicine, and “Logos” to mean study Pharmacokinetics: refers to the actions of the human body on the drug what the body does to the drug Pharmacodynamics: refers to the actions of the drug on the human body what the drug does to the body.

Definition …….. Pharmacotherapeutics: is the use of drugs to diagnose, prevent, mitigate or treat disease or to prevent pregnancy. is the study of “the medical use of drugs”. Toxicology: is the branch of pharmacology which deals with undesirable effects of chemicals on living systems, from individual cells to complex ecosystems. Chemotherapy: the effect of drugs upon micro organisms, parasites and neoplastic cells living multiplying in living organism..

Drugs. 5. any substance that brings about a change in biological functions. Prodrug is an ‘inactive’ form of a drug that requires metabolic activation inside the body (bioactivation) in order to release the ‘active’ form of the drug Poisons are drugs that have almost exclusively harmful effects. However, Paracelsus famously stated that “the dose makes the poison”. Toxins are poisons of biologic origin, i.e., synthesized by plants or animals.

Sources of drugs. Minerals: liquid paraffin, magnesium trisilicate, kaolin. Animals: insulin, heparin, thyroid extract, antitoxin sera. Plants: morphine digoxin: digitoxin lanata , digitoxin ? atropine : atropa belladonna castor oil pilocarpine: pilocarpus microphyllus and pilocarpus japorandi Synthetic: Aspirin, sulphonamide, paracetamol, zidovudine. Micro organisms: penicillin, streptomycin. Genetic engineering: human insulin, human growth hormone..

Naming of drugs. The three name classifications of drugs are Chemical/Molecular/Scientific name Generic or Non-Proprietary name and Brand or Trade or Proprietary name Chemical Name depicts the chemical/molecular structure of the drug states the structure in terms of atoms and molecules accompanied by a diagram of the chemical structure are long and useful to a few technically trained personnel only one chemical name for a drug E.g. acetyl-p-amino-phenol is for Paracetamol.

Naming of drugs ……………... Generic Name. 5. accepted internationally only one generic name for a drug most commonly used in prescriptions is the abbreviated and approved name of the drug is not capitalized; e.g. aluminum hydroxide Brand Name are names given to the drug by the manufacturing and marketing company several name for single drug may occur have letter ® expensive.

9. Chemical Name Generic Name Trade Name acetyl-p-amino-phenol acetaminophen Paracetamol® Panadol® Tylenol ®,tempra® (+/-)-2-(p-isobutyl phenyl) propionic acid ibuprofen Advil®, Motrin®, Nuprin®, Brufen®.

Pharmaceutical Dosage Forms. Dosage forms are different preparations of a drug which help to facilitate drug administration & delivery An ideal dosage form should: Deliver the right amount of the drug to the right site Minimize drug exposure to unwanted sites Associated with minimal discomfort or inconvenience Be economical & need lesser expertise knowledge But there is no such ideal dosage form.

Pharmaceutical Dosage Forms ………………… Four types of dosage forms exist Solid dosage forms Semisolid dosage forms Liquid dosage forms Gaseous dosage forms.

Solid dosage forms. are those drug preparations which exist as solids exist in different forms/preparations 1. Tablets are most common forms of solid dosage forms Written as tab or tabs on prescriptions Several kinds of tablets are available Scored tablets Enteric coated tablets Slow release tablets Caplets.

Solid dosage forms………... Lozenges are sweet tablets containing sugar, water & flavoring agents are to be chewed/held in the mouth not swallowed E.g. nystatin…….antifungal 3. Pellets/beads Prepared as sheets or beads for sustained release of drugs E.g. Norplant 4. Powders Are solid preparations which need to be reconstituted before use E.g. penicillin injection (PPF).

Solid dosage forms………... Lozenges are sweet tablets containing sugar, water & flavoring agents are to be chewed/held in the mouth not swallowed Pellets/beads Prepared as sheets or beads for sustained release of drugs E.g. Norplant 4. Powders Are solid preparations which need to be reconstituted before use E.g. penicillin injection.

Solid dosage forms……….. Capsules Written as cap or caps Prepared in two forms Soft capsules are made of soft gelatin Contain liquid inside & are sealed E.g. Vitamin A & E capsules Hard capsules: are made of hard gelatin Contain two separable pieces or cups Contain powder or granules inside E.g. Amoxicillin, tetracycline capsules.

Semi-solid dosage forms. are dosage forms that are too soft to be solid and too hard to be liquid are mainly used for topical administration Includes: Creams are semisolid emulsions of oil & water water is the main ingredient E.g. hydrocortisone cream Ointments are semisolid emulsions of oil & water. Oil is the main ingredient E.g. tetracycline ointment Suppositories & Pessaries used for local effects, or for children, vomiting & unconscious patients.

Liquid dosage forms. Are found in liquid states Can be either clear solutions or suspensions i. Solutions are clear mixtures/fluids They don’t need to be shaken/mixed even after long period of storage Elixirs are clear solutions which contain alcohol & water as solvent also contain flavoring agents are mainly used for pediatric use.

Liquid dosage forms ……….. Syrups. 16. are also clear solutions which contain water, sugar & flavoring agent don’t contain alcohol E.g. multivitamin syrup Tinctures are clear solutions which contain both water & alcohol as solvent and unlike elixirs, they are used for external use and don’t contain flavoring agent E.g. iodine tincture Miscellaneous solutions Includes injectable clear solutions, large volume preparations E.g. gentamicin injection, glucose preparations.

Liquid dosage forms ……….. Suspensions are not clear liquids Contain fine, undissolved drug particles suspended in a liquid Shaking is necessary before use since the solid particles sediment upon storage E.g. antacid suspensions.

Gaseous dosage forms. Contain medical gases & aerosols Medical gases: are preparations for intrapulmonary administration are inhaled through breathing apparatus The API is found as gas or volatile liquid E.g. Aerosols: are another gaseous dosage forms Contain an active drug suspended in a gaseous vehicle are dispersions of solid particles or liquid droplets in a gaseous vehicle E.g..

Fate of Administered Drug. Most drugs after administered to the body they undergo 2 major process Pharmacokinetics process:- involve ADME of the drug. great significance in the selection and administration of a particular drug for a particular patient Pharmacodynamics process:- involve receptor – drug interaction which determines types and selectivity of the drug effect and quantitative determination of drug effect play the major role in deciding whether that class of drugs is effective therapy for a particular disease or symptom.

Fate of Administered Drug …………. Figure 1: pharmacokinetics and pharmacodynamics.

Pharmakon=drug, kinetics=movement The study of what the body does to the drug: Absorption Distribution Metabolism Excretion.

Drug Adrninistration (e.g., parenteral. oral. etc.) Drug Absorption (from site of adrninistration into plasrna) PLASMA Compart rnent Bound Drug Excretion Free Drug Storage in Tissue E)epot (e.g., body fat) Site Of Action (e.g., cell receptor) N'letabolisrn liver, lung, GI tract) (e.g., kidney, expired air, sv.reat, feces) FIGURE.

PASSAGE OF DRUGS ACROSS A BIOLOGICAL- MEMBRANE. How are drugs transferred from site of administration to circulatory system???? Filtration (Aqueous diffusion) Requirements: Size of the drug should be less than size of pore (channel) which is filled with water. Has to be unbound and water soluble E.g. Na +, glucose, caffeine The capillaries of the brain, the testes, and some other tissues are characterized by the absence of pores that permit aqueous diffusion.

2. Lipid Diffusion. 16. Drug is supposed to pass through the membrane. Must be lipid soluble. Dependent on lipid soluble. Dependent on lipid /aqueous partition coefficient 3. Carrier mediated absorption i. Facilitated diffusion: passive diffusion but facilitated. E.g. levodopa and amino acid in to the Brain ii. Active transport Use ATP and carrier proteins Against concentration gradient. E.g. Penicillin secretion by the kidney Carrier mediated transports are saturated, structure specific, and competitive.

4. Endocytosis. 16. Pinocytosis is the engulfing of the extracellular fluid by cells. is a "cell-drinking". is important for the cell's absorption of extracellular fluids. Phagocytosis Process by which large molecules are engulfed by the cell membrane and release them in to the cell. Example: protein, toxin Vitamin B12 complexed with intrinsic factor is transported across the gut wall by endocytosis..

Route Of Drug Administration. Enteral Route Drug is absorbed into the systemic circulation through the oral or gastric mucosa, the small intestine, or rectum. Includes Oral Sublingual………. Nitroglycerin Buccal……………. nitrates Rectal…………….. rectal suppository.

Oral route. Advantage: Most convenient safest Most economical Reverse of dose management is easily done.

Sublingual Placing drugs under the tongue (Nitroglycerin) Rapid absorption, avoids first pass effect Rectal Drugs placed in the rectum Merits For unconscious & children patients , For nauseas or vomiting patients Can reduce first pass effect by 50% Good for vomiting inducing drugs Demerits Inconvenient, erratic absorption.

Parenteral Route. drugs delivered to the systemic circulation without crossing intestinal mucosa Intravenous (IV) Intramuscular (IM) Subcutaneous (SC) Intradermal (ID) Intrathecal (IT) Intraarticular (IA).

Intravenous (IV). Is the most common parenteral route for drugs that are not absorbed orally Advantage Fast onset of action(emergency case) 100 % BA Better for drug with irritation effect can be given in large volume Disadvantage Expertise is needed to give injection Pain, not convenient Expensive Only sterilized solution used Difficult to titrate over dose (irreversible effect ) No local action.

Intramuscular. Drugs administered IM can be aqueous solutions or specialized depot preparations often a suspension of drug in a non aqueous vehicle such as polyethylene glycol Absorption of drugs in aqueous solutions is fast whereas that from depot preparations is slow. Advantages: Uniform rate of absorption Fast onset of action Can be given in vomiting and diarrhea. Disadvantages: Pain at local site of injection Volume of injection < 10 ml..

Intra-arterial. Occasionally, a drug is injected directly into an artery to localize its effect in a particular tissue or organ, such as: in the treatment of liver tumors and Head/neck cancers. Diagnostic agents sometimes are administered by this route e.g., technetium-labeled human serum albumin. Intra-arterial injection requires great care and should be reserved for experts. The first-pass and cleansing effects of the lung are not available when drugs are given by this route.

Transdermal. Achieves systemic effects by application of drugs to the skin, usually via a transdermal patch. The rate of absorption can vary markedly, depending on the physical characteristics of the skin at the site of application. Most often used for the sustained delivery of drugs, such as The antianginal drug nitroglycerin The antiemetic scopolamine, and The once-a-week contraceptive patch (Ortho Evra) that has an efficacy similar to oral birth control pills.

Inhalation. Provides the rapid delivery of a drug across the large surface area of the mucous membranes of the respiratory tract and pulmonary epithelium Producing an effect almost as rapidly as with IV injection. Is particularly effective and convenient for patients with respiratory complaints (such as asthma, or chronic obstructive pulmonary disease) because the drug is delivered directly to the site of action and systemic side effects are minimized. E.g. albuterol and corticosteroids, such as fluticasone..

Topical. Application could be on mucous, skin or the eye Mucous membrane include conjunctiva, nasopharynx, oropharynx, vagina … Topical application is used when a local effect of the drug is desired. e.g. clotrimazole is applied as a cream directly to the skin in the treatment of dermatophytosis tropicamide or cyclopentolate are instilled (administered drop by drop) directly into the eye to dilate the pupil and permit measurement of refractive errors.

Drug Absorption. Process by which the drug leaves the site of administration and enters into the circulatory system Drugs can be absorbed from GI tract (oral, sublingual or rectally), mucous membranes, skin, lungs, muscle or SC tissues Factors affecting drug absorption Route of administration Physicochemical properties of the drug Dosage forms Circulation at the site of absorption Concentration of the drug Surface area of absorption site Contact time at site of absorption Presence & type of food.

Bioavailability is fraction of administered drug that reaches the systemic circulation. is expressed in %. Factors Affecting Bioavailability I. Extent of absorption After oral administration, a drug may be incompletely absorbed, e.g. only 70% of a dose of Digoxin reaches the systemic circulation. II. First pass elimination The metabolism of a drug while it pass through portal circulation to liver oral route ……………….high first-pass effect III. Rate of absorption is determined by the site of administration and the drug formulation.

Distribution of drugs. Is the delivery of drugs from systemic circulation to tissues is random (every tissues have equal chance) But concentration of drugs in different tissues differ Factors Which Influence Drug Distribution plasma protein binding Drug in systemic circulation exist as bound and unbound form Drug ordinarily bind with plasma protein in reversible fashion and in dynamic equilibrium D + P →[DP] → D + P As free drugs leave the systemic circulation the bound drug dissociate.

Only the unbound drug can diffuse through capillary and cell membrane (↓Vd), so Produce pharmacological effect Produce toxic effect Be metabolized Be excreted The major binding macromolecule: Albumin Mainly acidic and hydrophobic drug bind e.g. Warfarin -albumin→99% Some factor affect the binding of drugs with albumin: Age , Pregnancy, Disease state Others: include α1 –acid glycoprotein, Lipoprotein , Globulin,.

Tissue Uptake Some drugs have affinity to certain body organs Adipose tissue : drugs with extreme lipid solubility (excellent lipid water partition coefficient) Kidney : contain proteins, methallothionein, that has high affinity for metals Eye – drugs which have affinity for retinal pigment, melanin, accumulate in the eye Chlorpromazine (other phenothiazine) and chloroquine Bone- TTC, Lead, Cisplatin Liver – Chloroquine.

Factors Which Influence Drug Distribution………….. 43.

Physiological barriers……. placental barrier Blood vessel of mother and fetus separated by PBB Highly polar and ionized drugs do not cross placenta readily Drugs with high lipid solubility shouldn't be given to pregnant mother Eg TTC –accumulate in bone and teeth of neonate— ↓development of bone and teeth Chloramphenicol –cause gray baby syndrome Drugs which cross PBB cause fetal abnormalities and called teratogenic drugs Testicular Barrier.

Factors Which Influence Drug Distribution…………. Rate of Blood Flow The rate at which drugs are delivered to a particular tissue is determined by the blood flow to that tissue. Different tissue have d/t rate and amount of blood flow Highly perfused tissue:- heart, lung, brain, liver, kidney Intermediate perfused tissue:- skeletal muscle Poorly perfused tissue:- skin, bone, nail, fat tissue Generally the distribution of drugs to body compartment determined by volume of distribution (Vd).

Metabolism/ Biotransformation. A chemical change (transformation) of drugs by body enzyme to facilitate excretion of drugs by changing to more water soluble form Lipophilic → → hydrophilic Metabolism of drug occur in all body parts But mainly take place in liver Metabolism in liver involve 2 steps Phase I Phase II.

Phase I reaction. Called functionalizing reaction since include addition or exposure of functional group Produce more reactive metabolites and more hydrophilic Involve Cytochrome P-450 enzyme; not necessarily for all CypP-450 enzyme have different families and sub families CYP3A4 (30%), CYP1A2 (15%), CYP2C9 (20%), CYP2D6 (5%) Enzyme induction:- ↑ synthesis of microsomal enzyme - ↑ metabolism - ↑excretion e.g. Phenobarbitone: non selective inducer Enzyme inhibitor:- ↓liver enzyme function - ↓metabolism -- - ↓excretion-toxicity e.g. Cimetidine, Ketoconazole, Erythromycin, Chloramphinicol.

Phase II reaction. Called conjugation reaction Involve conjugation of more polar molecule to ↑ water solubility Drug + endogenous polar cpd Type of phase II rxn:.

Acetylation reaction Involve N-acetyl transferase E.g. isoniazide (INH), hydralazine Acetylation of isoniazide show genetic polymorphism Slow acetylator ↓ Acetylation --↓ excretion ↑ plasma level toxicity ( peripheral neuropathy) Fast acetylator Excessive enzyme-↑ Acetylation--↑ excretion……………. ↓ plasma level --↓out come of therapy.

iii. Sulphate conjugation:. Use sulfotransferase enzyme E.g. steroids Methyl conjugation Use methyl transferase Eg catecholamine, histamine Glutathione conjugation Use glutathione - - transferase Glutathione protect cells from reactive electrophilic cpds.