Introduction to Pharmacology - Pharmacokinetics, Pharmacodynamics PDF

General Pharmacology Prof. Dr. Ahmet Özer Şehirli 1  Learning Objectives Will be able to list Drug Administration Routes and Pharmaceutical Forms List the absorption, distribution, metabolism and excretion of drugs Will be able to comprehe...

General Pharmacology Prof. Dr. Ahmet Özer Şehirli 1  Learning Objectives Will be able to list Drug Administration Routes and Pharmaceutical Forms List the absorption, distribution, metabolism and excretion of drugs Will be able to comprehend drug interactions Will be able to understand the factors that change the effects of drug Will be able to the comprehend undesirable effects of drugs 2  Introduction ❑Pharmacology – ❑ This chapter will Science of drugs provide an overview of ❑Medication mistakes the role of drugs in can injure or even medical facilities cause death of a patient. You will need to have a good working knowledge of the foundations of pharmacology. 3 Dentist’s Role in Pharmacology ❑Have basic knowledge of medications ❑Be attentive to ensure that the dentist is aware of all the medications a patient is taking. ❑Ask patients about use of alcohol, vitamins, herbal medications 4  Drugs and Pharmacology ❑ Drug - chemical compound A doctor or a dentist used to prevent, diagnose or prescribes a drug when treat a disease or other he gives a patient a abnormal condition prescription to be filled ❑ Pharmacologist - specialist by a pharmacy. in pharmacology You are responsible to administer a drug by giving it directly by injection, by mouth, or by any other route to introduce the drug into a patient’s body. 5  Indication: The basis for initiation of a treatment for a disease or a diagnostic test; may be furnished by a knowledge of the cause, by the symptoms present, or by the nature of the disease. Side Effect: A side effect is usually regarded as an undesirable secondary effect which occurs in addition to the desired therapeutic effect of a drug or medication. Contraindication: Containdication is a condition or factor that serves as a reason to withhold a certain medical treatment due to the harm that it would cause the patient. Contraindication is the opposite of indication, which is a reason to use a certain treatment.  Side Effects any other action is a side effect – side effects may be adverse, beneficial – toxic effects due to overmedication common side effects that appear at therapeutic dosages idiosyncratic side effects (e.g., allergic reactions) that are not clearly related to dose – side effects vary from mild to life-threatening – side effects may develop insidiously over a long period of time or may occur in an idiosyncratic and unpredictable fashion  Side Effects Behavioral Effects Agitation and Restlessness Sedation Impaired memory Hostility, Disinhibition, Aggression Switch Mania Sleep disturbances Withdrawal Reactions (he symptoms of drug withdrawal, and the length of that withdrawal, vary depending on the drug of abuse and the length of the addiction.)  Side Effects Cardiovascular Effects hypertensive reaction orthostatic hypotension cardiac conduction delays Endocrine and Metabolic Effects hyperprolactinemia hypothyroidism nephrogenic diabetes insipidus hypercalcemia weight gain  Side Effects Hematologic Reactions aplastic anemia agranulocytosis leukocytosis eosinophilia benign leukopenia thrombocytopenia Hepatic effects changes in liver functions  Side Effects Reproductive and Adverse Sexual Effects changes in libido priapism impotence ejaculatory and orgasmic disturbances Renal and Genitourinary System Effects polyuria incontinence and enuresis urinary retention renal failure  Side Effects Immunologic and Gastrointestinal Effects dysphagia ( is difficulty in swallowing which may result in aspiration and asphyxiation (is a condition of deficient supply of oxygen to the body) gastroesophageal reflux nausea, vomiting and GI discomfort constipation or abnormal distension diarrhea  Side Effects Neuromuscular Effects myoclonus nocturnal myoclonus action (inaction) tremor of upper extremities acute extrapyramidal symptoms (including dystonia, neuroleptic-induced parkinsonism, bradykinesia, akinesia, tremor, and rigidity) Akathisia (is a movement disorder characterized by a feeling of inner restlessness and inability to stay still. Usually, the legs are most prominently affected) [ tardive symptoms ( is a disorder that results in involuntary, repetitive body movements, which may include grimacing, sticking out the tongue, or smacking the lips. neuroleptic malignant syndrome  Prophylactic Treatment: A prophylactic is a medication or a treatment designed and used to prevent a disease from occurring. Replacement Therapy: The therapy is any form of hormone therapy wherein the patient, in the course of medical treatment, receives hormones, either to supplement a lack of naturally occurring hormones, or to substitute other hormones for naturally occurring hormones. Radical Therapy: Completely eliminating the disease caused by drugs Palliative Care: is specialized medical care for people with serious illnesses. It focuses on providing patients with relief from the symptoms and stress of a serious illness. The goal is to improve quality of life for both the patient and the family. Rational Drug Use: The rational use of drugs requires that patients receive medications appropriate to their clinical needs, in doses that meet their own individual requirements for an adequate period of time, and at the lowest cost to them and their community. 14  PHARMACOEPİDEMİOLOGY, is the study of the uses and effects of drugs in well defined populations.[ PHARMACODYNAMİCS is the study of the biochemical and physiological effects of drugs on the body. Study of what a drug does to the body PHARMACOECONOMİCS refers to the scientific discipline that compares the value of one pharmaceutical drug or drug therapy to another PHARMACOGENETİCS is the study of inherited genetic differences in drug metabolic pathwys which can affect individual responses to drugs 15 PHARMACOGNOSY – study of characteristics of natural drugs and their sources PHARMACODYNAMİCS – study of what drugs do to the body PHARMACOKİNETİCS – what the body does to drugs PHARMACOTHERAPEUTİCS – study of how drugs are used to treat disease TOXİCOLOGY – study of poisonous effects of drug 16  Pharmacokinetics ❑The study of what the body does to a drug includes: ❑Absorbs – converts a drug into a form the body can use ❑Distributes – transporting a drug from its site of administration to its site of action ❑Metabolizes – drug molecules are transformed into simpler products ❑Excretes –manner in which a drug is eliminated from the body 17 Absorption Distribution Metabolism Excretion 18 DOSE : The amount of drug delivered at one time DAİLY DOSE: The amount of drug administration during the day. MAİNTENANCE DOSE: A maintenance dose is the maintenance rate [mg/h] of drug administration equal to the rate of elimination at steady state. LETHAL DOSE : of a toxin, radiation, or pathogen is the dose required to kill half the members of a tested population after a specified test duration. MAXIMAL DOSE: The maximum amount of a medicament capable of forming the desired effect without forming toxic effects. MINIMUM DOSE(minimum d.): Capable of forming a medicament therapeutic effect the lowest amount. THERAPEUTİC DOSE: Forming the desired therapeutic effect drug dose. TOXIC DOSE: Forming harmful side effects or symptoms of poisoning causing the amount of drug. LOADING DOSE: A loading dose is an initial higher dose of a drug that may be given at the beginning of a course of treatment before dropping down to a lower maintenance dose. RISK / BENEFIT RATIO A risk–benefit ratio is the ratio of the risk of an action to its potential benefits. Risk–benefit analysis is analysis that seeks to quantify the risk and benefits and hence their ratio.  Pharmacotherapeutics ❑Drug Names: ❑Generic – official name ❑Chemical name ❑Trade name – brand or proprietary name You will probably use only generic or trade names. 20  Apply Your Knowledge Which of the following is a generic drug name? Biocef Keflex Cephalexin 21 Apply Your Knowledge -Answer Which of the following is a generic drug name?  Biocef  Keflex  Cephalexin 22  Pharmacotherapeutics - Drug Categories ❑Their action on the body Example: ❑General therapeutic Antacid – neutralizes effect stomach acids ❑Body system affected 23  Sources of Drugs ❑Many drugs originate as natural products ❑Plants ❑Animals ❑Minerals ❑Bacteria or fungi ❑Synthesis also produced ❑Recombinant DNA technology Name this source of drug (Molecular cloning is a set of experimental methods and the drug it is used to in molecular biology that are used to assemble recombinant DNA molecules and to direct make. their replication within host organisms 24  New Drug Devlopment Levels of testing DRUG + receptor + transduction BINDING system (second functional messenger; enzyme) whole or BIOCHEMICAL TESTING part organs ISOLATED TISSUE EXPERIMENTS Anaesthetised or conscious animals WHOLE ANIMAL EXPERIMENTS 25  Animal models of efficacy Existing normal behaviours/effects (anaesthesia; contraception; paralysis) Create behaviours (fat rats; hypertensive rats; anxious rats; epileptic rats) Find unrelated behaviour affected by existing drugs (Straub tail for narcotic analgesics; learned helplessness for antidepressants) How predictive is the model? exact replica = 100% predictor mechanism same = good predictor mechanisms different = poor predictor 26  Chemical and biological characterisation CHEMICAL; structure, synthesis, solubility, etc BIOLOGICAL; acute pharmacological profile - binding data for many receptors, dose-effect relationships, 27  Safety & toxicity in animals Acute toxicity profile Chronic toxicity profile -- 14 day toxicity test in one rodent and one non-rodent species before use in man. -- 3 month study read out at 28 days -- longer studies (12 & 24 month) Three dose levels (below, about, well above human dose). It is insufficient to to use doses which are not toxic; the doses producing toxic effects and the nature of these effects MUST be established. 28  Clinical testing {Phase 0 (non-clinical)} Phase 1 (volunteers) Phase 2 (patients) Phase 3 (large scale multi-centre) Phase 4 (post registration monitoring) 29  Volunteer studies (phase I trials) pharmacologists & employees (15-30 in number) ethical approval healthy informed consent full rescussitation + medical backup monitor single and repeat doses increase dose levels 30  Volunteer studies (phase I trials) OBJECTIVES metabolic and excretory pathways variability between individuals; effect of route; bioavability (is a subcategory of absorption and is the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs.) tolerated dose range indication of therapeutic effects indication of side effects 31  Patient studies (phase 2 trials) 150-350 ill people; informed consent needs licence maximum monitoring; full rescussitation often patients where other treatment failed OBJECTIVES: indication for use; type of patient; severity of disease; dose range, nature of side effects and severity; effects in special groups. 32  Patient studies (phase 3 trials) 1500-3500 ill patients multicentre? more certain data for the objectives of phase 2 studies interactions between drugs start to become measurable in the larger population 33  Clinical trials Drug action depends on: pharmacodynamics pharmacokinetics and dose regimen drug interactions receptor sensitivity of patient mood/personality of patient & doctor patients expectations and past experience social environment of patient clinical state of patient Clinical trial controls these variables and examines action of drug in defined set of circumstances 34  Pharmacotherapeutics – Safety and Efficacy ❑Safety is how many and what kinds of adverse effects are associated with the drug. ❑An adverse reaction may require immediate action. ❑Be alert to complaints from patient after starting new drug. 35  Drug discovery/development process discovery; refinement; chemical & biological characterisation safety & toxicity in animals; formulation development volunteer studies; patient studies regulatory process lessons marketing & post registration development monitoring Discovery=find new active structure : Development=convert it to a useful drug 36  Apply Your Knowledge What is Pharmacokinetics? 37 Apply Your Knowledge -Answer What is Pharmacokinetics? The study of what a drug does to the body. 38  Pharmacokinetics Route Absorption Distribution Hepatic Metabolism Metabolic products Protein Binding Renal Excretion Half-life Toxicity 39 Pharmacokinetics  DISPOSITION OF DRUGS The disposition of chemicals entering the body (from C.D. Klaassen, Casarett and Doull’s Toxicology, 5th ed., New York: McGraw-Hill, 1996).  Routes of Administration Routes of Administration:Orally: Rectally: Inhalation: Absorption through mucous membranes: Topical: Parenterally: – Intravenous: – Intramuscular: – Subcutaneous: Routes of Administration  Absorption Distribution Route Parenteral Enteral Topical IV oral sublingual transdermal inhalation Absorption Absorption Systemic circulation 44 TYPES OF DOSAGE FORMS 45  Types of dosage forms: Definition: Dosage forms are the means by which drug molecules are delivered to sites of action within the body. The need for dosage forms: 1- Accurate dose. 2- Protection e.g. coated tablets, sealed ampules. 3- Protection from gastric juice. 4- Masking taste. 5- Placement of drugs within body tissues. 6- Sustained release medication. 7- Controlled release medication. 8- Optimal drug action. 9- Insertion of drugs into body cavities (rectal, vaginal) 10- Use of desired vehicle for insoluble drugs. 46  Types of dosage forms They are classified according to: Route of administration Physical form Oral Solid Topical Semisolid Rectal liquid Parenteral Vaginal Inhaled Ophthalmic Otic 47  ORAL DOSAGE FORMS Following oral administration, absorption of a drug is from the stomach or intestine directly via the hepatic portal system to the liver before reaching the general circulation. The liver is the main site of drug metabolism and inactivation. Many factors affect drug absorption from the gastrointestinal tract, including lipid solubility of the drug; its molecular weight; the pH of the local environment; the surface area of the absorbing membrane; gastric emptying time; the rate of removal from the gastrointestinal tract by the blood and the degree of plasma protein binding of the drug once in the bloodstream. 48  Oral dosage forms: 1-Tablet: A tablet is a hard, compressed medication in round, oval or square shape.. 49  1-Tablet A coating may be applied to: 1- hide the taste of the tablet's components. 2- make the tablet smoother and easier to swallow. 3- make it more resistant to the environment. 50  2-Buccal and sublingual tablet: - Sublingual and buccal medications are administered by placing them in the mouth, either under the tongue (sublingual) or between the gum and the cheek (buccal). - The medications dissolve rapidly and are absorbed through the mucous membranes of the mouth, where they enter into the bloodstream. - Avoid the acid and enzymatic environment of the stomach and the drug metabolizing enzymes of the liver. - Examples of drugs administered by this route: e.g. vasodilators, steroidal hormones. 51  3-Effervescent tablet: Effervescent tablets are uncoated tablets that generally contain acid substances (citric and tartaric acids) and carbonates or bicarbonates and which react rapidly in the presence of water by releasing carbon dioxide. -They are intended to be dissolved or dispersed in water before use providing: A- Very rapid tablet dispersion and dissolution. B- pleasant tasting carbonated drink. 52  4- Chewable tablet: - They are tablets that chewed prior to swallowing. - They are designed for administration to children e.g. vitamin products. 53 Hard gelatin capsule Soft gelatin capsule 5- Capsule: A capsule is a medication in a gelatin container. - Advantage: mask the unpleasant taste of its contents. - The two main types of capsules are: 1- hard-shelled capsules, which are normally used for dry, powdered ingredients, 2- soft-shelled capsules, primarily used for oils and for active ingredients that are dissolved or suspended in oil. 54  6 Pastilles: They are solid medicated preparations designed to dissolve slowly in the mouth. 8- Dental Cones: - A tablet form intended to be placed in the empty socket following a tooth extraction, for preventing the local multiplication of pathogenic bacteria associated with tooth extractions. - The cones may contain an antibiotic or antiseptic. 55  7-Liquid preparations: a- Oral solution: Oral solutions are clear Liquid preparations for oral use containing one or more active ingredients dissolved in a suitable vehicle. b- Oral emulsion: Oral emulsions are stabilized oil-in-water dispersions, either or both phases of which may contain dissolved solids. c-Oral suspension: - Oral suspensions are Liquid preparations for oral use containing one or more active ingredients suspended in a suitable vehicle. - Oral suspensions may show a sediment which is readily dispersed on shaking to give a uniform suspension which remains sufficiently stable to enable the correct dose to be delivered. 56  7-Liquid preparations d- Syrup: - It is a concentrated aqueous solution of a sugar, usually sucrose. - Flavored syrups are a convenient form of masking disagreeable tastes. e- Elixir: -It is pleasantly flavored clear liquid oral preparation of potent or nauseous drugs. - The vehicle may contain a high proportion of ethanol or sucrose together with antimicrobial preservatives which confers the stability of the preparation. 57  7-Liquid preparations (Cont.): f Gargles: - They are aqueous solutions used in the prevention or treatment of throat infections. - Usually they are prepared in a concentrated solution with directions for the patient to dilute with warm water before use. i- Mouthwashes: These are similar to gargles but are used for oral hygiene and to treat infections of the mouth. 58  Topical dosage forms: 1- Ointments: - Ointments are semi-solid, greasy preparations for application to the skin, rectum or nasal mucosa. - The base is usually anhydrous and immiscible with skin secretions. - Ointments may be used as emollients or to apply suspended or dissolved medicaments to the skin. 59  Topical dosage forms 2- Creams: - Creams are semi-solid emulsions, that is mixtures of oil and water. - They are divided into two types: A- oil-in-water (O/W) creams: which are composed of small droplets of oil dispersed in a continuous aqueous phase. Oil-in-water creams are more comfortable and cosmetically acceptable as they are less greasy and more easily washed off using water. B- water-in-oil (W/O) creams: which are composed of small droplets of water dispersed in a continuous oily phase. Water-in-oil creams are more difficult to handle but many drugs which are incorporated into creams are hydrophobic and will be released more readily from a water-in-oil cream than an oil-in-water cream. Water-in-oil creams are also more moisturising as they provide an oily barrier which reduces water loss from the stratum corneum, the outermost layer of the skin. 60  Topical dosage forms (Cont.): 3- Gels (Jellies): -. -They are used for medication, lubrication and some miscellaneous applications like carrier for spermicidal agents to be used intra vaginally. 61  Topical dosage forms 4- Transdermal patch: -A transdermal patch or skin patch is a medicated adhesive patch that is placed on the skin to deliver a specific dose of medication through the skin and into the bloodstream. -An advantage of a transdermal drug delivery route over other types such as oral, topical, etc is that it provides a controlled release of the medicament into the patient. - The first commercially available patch was scopolamine for motion sickness. 62  Topical dosage forms 5-Plasters: - Plasters are solid or semisolid masses adhere to the skin when spread upon cotton felt line,, as a backing material and they are mainly used to, A- Afford protection and mechanical support. B- Furnish an occlusive action. C- Bring medication into close contact with the surface of the skin. 63  Topical dosage forms 6-Lotions: - These are fluid preparations (aqueous) for external application without friction. - They are either dabbed on the skin or applied on a suitable dressing and covered with a waterproof dressing to reduce evaporation. 64  Topical dosage forms 7- Collodion: Collodion is a solution of nitrocellulose in ether or acetone, sometimes with the addition of alcohols. -Its generic name is pyroxylin solution. -It is highly flammable. - As the solvent evaporates, it dries to a celluloid-like film. 65  Topical dosage forms 8- Paints: - Paints are liquids for application to the skin or mucous membranes. - Skin paints contain volatile solvent that evaporates quickly to leave a dry resinous film of medicament. - Throat paints are more viscous due to a high content of glycerol, designed to prolong contact of the medicament with the affected site. 66  Topical dosage forms 9- Pressurized dispensers (aerosol sprays): - Several different types of pharmaceutical product may be packaged in pressurized dispensers, known as aerosols. - May be used as surface disinfectants, wound or burn dressing, relieve irritation of bites. - Spray-on dusting powders are also available from pressurized containers. 67  Rectal dosage forms: 1- Suppository: It is a small solid medicated mass, usually cone- shaped ,that is inserted either into the rectum (rectal suppository), vagina (vaginal suppository or pessaries) where it melts at body temperature. 68  Rectal dosage forms 2- Enema: An enema is the procedure of introducing liquids into the rectum and colon via the anus. 69  Vaginal dosage forms: 1- Pessary: - Pessaries are solid medicated preparations designed for insertion into the vagina where they melt or dissolve. - There are three types: A- Moulded pessaries: they are cone shaped and prepared in a similar way to moulded suppositories. B- Compressed pessaries: made in a variety of shapes and are prepared by compression in a similar manner to oral tablets. C- Vaginal capsules: are similar to soft gelatin oral Capsules differing only in size and shape. 70  Vaginal dosage forms 2- Vaginal ring: Vaginal rings are 'doughnut-shaped' polymeric drug delivery devices designed to provide controlled release of drugs to the vagina over extended periods of time. 71  Vaginal dosage forms 3- Douche: A douche is a device used to introduce a stream of water into the body for medical or hygienic reasons. 72  Vaginal dosage forms 4- Intrauterine device: -It is a birth control device placed in the uterus, also known as an IUD or a coil. -The IUD is the world's most widely used method of reversible birth control. -The device has to be fitted inside or removed from the uterus by a doctor. -It remains in place the entire time pregnancy is not desired. Depending on the type, a single IUD is approved for 5 to 10 years use. -There are two broad categories of intrauterine contraceptive devices: A- inert and copper-based devices. B- hormonally-based devices that work by releasing a progesterone. 73  Parenteral dosage forms: An injection is an infusion method of putting liquid into the body, usually with a hollow needle and a syringe which is pierced through the skin to a sufficient depth for the material to be forced into the body. There are several methods of injection, including: 1-An intravenous injection: It is a liquid administered directly into the bloodstream via a vein. It is advantageous when a rapid onset of action is needed. 74  Parenteral dosage forms 2- Intramuscular injection: -It is the injection of a substance directly into a muscle. - Many vaccines are administered intramuscularly. -Depending on the chemical properties of the drug, the medication may either be absorbed fairly quickly or more gradually. - Intramuscular injections are often given in the deltoid, vastus lateralis, ventrogluteal and dorsogluteal muscles. - Injection fibrosis is a complication that may occur if the injections are delivered with great frequency or with improper technique. 75  Parenteral dosage forms 3- Subcutaneous injection: Subcutaneous injections are given by injecting a fluid into the subcutis,the layer of skin directly below the dermis and epidermis. Subcutaneous injections are highly effective in administering vaccines and such medications as insulin. 76  Inhaled dosage forms: 1- Inhaler : - Inhalers are solutions, suspensions or emulsion of drugs in a mixture of inert propellants held under pressure in an aerosol dispenser. - In some types, the valve is actuated by finger pressure, in other types the valve is actuated by the patient breathing in through the mouthpiece. - It is commonly used to treat asthma and other respiratory problems. 77  Inhaled dosage forms 2- Nebulizer or (atomizer): A nebulizer is a device used to administer medication to people in forms of a liquid mist to the airways. - It is commonly used in treating asthma, and other respiratory diseases. - It pumps air or oxygen through a liquid medicine to turn it into a vapor, which is then inhaled by the patient. -As a general rule, doctors generally prefer to prescribe inhalers for their patients, because: 1-These are cheaper 2- more portable 3- carry less risk of side effects. Nebulizers, for that reason, are usually reserved only for serious cases of respiratory disease, or severe attacks. 78  Ophthalmic dosage forms: 1- Eye drops: Eye drops are saline-containing drops used as a vehicle to administer medication in the eye. Depending on the condition being treated, they may contain steroids, antihistamines or topical anesthetics. Eye drops sometimes do not have medications in them and are only lubricating and tear-replacing solutions. 2- Ophthalmic ointment & gel: These are sterile semi-solid Preparations intended for application To the conjunctiva or eyelid margin. 79  Otic dosage forms: 1- Ear drops: - Ear drops are solutions, suspensions or emulsions of drugs that are instilled into the ear with a dropper. - It is used to treat or prevent ear infections, especially infections of the outer ear and ear canal. 80  Nasal dosage forms: 1- Nasal Drops and Sprays: Drugs in solution may be instilled into the nose from a dropper or from a plastic squeeze bottle. The drug may have a local effect, e.g. antihistamine, decongestant. Alternatively the drug may be absorbed through the nasal mucosa to exert a systemic effect. The use of oily nasal drops should be avoided because of possible damage to the cilia of the nasal mucosa. 81  Intermediate products used in compounding: Extracts: These are concentrated preparations containing the active principals of vegetable or animal drugs which have been extracted with suitable solvents and concentrated to form liquid, soft or dry extract. Glycerins: These are solutions of medicaments in glycerol with or without the addition of water. Infusions: These are dilute solutions containing the readily soluble constituents of crude drugs and prepared by diluting 1 part of concentrated infusion with 10 parts of water. Concentrated infusions are prepared by cold extraction of crude drugs with 25% ethanol. 82  Membranes Types of Membranes: Cell Membranes: This barrier is permeable to many drug molecules but not to others, depending on their lipid solubility. Small pores, 8 angstroms, permit small molecules such as alcohol and water to pass through. Walls of Capillaries: Pores between the cells are larger than most drug molecules, allowing them to pass freely, without lipid solubility being a factor. Blood/Brain Barrier: This barrier provides a protective environment for the brain. Speed of transport across this barrier is limited by the lipid solubility of the psychoactive molecule. Placental Barrier: This barrier separates two distinct human beings but is very permeable to lipid soluble drugs. 84 85 86  Passive diffusion Drugs diffuse across a cell membrane from a region of high concentration (eg, GI fluids) to one of low concentration (eg, blood). Diffusion rate is directly proportional to the gradient but also depends on the molecule’s lipid solubility, size, degree of ionization, and the area of absorptive surface. Because the cell membrane is lipoid, lipid-soluble drugs diffuse most rapidly. Small molecules tend to penetrate membranes more rapidly than larger ones. 87  Active transport Active transport is selective, requires energy expenditure, and may involve transport against a concentration gradient. Active transport seems to be limited to drugs structurally similar to endogenous substances (eg, ions, vitamins, sugars, amino acids). These drugs are usually absorbed from specific sites in the small intestine. 88  Facilitated passive diffusion Certain molecules with low lipid solubility (eg, glucose) penetrate membranes more rapidly than expected. In such cases, the membrane transports only substrates with a relatively specific molecular configuration, and the availability of carriers limits the process. The process does not require energy expenditure, and transport against a concentration gradient cannot occur. 89  Pinocytosis In pinocytosis, fluid or particles are engulfed by a cell. The cell membrane invaginates, encloses the fluid or particles, then fuses again, forming a vesicle that later detaches and moves to the cell interior. Energy expenditure is required. Pinocytosis probably plays a small role in drug transport, except for protein drugs. 90  Absorption The amount and rate of absorption are determined by several factors: Physical nature of the dosage form Presence or absence of food in the stomach Composition of the GI contents Gastric or intestinal pH Mesenteric blood flow Concurrent administration with other drugs 91  Bioavailability Refers to the amount and the rate of appearance of the drug in the blood after administration in its initial dose form Orally administered drug bioavailability is directly related to the individual solubility in body fluids. Poor solubility = low bioavailability 92  Effect of Food Bioavailability of some drugs is affected by the presence of food. E.g penicillin's, erythromycin, rifampicin, thyroxine Some drugs are taken before meals to allow time for drug to act before food is taken Gastric irritation can be caused by drugs taken on an empty stomach Effect of food on the absorption of drugs 93  First Pass Effect Drugs that are absorbed via the GIT are circulated to the liver first via the hepatic portal vein Liver then acts as a filter Only part of the drug is circulated systemically The combination of processes is termed the ‘First Pass’ effect 94  Enterrohepatic Circulation Circulation of substances such as bile salts, drugs which are absorbed from the intestine and carried to the liver, where they are secreted into the bile and again enter the intestine. A route by which part of the bile produced by the liver enters the intestine, is resorbed by the liver, and then is recycled into the intestine. The remainder of the bile is excreted in feces. There are important intoxication, 95  Absorption Distribution Metabolism Factors affecting Problems with: Low albumin Heart Circulation Diabetes IMPORTANT Bound drugs are pharmacologically inactive because the drug-protein complex is unable to cross cell membranes. Plasma proteins albumine (basic drugs), α1- acid glicoprotein (asidic drugs) Not be the glomerular filtration. 96 Not binding drugs in the body of the duration is short they should have given more often.  Metabolism Drugs are metabolised in the liver, lungs, kidneys, blood and intestines. In order for drugs to pass across the lipid cell membrane they must be lipophilic The higher the solubility in lipids compared to water, the more rapid the tissue entry Metabolic rate determines the duration of the action of the drugs Which BNF appendix relates to patients’ ability to metabolise? 97  Drug Metabolism Most metabolic products are less pharmacologically active Important exceptions: Where the metabolite is more active (Prodrugs, e.g. Erythromycin-succinate (less irritation of GI) --> Erythromycin) Where the metabolite is toxic (acetaminophen- n-acetyl-p-benzoquinoneimine) Where the metabolite is carcinogenic 98  Drug Metabolism Close relationship between the biotransformation of drugs and normal biochemical processes occurring in the body: – Metabolism of drugs involves many pathways associated with the synthesis of endogenous substrates such as steroid hormones, cholesterol and bile acids – Many of the enzymes involved in drug metabolism are principally designed for the metabolism of endogenous compounds – These enzymes metabolize drugs only because the drugs resemble the natural compound 99  Really fundamental concepts in drug biotransformation Lipid soluble drugs are poorly excreted in the urine. They tend to store in fat and/or circulate until they are converted (phase I biotransformation) to more water soluble metabolites or metabolites that conjugate (phase II biotransformation) with water soluble substances. Water soluble drugs are more readily excreted in the urine. They may be metabolized, but generally not by the CYP enzyme systems.  Biotransformation & urinary excretion Drugs with major first pass effect (bioavailability) [% urinary excretion] imipramine (39) [