W1-Intro to Pharmacology.pptx

Clinical Pharmacology Why is it important to have an understanding? Prof. Reem Kayyali Learning outcomes  Understand basic concepts in relation to drugs and their effects and routes of administration  Understand the basic mechanisms by which drugs exert their pharmacological effect  Describe wh...

Clinical Pharmacology Why is it important to have an understanding? Prof. Reem Kayyali Learning outcomes  Understand basic concepts in relation to drugs and their effects and routes of administration  Understand the basic mechanisms by which drugs exert their pharmacological effect  Describe what is meant by a receptor and a drug acting as an antagonist, blocker, inhibitor or agonist Drug Pharmacokinetics – What the body does to a drug Pharmacodynamics – what the drug does to the body Pharmacokinetics     Absorption Distribution Metabolism Excretion Pharmacokinetics - absorption  Absorption Bioavailability  Fraction of drug that reaches the systemic circulation Different routes  Oral  most commonly used and convenient route  Variable bioavailability  Drugs are absorbed more rapidly from the small intestine than from the stomach Parenteral administration  Par = around the enteral = GI  For:  Low oral bioavailability  Patients can’t take oral drug  Need for immediate effect IV, IM, SC  IV= 100% bioavailability  IM  absorption dependent on muscle blood flow  Depot formulation  SC  For drugs with low oral bioavailability  Formulation should not cause irritation Other routes  Transdermal = through the skin  Topical  Eye, nose, ear (local but can get systemic absorption)  Inhalation therapy Beware of terminology to use for direction of use Inhalation Therapy  The pulmonary alveoli represent a large surface  The lungs receive the total cardiac output as blood flow.  Thus, absorption from the lungs can be very rapid and complete.  Drugs must be gaseous or as very fine aerosols.  The intended effects may be systemic (e.g. inhaled general anaesthetics) or local (e.g. bronchodilators in the treatment of asthma). Ways in which drugs work  They act on target proteins  Receptors  Enzymes  Carriers molecules (transporters)  Ion channels Ways in which drugs work  Some exceptions to this general rule  many antimicrobials  many anti-cancer agents Receptors  There are four main types of receptors at a molecular level:  ligand-gated ion channels eg. Histamine  G-protein-coupled receptors (these use a second messenger, a ‘G protein’ to exert an effect) eg. adrenergic receptors  kinase-linked receptors (these use enzyme systems to exert an effect) eg. insulin  nuclear (intracellular) receptors (these receptors are within the cells) eg. Steroids, vitamin D Receptor theory • Receptor – molecular target for a drug • Agonist - activates receptor to produce a response (↑ or ↓ a particular cell function) • Antagonist - interacts with a receptor to inhibit action of agonist (can be called blocker or inhibitor) How receptors work  Lock and key principle - agonist Lock Key + Transmitter Door opens = Receptor Action Example - histamine  Histamine - found in many tissues in the body, and located in Mast cells  Released from Mast cells in response to injury and is responsible for some of the initial changes to tissue during the inflammatory response  Skin: responsible for the itching sensation  Hayfever: largely responsible for the sort of inflammation you see on mucus membranes in the eyes, resulting in the well recognised symptoms of hayfever.  Stomach: acts on the acid producing cells within the stomach, to increase the amount of acid released. How receptors work  Lock and key principle – antagonist  many drugs act by blocking receptors to inhibit the action of an agonist = antagonist (blockers, inhibitors, or sometimes referred to as anti-)  work by locking into the receptor without actually having an effect on the cell Antagonist Door does not open Lock False Key + Drug = antagonist = Receptor No Action and normal action is prevented Example - histamine  Different types of histamine receptor in different parts of the body. Histamine receptors in the stomach are slightly different to those on the mucus membranes and are called “H2” receptors. The ones on the mucus membranes we call “H1” receptors  histamine is able to stimulate both H1 and H2 receptors  but histamine can only be blocked in the stomach by drugs that can block the H2 receptor i.e. the H2 antagonists  drugs that block the H1 receptor are known as antihistamines Second messengers - receptors  In the case of a number of drugs, following receptor binding, a second messenger called a “G protein” is stimulated within the cell membrane  G proteins are able to activate an enzyme called adenyl cyclase which converts adenosine triphosphate (ATP) into cyclic AMP (cAMP)  The presence of increased amounts of cyclic AMP activates the enzyme protein kinase, and this in turn causes the drug effect in the cell  Eg. in bronchial smooth muscle, an increased amount of cAMP within the smooth muscle cells will cause them to relax and this has the effect of opening up the airways – (bronchodilators) Second messengers Cell Cell membrane membrane GGprotein protein aa bb gg Effector protein protein ATP Cytoplasm Cytoplasm cAMP A second messenger system is a method of cellular signalling where the signalling molecule does not enter the cell, but rather utilizes a cascade of events that transduces the signal into a cellular change. Which condition do we use bronchodilators? Predicting side effects  Example: Adrenergic receptors Adrenaline is released from the adrenal gland and give the various responses to the flight and fight reaction  receptors are found on blood vessels. Adrenaline will constrict arteries and raise blood pressure  ß1 receptors are found mainly on the heart. Adrenaline will increase the heart rate  ß2 receptors are found mainly on the bronchioles. Adrenaline will dilate them Predicting side effects  ß2 (beta) agonists - salbutamol was designed to act specifically to stimulate ß2 receptors. It is used extensively in the management of asthma   -blockers (antagonists) eg. propranolol and atenolol  propranolol: non-selective ß blocker and will block both ß1 and ß2 receptors What side effects and contraindications would you expect? Ways in which drugs work  They act on target proteins  Receptors  Enzymes  Ion channels  Carriers molecules (transporters) Function of the COX-1 and COX-2 enzymes Arachidonic acid Physiological stimulus Inflammatory stimulus COX-1 Enzyme (Physiological) COX-2 Enzyme (Induced) TxA2 PGE2 PGI2 Control of platelet aggregation Protection of gastric mucosa Control of renal blood flow Prostaglandins INFLAMMATION What class of drug is the most common used anti-inflammatory? Drug Desired effects Advers e effects Other concepts to think about  Side effects  Caution (we also put on medications cautionary labels)  Contraindication Main source of information BNF Drugs with a non-specific action  Antacids e.g. Aluminium Hydroxide - effectively alkali type substances which can neutralise or buffer acid in the stomach  Emollients e.g. Aqueous Cream - used in dry skin conditions such as eczema. Regular use will improve skin quality, and actually lessen inflammation and discomfort. The oil component of the emollient, effectively prevents moisture from leaving the surface of the skin, thus hydrating the skin. Antimicrobials  ‘antimicrobial’ refers to agents that might be used to treat fungal, viral or bacterial infections. The term antibiotic is usually used to refer to those agents used to treat bacterial infections  Bacteria possess cell walls, whereas mammalian cells do not   beta lactam antibiotics (penicillins, cephalosporins) act by inhibiting bacterial cell wall synthesis macrolides act by inhibiting certain proteins that are only synthesised in bacteria e.g erythromycin  Fungal membrane is composed of ergosterol, whereas in mammalian cells cholesterol is found. Antifungal agents mostly act by affecting the ergosterol in fungi cell membranes in some way e.g nystatin, clotrimazole, fluconazole, terbinafine In future lectures we will talk about ADRs and Drug interactions Reading material  Basic pharmacology for nurses. Edited by Bruce D. Clayton, Yvonne N. Stock, Renae D. Harroun.  Introductory clinical pharmacology. Edited by Sally S. Roach, Susan M. Ford. Merck Manuals: Clinical Pharmacology: http://www.merck.com/mmpe/sec20.html  Rang and Dale’s Pharmacology – latest edition  BNF – latest edition  Concise Clinical Pharmacology – Greenstein and Greenstein Reading material  Oxford Handbook of Practical Drug Therapy – Richards & Aronson.  Oxford Textbook of Clinical Pharmacology and Drug Therapy – D.G. Grahame-Smith and J.K. Aronson.  Avery’s drug treatment – Trevor M. Speight  Principles of Biochemical Toxicology – J.A.Timbrell  Clinical Biochemistry – Allan Caw et al.