L1&2: Introduction, ROA and absorption WHAT IS A DRUG? • A chemical entity of known structure, other than a nutrient/dietary supplement, which causes a biological effect in a living organism. • The defining feature of drugs is that they selectively interact with endogenous molecules (Biomolecules) to modify the functions of cells, tissues, physiological systems and in some cases the Behaviour of organisms. • Many drugs cannot Be used therapeutically Because the unwanted effects the drug produces outweigh its beneficial effects. • However, drugs used in the prevention or treatment of disease are often referred to as medicines, although that term refers to a preparation of one or more drug, alongside other substances (stabilisers, solvents, etc.), which is used therapeutically … i.e. to treat, cure, prevent or diagnose disease. WHAT IS A MEDICINE? • A preparation of one or more drug, alongside other suBstances (staBilisers, solvents, etc.), which is used therapeutically … i.e. to treat, cure, prevent or diagnose disease. • Note the difference Between a drug and a medicine … most drugs we’ll cover are components of medicines … but some “recreational drugs” clearly don’t fit the cure/treat/prevent/diagnose definition. Drugs classification: • Molecular Structure (catecholamines, tricyclics) • Mode of Action (acetylcholinesterase inhibitors, β-blockers) • Therapeutic Use (bronchodilators, antihypertensives) How are drugs named? • Drugs are named in three ways 1) chemical name 2) generic name 3) proprietary name (trade name) • Pharmacology- the science-orientated study of drug action • Toxicology- the study of adverse effects of chemicals on living organisms • Pharmacy- patient-orientated health service profession Two branches of pharmacology: 1. Pharmacodynamics: o What a drug does to the Body • Does the drug work? How well? • What is the dose-response relationship? • What is the molecular target? • How strongly does the drug Bind? • What is the mechanism of action? 2. Pharmacokinetics: o What the Body does o a drug • How is the drug administered? Why? • How much is bioavailaBle? • How much gets to the right place? • How long does it stay at the target site? • How much gets to the wrong place? • How does the drug leave the Body? ADME: • Absorption • DistriBution • MetaBolism • Excretion • ADME determines the concentration of the drug at the target site which effects the Onset, Intensity & Duration of the drug’s action • The concentration of a drug at its target site is very important it will be what determines its efficacy • However, to get to its target, a drug must first Be aBsorBed and then Be distriButed to the correct tissue -> These two processes contribute to drug DELIVERY -> While this is taking place, the body will be metabolising and excreting the drug, hence reducing its concentration in the body and hence at the target site • The latter two processes contribute to drug ELIMINATION/ • When you take a drug, it must first get into the systemic circulation (aBsorption) • Some may be metabolised even before getting there (e.g. by endothelial cells of the gut) and more will Be start to Be metaBolised and excreted as soon as it is absorbed • Meanwhile, some drug leaves the circulation and enters tissues no all the drug will enter the target tissues and this may be a cause for adverse effects but hopefully some gets to the target tissue and binds to the target molecules Administration and Absorption: • Absorption is the movement of drug from the site of administration to the systemic circulation (n.b. NOT to the site of action) • Before any drug can have an effect it must Be presented in a suitable form at an appropriate site of administration. For an action within the body, the drug must be absorbed from its site of administration and distributed via the blood to the tissue(s) where it acts. In general, drugs must cross Biological membranes to gain access to the blood and to their sites of action • Route of administration (ROA) plays a crucial role in absorption. o intra venous (I.V.) infusion - all drug reaches the systemic circulation the drug is “100% Bioavailable”! -> However, I.V. administration is unpleasant and requires supervised in- patient care hence not convenient for everyday use o All other routes of administration have <100% BioavailaBility But are much more convenient for patients! ROA: • Enteral (via GI tract)- Drugs must cross a tight Barrier composed of the epithelial cells of the gastrointestinal tract o Oral o Sublingual o Rectal • Parenteral: o I.V. o subcutaneous o intra muscular (I.M.) o inhalation o intranasal o topical o transdermal Oral drug administration: • Most common route – good for self-dosing, cost-effective to make, easy to dose • Most oral drugs are taken in taBlet form, although liquid/suspension form is more common for young children. • Onset is rapid (10-20 min) But the drug must dissolve first • there is a huge capacity for absorption due to the large surface area of the small intestine • The small intestine is the major site for absorption from the GI tract by passive diffusion because of its huge surface area, which is about 200 m2, and thin membrane (one cell layer thick). In addition, the small intestine has a high blood flow relative to other areas of the GI tract. This helps to maintain the concentration gradient between drug in the lumen of the small intestine and drug in blood; hence the direction of diffusion is into the body (blood). • Most common But also most complicated: o Survive gastric acid. • e.g. Benzylpenicillin (penicillin G) hydrolysed By gastric acid and hence usually is given via IV route. Penicillin V (phenoxymethylpenicillin) is taken on an empty stomach • Some drugs have an “enteric coat” for protection. o Survive digestive enzymes. • e.g. insulin and other peptide drugs cannot Be given orally. o Co-exist with, or need to avoid, food. • e.g. tetracycline antiBiotics Bind to Ca2+ in food, Become insoluBle and are not absorbed • The presence of food also changes gastric emptying times o Cope with gut bacteria – metaBolism and metaBolites • e.g. simvastatin (anti-hypolipidemic drug) activity is altered by the presence of certain bacterial metabolites, which differ in different individuals. • e.g. sulphasalazine is cleaved into active anti-inflammatory component 5-ASA and sulphapyridine by colonic bacteria. • Drug formulation can have a major impact on absorption from the gut. If the drug is swallowed in solution, for example, its rate of absorption will be much quicker than if it were taken as a tablet. The tablet has to disintegrate to release solid particles of drug. The drug must then dissolve before absorption can occur. These processes take time; hence a drug that is already in solution will be aBsorBed more quickly than the same drug compacted into a solid tablet, so a drug in solution will have a faster onset of action than a drug in a tablet. • For drugs to be effective by the oral route, route they have to cross the epithelial lining of the gastrointestinal (GI) tract • The epithelial cells of the GI tract have tight junctions between them; hence to penetrate this layer of cells and to access the blood, drug molecules must pass through cell membranes -> This process is often referred to as transcellular diffusion. • The key structure of a cell membrane is the phospholipid bilayer. o This “fatty” layer forms a physical barrier to the entry of drugs into cells. o To penetrate this barrier drug molecules must be lipid soluble. o Lipid soluble drugs have an affinity for fat; they readily dissolve in fatty substances (such as phospholipids) and can diffuse through them -> Substances that do this are often called lipophilic. • Sometimes drugs are transported via carrier-mediated transport – however, for oral (and all enteral) routes, aBsorption is usually via transcellular diffusion ->This is via the process of diffusion • Lipophilic drugs penetrate cell membranes By passive diffusion o This is when molecules move from a region of high concentration to one of low concentration o Passive diffusion occurs Because of the random thermal motion of molecules and is described by Fick’s Law o This law states that the rate of diffusion is directly proportional to the concentration gradient across the memBrane; to the surface area of the memBrane and the lipid solubility of the molecule. o The rate of diffusion, however, is inversely proportional to the thickness of the memBrane(in this case we consider the “memBrane” to Be the Barrier, which may Be composed of one or more cell so actually, there are more than one plasma membranes involved). o Rate = (conc. gradient x area x lipid soluBility) / thickness of membrane o Fick’s law predicts the rate of diffusion will increase as the concentration gradient, membrane surface area and lipid solubility increase o By contrast, the rate of diffusion will decrease when the membrane thickness increases. Accordingly, rates of diffusion across a membrane one cell layer thick (e.g. small intestine) will be greater than when the membrane is several cell layers thick (e.g. skin) o Diffusion is an important mechanism for absorption of drugs from the GI tract and for absorption from other sites of drug administration such as the lung, skin and muscle. • P-glycoprotein is an ATP-powered drug-efflux pump which removes a wide range of substrates from the cell interior back into the gut lumen • Drug Bioavailability may Be reduced By activity of the ATP powered drug efflux pump, P-glycoprotein • This transporter is expressed By the epithelial cells of the small intestine and is embedded in the apical surface of these cells • It functions to pump a wide range to drug substrates out the cell and back into the gut lumen. Thus the permeaBility of the gut mucosa to its substrate drugs is reduced • Not all drugs are aBsorBed from the gut By passive diffusion o Some drugs are absorbed from the GI tract by carrier-mediated transport.