Introduction to Pharmacology Diploma (1) PDF

Fundamental concepts of pharmacology Prof Janet Mifsud Department of Clinical Pharmacology and Therapeutics University of Malta [email protected]....

Fundamental concepts of pharmacology Prof Janet Mifsud Department of Clinical Pharmacology and Therapeutics University of Malta [email protected] Who are we? Department of Clinical Pharmacology and Therapeutics Faculty of Medicine and Surgery https://www.um.edu.mt/ms/ourdepartments https://www.um.edu.mt/ms/pharmacology Textbooks Ritter JM, Flower R, Henderson G, Rang HP. Rang & Dale's Pharmacology. 2019. 9th Ed. Churchill Livingstone. British National Formulary. Pharmaceutical Press Pharmacology for Health Care Professionals. Wiley-Blackwell ISBN978-0-470-51017-9 Knollmann B, Brunton L, Hilal-Dandan R. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 2017. 13th Ed. McGraw- Hill. Overview Overview Understanding what drugs and medicines are Defining pharmacology Finding reliable sources of drug information Nomenclature Understanding various properties of drugs and how this is related to their chemical structure What happens to drugs in the body? What are medicines? Examples of medicines? What is in a medicine? What is in a medicine? Everything in the universe is made up of elements : – Hydrogen – Oxygen – Sodium – Carbon – Etc… These combine to form chemical compounds Are these medicines? What exactly O is there in a medicine? H Water H2O Glucose C6H12O6 Are these medicines? What exactly O is there in a medicine? Calcium Carbonate CaCO3 Lithium Carbonate Li(CO3)2 How many medicines are there? How many medicines are there? Medicines Manufactured @ 6000 medicines Medicines in a Formulary @1500 medicines WHO Essential Medicine List @500 medicines How do you remember all those names? A medicine generally has three names: Chemical name It is the full chemical name or a code, e.g. 1(Isopropylamino)3(1naphthyloxy) propan2ol for propranolol. This is cumbersome and not suitable for use in prescribing. A code name, e.g. RO 151788 (later named flumazenil) may be assigned by the manufacturer for convenience and simplicity before an approved name is coined Nonproprietary name It is the International Nonproprietary Name (rINN) in all member countries of the WHO It is the name accepted by a competent scientific body/authority, e.g. EMA. In common parlance, the term generic name is used in place of nonproprietary name. A medicine generally has 3 categories of names: Proprietary (Brand) name It is the name assigned by the manufacturer(s) eg Panadol® for paracetamol Brand names are designed to be catchy, short, easy to remember and often suggestive, e.g. LOPRESOR suggesting drug for lowering blood pressure. Brand names generally differ in different countries, This is responsible for much confusion in drug nomenclature. In Malta, in a clinical setting, the generic nonproprietary name must be used. How do you remember all those names? from the generic names olol…..beta blockers medicines used for high blood pressure fen…..NSAIDS How do we match medicines/drugs to persons? = ?? We are all different… Gender Age Height Ethnicity Weight Why do medicines act differently in different persons? Why do medicines act differently in different persons? Genetic factors: pharmacogenetics Pharmacology vs pharmacy Pharmacology vs pharmacy Why do medicines act differently in different persons? Physiological factors Why do medicines act differently in different persons? Environmental factors Where do medicines come from? From the pharmacy ? From laboratories? From nature ?  What are drugs? What are medicines? Why are they sold from pharmacies?  Drugs vs medicines Drugs Medicines Opium Poppy Used to be widely cultivated in 1800s Opium widely used at the time The British used to cultivate the opium poppy in many countries including Malta. Many famous people took it Opium use in 19th and early 20th centuries Different routes of administration: drug formulations Opioids : morphine and heroin (diamorphine) Cannabis….. Contains more 104 cannabinoids. Two of these have pharmacological properties: – Δ9-tetrahydrocannabinol (Δ9-THC) primary psychoactive cannabinoid in cannabis – Cannabidiol (CBD): possible therapeutic effects as analgesic antiemetic to treat side-effects of cancer chemotherapy appetite stimulant in AIDS patients. in multiple sclerosis in epilepsy Cannabis Other medicines from nature….. Willow tree and aspirin ….. discovered by Greeks, around 500 B.C. a substance in the bark of the willow tree, we now know as salicin, could relieve pain. acetylsalicyclic acid (aspirin) is derived the naturally occurring compound salicin. Bayer commercialized aspirin in 1899 aspirin vs paracetamol (Acetylsalicylic acid) (Acetaminophen) Penecillin Penecillin In 1928, he noticed that in a pile of Petri dishes where he had been grown staph aureus, a mould had killed all the bacteria around it In WW2, penicillin saved millions of lives. What do we aim for in pharmacological therapy? What do we aim for in pharmacological therapy? Comes from greek pharmakon- poison Pharmacology: the study of drugs (chemical molecules) and their interactions with living systems What do we aim for in pharmacological therapy? Study of Physical and chemical properties of drugs Biochemical and physiological effects of drugs Knowledge of the history, source, and use of drugs Clinical Pharmacology: study of drugs in humans (patient and volunteers) Therapeutics: use of drugs to diagnose, prevent and treat illness (and/or pregnancy) the medical use of drugs What makes a medicine different from other chemical compounds? eg In constipation What do we aim for in pharmacological therapy? eg In constipation What do we aim for in pharmacological therapy? Drugs are usually administered in small quantities – mg (1/1000 g) – micrograms (1/1000000 g) Thus drugs are usually taken as a formulation with excipients (vehicle) Panadol excipients Sodium bicarbonate Starch, pre-gelatinised Povidone Maize starch Potassium sorbate (E 202) Microcrystaline cellulose Magnesium stearate Carnauba wax Titanium dioxide (E171) Polydextrose Hypromellose Glycerol triacetate Polyethylene glycol Originator vs generic formulations: equal or not equal? Generic vs originator? =? =? =? =? Nomenclature Trade name ® or TM vs Generic name British names vs American names – e.g. adrenaline and epinephrine – e.g. lidocaine vs lignocaine What do we aim for in pharmacological therapy? What do we aim for in pharmacological therapy? Drugs are essentially chemical compounds introduced from outside the system (exogenous) Thus they are called XENOBIOTICS All drugs are xenobiotics BUT Not all xenobiotics are drugs What do we aim for in pharmacological therapy? Drugs change certain biological functions and are thus used to: 1. Treat disease 2. Prevent ill effect 3. Mimic endogenous substances 4. Diagnose illness Info about drugs……reliable sources Info about drugs……reliable sources British National Formulary www.bnf.org Maltese Formulary Martindale British Pharmacopoeia National Institute of Health, US www.nlm.nih.gov/medlineplus/druginformation.html European Medicines Agency http://www.ema.europa.eu Medicines Authority Malta www.medicinesauthority.gov.mt Info about drugs……BNF Contents Gastro-intestinal system Cardiovascular system How to use the BNF Respiratory system Guidance on prescribing Nervous system Prescription writing Infection Endocrine system Emergency supply of medicines Genito-urinary system Controlled drugs and drug dependence Malignant disease Adverse reactions to drugs Blood and nutrition Guidance on intravenous infusions Musculoskeletal system Eye Prescribing for children Ear, nose, and oropharynx Prescribing in hepatic impairment Skin Prescribing in renal impairment Vaccines Prescribing in pregnancy Anaesthesia Prescribing in breast-feeding Prescribing in palliative care Emergency treatment of poisoning Prescribing for the elderly Appendices and indices Drugs and sport Appendix 1 Interactions Prescribing in dental practice Appendix 2 Borderline substances Notes on drugs and preparations Appendix 3 Cautionary and advisory labels for dispensed medicines Appendix 4 Wound management products and elasticated garments Maltese Government Formulary List https://deputyprimeminister.gov.mt/en/pharmaceutical/Pages/formulary/formulary.aspx Maltese Government Formulary List: example Info about drugs……Martindale Info about drugs……British Pharmacopoeia Info about drugs……Medline Plus European Medicines Agency (EMA) Malta Medicines Authority Sources of drugs Other Sources of drugs Natural eg animal insulin; digitalis Inorganic eg arsenic trioxide, Magnesium sulphate (Epsom salts) Other Sources of drugs Synthetic drugs ie made in the lab eg sodium valproate Semisynthetics eg amoxycillin Other Sources of drugs Biotechnology/biosimilars eg human insulin, infliximab Other Sources of drugs IMPORTANT They all have different physical and chemical properties: Size and molecular weight pKa: Acids or bases or neutral Solubility: Lipophilic or hydrophilic May have a chiral centre Aspects of drug disposition But how do drugs work? How do drugs work? How do medicines know where they have to Medicines work because of their 3D structure ie physical go to work? and chemical properties : The key which fits into the lock (receptor) in the cells How do drugs work? How do medicines know where they have to Medicines work because of their 3D structure ie physical go to work? and chemical properties : The key which fits into the lock (receptor) in the cells How do drugs work? The lock and key mechanism How do medicines know where they have to go to work? This is called the lock and key mechanism Key medicine Lock Receptor in the cell What do we need to consider when understanding drug action in the body? The pharmacological effect is due to the lock and key mechanism But how does the drug get to the receptor site? Dose? How much? Dosage regimen How often? Formulation Active ingredient and excipient? Generic vs originator product What happens to the drugs in the body? However do we just – ingest? – inject? – inhale drugs? – and somehow it arrives at the appropriate site of action? NO: they undergo many different physiological processes to arrive a receptor site based on the physical AND chemical properties of – Drug – Vehicle (excipents) What is happening to the drug in the body? What is the body doing to the drug? What is the body doing to the drug? What isthe What is thebody body doing doing to the drug? to the drug? Paracetamol Take 2 tablets With what? What is the body doing to the drug? Liberation Paracetamol 2 tablets With what? 250 mls of water Why? What is the body doing to the drug? Liberation Paracetamol 2 tablets With what? 250 mls of water Why? Stomach? Functions? What is the body doing to the drug? Liberation Paracetamol 2 tablets With what? 250 mls of water Why? Stomach? Functions? Small intestine? Structure? Functions? What is the body doing to the drug? Liberation Absorption Paracetamol 2 tablets With what? 250 mls of water Why? Stomach? Functions? Small intestine? Structure? Functions? What is the body doing to the drug? Liberation Absorption Paracetamol 2 tablets With what? 250 mls of water Why? Stomach? Functions? Small intestine? Structure? Functions? Large intestine? Functions? What is the body doing to the drug? Liberation Absorption Paracetamol 2 tablets With what? 250 mls of water Why? Stomach? Important vein? Functions? Small intestine? Structure? Functions? What is the body doing to the drug? Liberation Absorption Paracetamol 2 tablets With what? 250 mls of water Why? Hepatic portal vien Stomach? Functions? Small intestine? Structure? Functions? What is the body doing to the drug? Liberation Absorption Paracetamol 2 tablets With what? 250 mls of water Why? Liver? Functions? Stomach? Functions? Small intestine? Structure? Functions? What is the body doing to the drug? Liberation Absorption Paracetamol Metabolism 2 tablets With what? 250 mls of water Why? Liver? Functions? Stomach? Functions? Small intestine? Structure? Functions? What isthe What is thebody body doing doing to the drug? to the drug? Liberation Absorption Paracetamol Metabolism 2 tablets With what? 250 mls of water Why? Liver? Functions? Stomach? Functions? Small intestine? Structure? Functions? What is the body doing to the drug? Liberation Absorption Paracetamol Metabolism 2 tablets Distribution With what? 250 mls of water Why? Liver? Functions? Stomach? Functions? Small intestine? Structure? Functions? What isthe What is thebody body doing doing to the drug? to the drug? Blood brain barrier Liberation Absorption Paracetamol Metabolism 2 tablets Distribution With what? 250 mls of water Why? Liver? Functions? Stomach? Functions? Small intestine? Structure? Functions? What is the body doing to the drug? Blood brain barrier Liberation Absorption Paracetamol Metabolism 2 tablets Distribution With what? 250 mls of water Why? Liver? Functions? Stomach? Functions? Small intestine? Structure? Why do we need to take Functions? tablets again 6 hours later? What isthe What is thebody body doing doing to the drug? to the drug? Blood brain barrier Liberation Absorption Paracetamol Metabolism 2 tablets Distribution With what? 250 mls of water Why? Liver? Functions? Stomach? Functions? Small intestine? Structure? Functions? Kidneys? functions What is the body doing to the drug? Blood brain barrier Liberation Absorption Paracetamol Metabolism 2 tablets Distribution With what? Elimination 250 mls of water Why? Liver? Functions? Stomach? Functions? Small intestine? Structure? Functions? Kidneys? functions What isthe What is thebody body doing doing to the drug? to the drug? Liberation Absorption Metabolism LADME: Distribution Elimination The movement of the drug in the body with time What is the body doing to the drug? Liberation Absorption LADME: Metabolism pharmacokinetics Distribution Elimination Pharmacokinetics: Drug therapy is a dynamic process The fate of the drug proceeds over a certain time interval and the processes which determine the time course of the drugs Input → output The complicated fate of the drug in the body is known as PHARMACOKINETICS These parameters will determine the – onset, – duration, and – extent of drug action. Pharmacokinetic processes PK determines how much of an administered dose gets to its sites of action - LADME drug liberation drug absorption drug distribution drug metabolism drug excretion PK is what the body is doing to the drug What does PK mean? How to model PK? Drug is extracted from whole blood and measured in the lab Blood collection, plasma extraction Extraction of drug from plasma Measurement of drug via HPLC etc Plasma concentration time curves: oral Plasma concentration time curves: how high? Plasma concentration time curves: IV Plasma concentration time curves: different routes Plasma concentration time curves: different formulations PK compartment models Drug in Urine Drug at Drug in administration body site Drug metabolism Pharmacodynamics: PD What the drug is doing to the body PD describes the relationship between drug effect and dose Once a drug has reached is site of action, pharmacodynamic processes determine the type of response and intensity It is the result of the lock and key mechanism Pk/PD: from drug to patient PK/PD from drug to patient How do we measure PK? How do we measure PK? IV route IV route Plasma concentration vs time Log plasma concentration vs time Log Cp v time 16 Half-life in PK This is the time required for the drug blood levels concentration to decrease by half It is called the half-life of elimination. The drug dosage and formulation generally do not change the half-life of elimination for a specific drug. Half-life in PK What happens to half-life (and plasma concentration time curve) if: – Patient is overweight – Patient is a child – Patient is elderly – Patient has renal or liver failure – Patient is a smoker Designing Multiple Drug Dosage Regimens Devising Multiple drug dosage regimens Most clinical situations require multiple doses It is important to keep amount of drug in body within the therapeutic range Accumulation occurs if 2nd dose is administered before 1st dose is completely eliminated Principle of superimposition: early doses do not affect PK of later doses i.e. plasma conc time curves for the different doses are the same Administration of several doses Administration of several doses Steady state and dosage regimens Thus at a certain point Cmax and Cmin increase until steady state (ss) is achieved. Steady state is achieved when rate of drug going in = rate of drug going out drug eliminated over the dosing interval = dosage regimen Thus at steady state occurs after 5 half lives Steady state “Steady state” Amount eliminated = 1 dose Amount eliminated