The Pharmacist: Effects of the Drug on the Body

What are drugs used for in clinical practice? - To correct gain of function - To correct loss of function What are the different drug groups in clinical practice? - Receptor agonists (like beta agonists) - Receptors antagonists (like beta blockers) - Enzyme inhibitors (like ACE inhibitors) - Ion channel openers - Ion channel blockers - Inhibitors of transporters/reuptake inhibitors (SSRIs, PPIs) - Pro-drugs (drugs that get activated after metabolism by P450s) - Hormones that supplement reduced levels (like insulin) Agonist activates a receptor, this can open or close ion channels, or there What do agonists do and what are the can be a transduction mechanism which responses? can activate/inactivate enzymes, modulate ion channels, or cause DNA transcription. What do antagonists do? Antagonists have no effect, endogenous mediators blocked. Replace and enhance neurotransmitters. - Parkinson's disease - dopamine D2/D2 What can agonists do to correct for loss agonists (rotigotine, pramipexole, ropiniof function? What are some examples? role). - Asthma - beta 2 adrenergic receptor agonist (salbutamol, albuterol, salmetrol) - Type 2 diabetes - glucagon (peptide-1) Block overactivity resulting from increased receptor activation by an enWhat do antagonists do to correct for dogenous agonist (usually a neurotransgain of function? What is an example? mitter). - Hypertension - beta 1 adrenergic receptor antagonist (atenolol, bisoprolol) 1/6 - Molecular/chemical pharmacology (drug receptor interaction) - Cell pharmacology (cell biochem effect) - Cell physiology effect (change in organ, What is the system pharmacology chain such as relaxation of smooth muscle) of effects? - Tissue physiology (tissue function altered) - Organ physiology (organ function altered) - Clinical effect (illness treated) A beta 2 adrenoceptor agonist (salbutamol) activates adenylyl cyclase (at the cellular level). This increases cAMP and What is the system pharmacology for a the smooth muscle cell relaxes (cell beta 2 adrenoceptor agonist? response), causing bronchodilation (tissue response). This improves lung function (organ response), leading to better breathing (clinical effect). How do we classify propranolol? Propranolol is a beta adrenoceptor antagonist (molecular mechanism). It prevents cAMP alteration (cellular response). It slows the pacemaker (tissue response). The heart rate slows (organ response). This prevents exercise induced angina pectoris (clinical response). Therefore, propranolol is a beta blocker, cAMP inhibitor, pacemaker depressant, cardio protecting drug, and anti-angina drug. How do many pharmacology texts list drugs? What are some examples? According to their systems effect, such as anti-hypertensives, anti-epileptic, anti-asthmatic, diuretics, and anti-gastric acid. 2/6 - Beta blockers (atenolol, bisoprolol) - Alpha blockers (doxazosin) - Diuretics (Chlortalidone and indapamide) What are some examples of anti-hyper- - ACE inhibitor (ramipril, lisinopril) tensives? - Calcium channel blockers (like amlodipine) - Vasodilators (hydralazine and minoxidil) - Drugs affecting CNS control of blood pressure (clonidine, methyldopa) What are ligand-gated ion channels? Activated after binding to specific ligands or drugs. Many neurotransmitters and drugs activate membrane-bound ligand ion-gated channels. Including several types of glutamate receptors. - Drugs that inhibit excitation (GLU antagonists) What are some examples of anti-epilep- - Drugs that potentiate inhibition (GABA tics? mimetics) - Sodium ion channel blockers - Potassium ion channel openers - Beta 2 agonist (salbutamol) - Anti-cholinergics (ipratropium, tiotropium) What are some examples of anti-asthma - Corticosteroids (beclometasone, flutidrugs? casone) - Potentiator of beta 2 agonist (xanthines) - Chromoglicate - Leukotriene inhibitors (montelukast) What are some examples of diuretics? - Osmotic (mannitol) - Inhibitor of salt reabsorption - Aldosterone antagonists (eplerenone and spironolactone) - Carbonic anhydrase inhibitors (acetazolamide, methazolide) - Antacids (like Gaviscon, magnesium carbonate, aluminium hydroxide) 3/6 - Anti-cholinergics What are some examples of anti-gastric - H2 receptor antagonists (famotidine, raacid drugs? natidine) - Proton pump inhibitors (omeprazole). - Blocks formation of angiotension II, blocking vasoconstriction but it also What are the multiple molecular actions blocks aldosterone preventing water refor ACE inhibitors (to treat cardiac fail- tention. ure)? - It also blocks bradykinin breakdown, leading to vasodilation. - This all leads to less work for the heart. - Vaccination through response of immune system. - Antidepressants, primary action to block re-uptake of noradrenaline/seroWhat are some system effects through tonin. This adaptive response of neuadaptation? What are the issues with this rons to increased levels of noradrenaadaptive change? line/serotonin which is thought to mediate therapeutic effect. Adaptive change can normally produce tolerance. What are some mechanisms of tolerance? - Target cell tolerance (depletion of endogenous mediator), such as ephedrine depletion of noradrenaline. - Tolerance of physiological homeostatic mechanism such as reflex tachycardia. - Pharmacokinetic tolerance such as induction of metabolism. - Industrial exposure Munitions factory produces nitro-glycerine (GTN). You develop headaches at initial exposure, but tolerance develops, How is organic nitrates a drug tolerance and headaches lessened. After days off, example? the headaches returned when they went back to work. Clinical parallel is that patient on long-term release GTN (for angina) fail to respond to acute effect of GTN. 4/6 - GTN produces vasodilator (nitrous oxide). This causes depletion of agent that converts nitrate to NO. Vasodilation is reWhat is the GTN tolerance mechanism? versed by increased production of vasopressin, increased plasma volume, and increased production of endothelin via activation of renin-angiotensin system. Cocaine causes release of noradrenaline and will produce euphoria because of a neurotransmitter knock-on effect. What is an example of rapid tolerance in The first dose required is small to prosingle administration? duce euphoria, the second dose requires a lot more to produce the same degree of euphoria. - Compound applied - Mechanism of action - Target - Biomarkers you can use - Any toxicity - Results What should you consider in systems pharmacology when administering a drug? - What is the molecular mechanism that leads to drug efficacy? (It should have good receptor activation and good pharmacokinetics.) What makes a perfect drug? - How well does a drug fit the efficacy What are the key questions when looking model? How well does it correspond to at the effect of a drug on the body? the perfect profile? - What are the key risk factors for the drug and how do they impact efficacy? - What are the key biomarkers for efficacy and stratification? - What do I screen against to find the perfect drug? - Vioxx (anti-inflammatory for arthritis) - Tysabri (humanised antibody to treat MS and Crohn's disease) 5/6 What are some interesting drugs with adverse drug reactions? - Torcetrapib (treats elevated cholesterol levels) - Avandia (anti-diabetic) Why was Vioxx withdrawn? COX-2 inhibitor but withdrawn due to increased risk of myocardial infarction from long term use What is the issue with Tysabri? Long term use led to progressive multifocal leukoencephalopathy and hepatotoxicity, but clinical benefits still outweigh the risks. What is the problem with torcetrapib? Increased mortality when taken in combination with a statin. Why was Avandia withdrawn? Withdrawn after increased risk of potentially fatal cardiovascular events. The drugs exert their effects at the molecular level (agonism and antagonism of molecular targets). Drug developments assesses drugs at the animal level (assessing clinical pheWhy are drugs so complex and difficult notypes) to understand? High failures are due to a primitive understanding of the molecular actions of drugs. A better understanding of molecular action will help to reduce failures. 6/6