PCC2 Cardiovascular System - Ischaemic Heart Disease

Stenosis (arteries) Abnormal narrowing of the arteries - Caused by the development of atheromatous plaques in the coronary arteries. Role of the coronary arteries Supply the heart with blood Risk factors for developing ischaemic heart disease - Hypertension - Hypercholesterolaemia - Genetic predisposition (family history) - Diabetes - Obesity - Lack of physical exercise - Poor diet - Smoking - Ageing - Gender Risk factors for developing ischaemic heart disease - Gender - Men are more at risk than pre-menopausal women - After menopause women have a similar risk to men What happens if blood flow to the myocardium is disturbed ? This results in poor oxygen supply to areas of cardiac muscle = causing ischaemia Pain associated with angina Likely due to tissue release of K+, H+ and adenosine which accumulate in the poorly perfused tissue. Angina symptoms - Pain - Range from mild to severe pain - Triggers sweating and feelings of fear - Often radiates from the chest to the neck, jaw or down the arm and is often described as being a heavy 'gripping' or 'crushing' pain. - A predictable condition Classical stable or exertional angina - Coronary blood supply may be adequate at rest, but is unable to increase to meet cardiac demands during stress or exercise 1/9 - Supply of blood cannot meet the demand of the heart muscle tissue (myocardium) causing ischaemia Unstable angina - Rapid onset - Pain occurs at rest and/or with increasing severity or frequency - Symptoms are unpredictable and longer lasting than for stable angina + may not respond to vasodilator treatment What causes unstable angina ? - Caused by atherosclerotic plaques rupturing and platelets adhering which results in the formation of thrombi - These may partially occlude a coronary artery and cause ischaemic pain They may progress to a myocardial infarction (heart attack) in which a maWhy are unstable angina symptoms conjor branch of the coronary artery besidered to be an emergency situation ? comes either intermittently or completely occluded (blocked). What term can unstable angina be classed under ? Acute Coronary Syndromes (ACS) - Caused by a coronary artery spasm (often around the site of atheromatous lesions) Prinzmetal's variant angina - There is no obvious provocation and it mostly occurs in early mornings or at night Decubitus angina - Occurs when lying down - Associated with heart failure = blood redistributes to increase central blood volume, so increasing cardiac workload Nocturnal angina - Usually occurs in severe coronary artery disease - Maybe provoked by vivid dreams 2/9 - Reduce cardiac workload Aim of Angina treatment Nitrates - So this reduces the heart's O2 demand in an attempt to restore balance between blood supply and demand. Have a role in: - treatment of angina attacks - reducing the frequency of angina attacks - Used to produce a generalised vasodilation - Arteriolar vasodilation = reduces peripheral resistance and cardiac afterload - Coronary artery and Collateral vessel vasodilation = improves blood supply to cardiac tissue Nitrate drugs MOA's Nitric Acid (HNO3) - Venodilatation (causing venous pooling of blood) = reduced venous return of blood to the heart, this reduces cardiac preloading, reduces the heart's workload and hence O2 demand. - Nitrate drugs form nitric acid in vivo - It is formed naturally by endothelial cells - It relaxes precontracted aortic vessels - NO causes a fall in the free intracellular How does Nitric oxide affect intracellular Ca2+ ion concentration = smooth muscle Ca2+ ions ? cells can't contract - blood vessels relax and dilate 3/9 - In the presence of tissue thiol groups NO (nitric oxide) - NO stimulates guanylyl cyclase = forms cGMP - cGMP causes free intracellular Ca2+ ions to be taken up into the sarcoplasmic reticulum (S.R.) How do nitrates derived from drugs such as glyceryl trinitrate and isosorbide - There are now fewer Ca2+ ions available to interact with calmodulin mononitrate work ? - Smooth muscles relax and vessels dilate - Completely metabolised on its first pass through the liver - 0% bioavailability if swallowed GTN - Metabolism + Administration - GTN is administered as a sublingual tablet or spray to treat or prevent attacks of chest pain when required - Effective for ~30 minutes - IV injections and infusions of GTN are also available and similarly avoid first pass metabolism - Available as a patch formulation = pro4/9 vides a sustained 24hr release of the drug into the bloodstream - Reactive ester of nitric acid and glycerol (propan-1,2,3-tiol) - Decomposed in the blood stream to give nitric oxide Glyceryl trinitrate chemical properties - NO breakdown is responsible for its Mode of action API used in GTN ? (based on commonly prescribed sublingual 500µg tablets) Glycerin trinitrate (500µg) Binder used in GTN ? (based on commonly prescribed sublingual 500µg tablets) - Lactose - Acacia Filler used in GTN ? (based on commonly prescribed sublingual 500µg tablets) Lactose Lubricant used in GTN ? (based on commonly prescribed sublingual 500µg tablets) - Stearic acid - Magnesium stearate Adsorbent and/or glidant used in GTN ? (based on commonly prescribed sublingual 500µg tablets) Colloidal silicon dioxide Sweeting agent used in GTN ? (based on commonly prescribed sublingual 500µg tablets) Mannitol Stabilising agent, binder, viscosity-increasing agent used in GTN ? (based on commonly prescribed sublingual 500µg tablets) Acacia 5/9 - Supplied in air-tight containers to protect from air + prevent moisture ingress - GTN tablets should not be kept in close proximity to the body as this will increase their temperature, they are advised to be kept in outer clothing, bags etc. What precautions are taken to protect GTN tablets ? - Packed with a desiccant (often a small capsule of silica gel) to protect from moisture - Often supplied in amber glass bottles which protect the contents from sunlight - Bottle caps are lined with aluminium foil to prevent loss of API GTN is volatile and sublingual tablets are subject to considerable loss of potency (loss of API) if: - They are not stored in tightly sealed What factors can cause a loss of API in containers regards to packaging GTN tablets? - They come into contact with packaging components e.g., adhesive labels, cotton and rayon fillers and plastic bottles and caps GTN storage advice ? Due to their incompatibility with plastics - it is advised that GTN tablets are kept within their original container (not transferred into tablet boxes). When should GTN tablets be discarded once opened ? 8 weeks after the packaging has been opened to ensure potency IV administration of GTN - Can be administered as an IV solution - Standard PVC giving sets cannot be 6/9 used since GTN will bind to the plastic - Non-PVC giving sets should be used - Delivers 400µg of GTN per actuation - API is contained within an pharmacologically inert spray solution within an aerosol canister GTN spray - metered dose device Additional excipients: - Peppermint oil = to provide a pleasant - Propellant = HFC 134A (1,1,1.2 Tetrafluoroethane) and ethanol as a solubilising agent/vehicle Isosorbide Mononitrate - More stable - Longer acting (half life ~ 4hrs) - Administered orally in the morning and at lunchtime or once daily in a prolonged release formulation May depend on the production of acWhat does the effect of isosorbide dinitive metabolites , particularly isosorbide trate depend on ? mononitrate - Overuse of nitrates impairs their antianginal actions, as free tissue thiol groups become depleted Nitrate tolerance - Tolerance to isosorbide mononitrate does not tend to occur if dosed at the correct times = drug free period during the night allows for thiol recovery. - Suspected tolerance to GTN patches should be managed by removing the patches for 8-12hrs (usually overnight) Due to blood vessel dilatation: - Postural hypotension - Tachycardia - Headache Nitrate - Side effects (GTN) 7/9 - Flushing - Dizziness What advice can be given to patients when they first start using Nitrates ? Profound hypotension can occur with glyceryl trinitrate so patients are advised to sit down or lie down when they first start using the drug, until they become used to its effects. Nitrates (GTN) - Cautions and Contraindications - Hypotension - Hypovolaemia - Nitrate hypersensitivity - Because a spray canister can be kept for relatively long periods before it needs replacing, according to the expiry date on Why is it more cost effective for patients the canister. with mild angina to use GTN spray instead of sublingual tablets ? - A bottle of GTN tablet, however, needs to be replaced 8 weeks after opening as the tablets will begin to lose their potency. - Patients should be told to administer the drug under the tongue for attacks of chest pain and to repeat the dose every 5 mins if the pain does not resolve. - If pain does not subside after a 3rd dose, they must call 999 and continue to administer doses every 5 mins until the ambulance arrives. Sublingual GTN Counselling for Patients - Patient should be informed of the common side effects + how to first use the product. - Patient should be informed on when to discard sublingual tablets or spray while always ensuring they have an 'in date' supply. 8/9 - Tablets must not be transferred from the original glass bottle. 9/9