T1 L21-L22: Drug treatments - ischaemic heart disease

• How is coronary blood flow regulated?

  nitric oxide (endothelium-derived relaxing factor)

  calcium → NOS (nitric oxide synthase) → L-arg → NO → soluble guanylyl cyclase (sGC) → cGMP → dephosphorylate myosin light chain kinase → relaxation

  
• What is end diastolic volume (preload) regulated by?

  sympathetic NS

  RAAS (Na+ and H2O retention)

  contractility of venules
• What is heart rate and contractility regulated by?

  sympathetic NS

  Ca2+
• What is total peripheral resistance regulated by?

  sympathetic NS

  RAAS
• What is the definition of stable angina?

  A predictable pattern of pain

  during exercise

  that is relieved by rest
• What does drug treatment of IHD aim?

  decrease work done by heart

  and/or increase blood supply

  and treat risk factors
• How do nitrates help IHD?

  increase oxygen supply to heart muscle - dilate coronary arteries

  decrease workload - decrease preload through venodilation
• What are the side effects of nitrates?

  • Postural hypotension
  • Headache
  • Dizziness
  • Reflex tachycardia
• What is reflex tachycardia?

  Increased heart rate in response to a sudden drop in blood pressure

  due to activation of sympathetic nervous system
• What to do if nitrate treatment causes reflex tachycardia?

  should look to block effects of sympathetic NS

  using a beta blocker eg bisoprolol
• How do beta blockers help IHD?

  decrease cardiac output (by decreasing frequency and force of contraction)

  inhibit RAAS (inhibit renin release from kidney)
• What are the side effects of beta blockers?

  fatigue, bronchoconstriction
• What is the contraindication of beta blockers?

  peripheral vascular disease
• How do calcium channel antagonists help IHD?

  decrease cardiac workload by:

  • decrease frequency and force of contraction (phenylalkylamines / Benzothiazepines)
  • increase dilation of arterioles (dihydrophyridines)
• What to do if IHD patient is an asthmatic?

  beta blockers contraindicated

  cardiac selective calcium channel blockers (verapamil, diltiazem)
• What is the contraindication of calcium channel blockers?

  asthma
• What can mixtures of cardiac selective calcium channel blockers and beta blockers cause?

  severe badycardia

  heart block
• How do CCBs (calcium channel blockers) reduce heart rate?

  block L-type channels in SA and AV nodes

  slow rate of depolarisation

  reduce rate of action potential generation & decrease force of contraction
• What are some examples of long acting nitrates?

  isosorbide mononitrate / dinitrate
• What is Ivabradine?

  pacemaker current inhibitor

  reduce Na entry through If channels

  slow rate of depolarisation of SA node cells

  reduce firing frequency & heart rate

  (does not alter directly the force of contraction)
• What are the side effects of ivabradine?

  luminous phenomena (brightness, halos, image decomposition)

  blocks Ih in retina

  blurred vision

  dizziness

  
• What is an alternative to ivabradine?

  Nicorandil

  • produce nitric oxide
  • open K channel (inside of cell becomes more negative & stable)
• What does the secondary prevention treatment of IHD consist of?

  reduce hypercholesterolaemia

  drugs designed to either:

  • inhibit cholesterol uptake from GI tract
  • reduce cholesterol production in liver

  frontline treatment: statins (eg simvaSTATIN, atorvaSTATIN)
• How do Statins reduce cholesterol production in liver?

  inhibit HMG CoA reductase

  so Acetyl CoA can't be converted to cholesterol
• What is PCSK9?

  proprotein convertase subtilisin-kexin type 9

  Serine protease that degrades intracellular LDL receptors

  plays pivotal role in LDL-C metabolism
• How does Evolocumab work?

  inhibits PCSK-9

  less LDL receptors on surface

  less LDL-C taken up by liveer
• What are some other further secondary prevention treatments of IHD?

  Aspirin: antiplatelet agents

  ACE inhibitors (eg ramipril) and ARBs (angiotensin receptor blockers, eg losartan): decrease workload on the heart
• What is the treatment of ACS; unstable angina NSTEMI & STEMI?

  as for stable angina + antiplatelet

  (aspirin + clopidogrel)
• What is the mechanism of action of some key antiplatelet agents?

  Aspirin: inhibit COX irreversibly

  Clopidogrel and prasugrel: ADP antagonists; block P2Y12 receptors

  
• What is the metabolic mechanism of action of clopidogrel, prasugrel and ticagrelor (anti-platelet agents)?

  oxidised into active form

  bind to platelet
• What are the symptoms of MI?

  pain

  sweating, tachycardia, cold clammy skin
• What is the treatment of MI?

  Pain relief:

  • diamorphine delta-opioid receptors
  • decreases pain, anxiety, sympathetic drive, vasodilates

  Oxygen

  Aspirin / GTN

  Clot busting drugs: Alteplase
• How does Alteplase work?

  stimulate Plasmin

  breaks down fibrin

  bust clot
• What are the different types of beat blockers?

  metoprolol - short acting (hospital)

  bisoprolol - long acting (community)
• How do ACE inhibitors help IHD?

  decrease cardiac workload

  prevent remodelling and development of heart failure

  eg ramipril
• How do anticoagulants help IHD?

  prevent chances of blood clot due to long-term bed rest

  eg. Apixaban, heparin, warfarin
• How does Warfarin work?

  inhibits VKOR (vitamin K oxide reductase)
• How does Enoxaparin work?

  facilitate binding of antithrombin to factor Xa

  inhibit factor
• What do most short acting anticoagulants target?

  Factor Xa