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Flashcards in Cardiovascular System Deck (146):

What is Dyslipidaemia?

  • Abnormal levels of triglycerides and cholesterol in the blood due to a disorder in lipid metabolism
  • includes increase in TG, LDL and TC and decrease in HDL


Describe the characteristics and key roles of cholesterol

  • Lipid, almost completely insoluble in water
  • Functions:
    • Component of cell membranes 
      • modulating fluidity of membranes
    • Precursor for synthesis of
      • bile acids
      • steroid hormones
      • vitamin D


Describe the characteristics and key roles of Triglycerides

  • Stored or metabolised form of fat
  • 3 fatty acids + glycerol


What is the role of lipoprotein?

  • Enables the body to transport round these lipid materials which are hydrophobic within a membrane, which has a hydrophilic outside, enabling it to dissolve in blood and plasma


What is the role of Cylomicrons?

  • Lipoproteins that transport TG and C absorbed in the intestine to the liver


What is the role of VLDL?

  • Made up of TG (65%) and C (20%) transported from the liver to the tissues


What is the role of LDL?

  • C rich lipoproteins which deposit C in the tissues
  • High levels of LDL is bad


What is the role of HDL?

  • Very small lipoproteins that transport C from tissues back to liver
  • High levels of HDL is good


What are the functions of Apolipoproteins?

  • Structural
  • Ligands
  • Activate enzymes


Describe the Exogenous Pathway

  1. TG and C are packaged into chylomicrons in gut endothelium
  2. Chylomicrons enter the lymph and are deposited into circulation via the thoracic duct
  3. As they pass through fat and muscle tissues, they encounter LPL on endothelium which breaks down the TG to FAs and Glycerol, which are taken up by the tissues. The lipoprotein is now a chylomicron remnant which reaches the liver
  4. In liver, C may be converted to bile acids or excreted unchaged in bile or enter the endogenous pathway


Describe the Endogenous Pathway

  1. C and newly synthesised TG in liver are transported as VLDL to the tissues. LPL aids the release of TG, and VLDL now become LDL particles
  2. LDL particles can transport C to other tissues or return it to the liver. LDL uptake is mediated by LDL receptors on the hepatocyte which interact with ApoB100
  3. HDL particles remove C from the tissues and return it to the liver (reverse liver transport) (50%) or transfer it to LDL and VLDL particles


What is Primary Dyslipidaemia caused by?

  • Caused by genetic defects in lipoprotein metabolism


What is Secondary Dyslipidaemia caused by?

  • Medical conditions
  • Lifestyle factors
    • sedentary lifestyle, cigarette smoking, excessive saturated and trans-fatty acid consumption
  • Medication


What are the Physical Symptoms of Dyslipidaemia?

  • Patients generally asymptomatic
  • Elevated C increases risk of atherosclerosis
  • Potential physical findings include
    • xanthomas (cholesterol deposits in tissues)
    • pancreatitis 
    • renal or hepatic disease
    • peripheral vascular disease
    • cerebrovascular disease
    • coronary artery disease


What is Atherosclerosis?

  • Thickening and hardening of arterial walls characterised by deposition of fatty material


What are the Consequences of Atherosclerosis?

  • Reduced blood flow
    • angina, transient, ischaemic attack, intermittant claudication
  • No blood flow
    • myocardial infarction, ischaemic stroke
  • Also aneurysms


What is the Development of Atherosclerosis?

  1. Endothelial Injury
  2. Fatty Streak Formation
  3. Fibrotic Plaque Formation
  4. Complicated Lesion


What is the Development of Atherosclerosis: 1. Endothelial Injury?

  • Inflammatory cells move from lumen to intima


What is the Development of Atherosclerosis: 2. Fatty Streak Formation?

  • LDL deposited in arteries and diffuses across the endothelium
  • LDL is oxidised by chemicals produced by macrophages
  • Macrophages engulf oxidised LDL to become foam cells
  • Accumulation of foam cells = fatty streak


What is the Development of Atherosclerosis: 3. Fibrotic Plaque Formation?

  • Cytokines and growth factors cause smooth muscle cells to multiply, migrate over fatty streak, produce collagen and form a fibrous cap
    • also take up oxided LDL and become foam cells


What is the Development of Atherosclerosis: 4. Complicated Lesion?

  • Rupture of Fibrous Cap and Thrombus Formation
    • Slowing growing usually more stable
      • have thicker fibrous cap


What are Treatment Strategies of Atherosclerosis?

  • High C concentration
    • implies high LDL
    • LDL causes atherosclerosis
  • Treatment includes
    • lowering LDL C
    • Increasing HDL
    • Lowering TG


How are lipid levels measured?

  • TC, TGs and HDL - directly measured by blood tests
  • LDL usually calculated using Friedwald's Formula
  • Fasting
    • at least 12h to obtain accurate TG levels


What is the MOA of Statins e.g. atorvastatin, simvastatin

  • Competitive inhibitors of HMG-CoA reductase
    • leads to decreased concentration of C within cell stimulating the synthesis of LDL receptors
      • increased number of LDL receptors promotes uptake of LDL from blood
      • low intracellular c decreases secretion of VLDL


What are other pharmalogical effects of statins?

  • Improved endothelial function
  • Antithrombotic
  • Plaque stability
  • anti-inflammatory
  • anti-proliferative
  • anti-oxidant


What are the Adverse Effects of Statins?

  • Mild GI symptoms, headache, changes to liver function tests
  • Muscle-related side effects (myopathies)
    • myalgia - muscle pain
    • myositis - muscle inflammation
    • rhabdomyolysis - life threatening
      • destruction of striated muscle cells
      • myoglobin, K+, creatinine kinase released
      • high myoglobin in bloodstream = kidney injury


What is the MOA of Fibrates? e.g. fenofibrate, gemfibrozil

  • Activate peroxisome proliferator - activated receptors (PPAR) and modulate lipoprotein synthesis and catabolism
    • PPARa activation:
      • increases LPL in muscle
      • increases uptake and oxidation of fatty acid in muscle cells
      • increases fatty acid oxidation
      • decreases TG synthesis
      • increases apoprotein A1 and 2 synthesis thus increase HDL


What are the Adverse Effects associated with Fibrates?

  • Mainly GI
  • Photosensitivity (rare)


Discuss Fibrates and their interaction with Statins

  • Increased risk of myopathy with statins
  • Gemfibrozil acts on liver to decrease:
    • uptake of statins
    • glucoronidation of statins


What is the MOA of Ezetimibe?

  • Selectively inhibits absorption of C from the intestine
    • binds to the NPC1L1 sterol transport protein in brush borders blocking the absorption of cholesterol


What are the effects of ezetimibe?

  • Decreased absorption (of C)
    • depletes hepatic C pool
    • increases expression of the LDL receptor on hepatocytes
    • increases LDL uptake from blood stream thus reducing plasma LDL concentration
  • Enterohepatic recirculation
    • acts in intestine, will get absorbed
    • enters hepatic portal circulation, ends up in liver, gets excreted in bile where it acts


What is the MOA of Plant Sterols?

  • Inhibit dietary C absorption by displacing C from micells
    • c eliminated in faeces
  • Instead of C being solubilised in micelles in intestines, it doesn't end up in micelle particles
    • plant sterols are there instead, so C won't be delivered to intestinal brush border cells and absorbed into the body so C just gets eliminated in the faeces


What is the MOA of bile acid binding resins? e.g. cholestyramine, colestipol

  • Sequester bile in GI tract = increase excretion in faeces
    • more LDL cholesterol moves from blood stream to liver to form bile acids
  • Exchange anions (e.g. Cl-) for bile acids
  • Insoluble in water
  • Not absorbed systemically


What are the Adverse Effects of bile acid binding resins? e.g. cholestyramine, colestipol

  • GI side effects (bloating, flatulence, nausea, constipation, steatorrhea)
  • May increase C and TG synthesis
  • Reduce absorption of Fat SOluble Vitamins (A, D, E, K)


How may bile acid binding resins interact with other drugs?

  • May bind to and alter absorption of other medications


What is the MOA of nicotinic acid?

  • Inhibit breakdown of TG into fatty acids and glycerol in adipose tissues which decrease VLDL and increases levels of apoAI thus increases HDL


What are the adverse effects of Nicotinic Acid?

  • flushing (prostaglandin release)
  • GI upset/bleeding
  • hyperglycaemia
  • myopathy (rare)
  • elevated uric acid


Discuss how nicotinate functions as counter-ion

  • Nicotinate functions as counter-ion for uric acid transporter URATI
    • increases urate resorption in kidney
    • decreases urate excretion


What is the MOA of PCSK9 Inhibitors? e.g. evolocumab

  • Humanised MAb
  • Normally PCSK9 binds to LDL receptor on hepatocytes which promotes degradation of LDL
  • MOA: Evolocumab blocks PCSK9 from binding to LDL receptor, increasing LDL uptake


What is the MOA of Omega-3 Fatty Acids?

  • Inhibit release of TGs from liver
    • reduces VLDL and therefore LDL
    • stimulate LPL to increase clearance of TGs from plasma


What are the Adverse Effects of Omega-3 Fatty Acids?

  • GI upsets
  • Fishy aftertaste


Dietary Interventions for Dyslipideamia etc.

  • Decrease saturated fat intake
  • Decrease trans-fat intake
  • High Fibre Diet
  • Plant sterols
  • Fish oils 


What is Ischaemic Heart Disease?

A condition whereby the blood flow to the heart tissues does not meet the demands of the myocardium


What is the Classification of Ischaemic Heart Disease?

  • Chronic Coronary Artery Disease
    • Stable Angina
    • Variant Angina
  • Acute Coronary Syndromes
    • Unstable Angina
    • Myocardial Infarction


What is Angina Pectoris?

What are the symptoms?

  • Crushing/squeezing/burning chest pain or diffuse discomfort
    • can radiate to shoulders, down arms, to throat, jaw or back
    • tightness or heaviness
  • Symptoms:
    • shortness of breath
    • unexplained fatigue
    • sweating
    • nausea
    • anxiety
    • dizziness


Discuss Stable Angina.

What is its Clinical Presentation?

  • Coronory artery plaque (usually thick fibrous cap)
  • When O2 demand increases, blood flow does not increase proportionally
    • exercise, stress
  • Endothelial Dysfunction
    • inappropriate vasocontriction
      • increases sympathetic tone when physical or emotional stress (decreases nitric oxide)
      • prothrombotic
  • Clinical Presentation:
    • short lasting pain (3-15mins)
    • predictable (i.e. stress)
    • reversible
    • no variation over last 2 months in:
      • symptoms, frequency, precipitating factors


Discuss Variant Angina (Prinzmetal Angina)

  • No obvious plaques (not associated with atherosclerosis)
  • Intense coronary artery spasm (blood flow constricted)
  • Occurs at rest
  • Often experienced at night


What are the types of Acute Coronary Syndromes (ACS)?

  • ACS unstable angina
  • ACS myocardial infarction (MI)


Discuss Acute Coronary Syndromes 

  • Sudden blockage in a coronary artery greatly reduces or cuts off the blood supply to an area of the heart muscle
  • The form of ACS depends on degree of obstruction


What are the causes of ACS?

  • Rupture of atherosclerotic plaque which leads to:
    • platelet aggregation
    • vasoconstriction
    • thrombus formation


Discuss ACS Unstable Angina

  • Progressive form
    • acceleration of stable angina
    • occurs more frequently, more severe over time, pain occurs at rest
    • occurs with lesser degree of exertion
  • Rupture of atherosclerotic plaque, subsequent platelet aggregation and thrombosis
    • without myocardial necrosis


Discuss ACS Myocardial Infarction (MI)

  • Symptoms:
    • no difference between STEMI and NSTEMI
    • similar to angina (more severe & prolonged)
      • chest pain
      • breath difficulty
      • nausea & vomiting
      • sweating
      • tachycardia


What is MI classified based on?

Changes to ST segment of ECG


Describe NSTEMI

  • Non-ST segment elevation MI
    • involves partial occlusion and partial thickness damage to heart muscle
      • less severe MI


Describe STEMI

  • ST segment elevation MI
    • Indicates complete occlusion and full-thickness heart muscle injury


If there is an ST elevation what does that mean?

  • More severe damage
  • Causes changes in conduction of heart


Cardiac Ischemia Pathophysiology: > 8-10secs ischaemia

  • O2 reserves used up 
    • build up of metabolites


Cardiac Ischemia Pathophysiology: > 20 mins ischaemia

  • Irreversible injury, damaged cell membranes
    • Intracellular troponins released
      • troponin I and T
    • Intracellular enzymes released
      • creatine kinase (myocardial bound)
      • lactate dehydrogenase


Cardiac Ischemia Pathophysiology: Post MI

  • Acute inflammatory response (neutrophils)
    • approx 4 hours
  • Myocardial Oedema
    • 4-12 hours
  • Catecholamines secreted 
    • over 24 hrs (immediately)
    • increase glucose and FFA


Cardiac Ischemia Pathophysiology: Later Changes

  • Injured myocyte replaced with fibrous tissue
  • Ventricular Dilation


Treatment to Prevent Angina Attacks

  • b-blockers
  • calcium channel blockers
  • nitrates (also for acute treatment)
  • nicorandil
  • ivabradine
  • perhexiline


What is the aim of pharmalogical treatment of chronic coronary artery disease and what are two methods of relieving the angina?

  • AIM: to restore the balance between myocardial oxygen supply and demand
  • Two methods of relieving the angina
    • reduce O2 demand ✓
    • increased blood flow by dilation of the coronary arteries
      • stable angina X
      • variant angina ✓


Beta-blockers MOA

  • Competitive antagonism of beta-adrenoceptors
  • Reduce myocardial O2 demand by:
    • Decreasing HR
    • Decreasing Contractility


Beta-blockers Differ in Terms of:

  • Cardio-selectivity
  • Lipophilicity
  • Intrinsic sympathomimetic activity


Adverse Effects of Beta-Blockers?

  • Bronchoconstriction
  • Bradycardia, Hypotension, Cold Extremities
  • Sedation
  • Exaggeration/mask signs of hypoglycaemia, adverse effects on blood lipids
  • Impotence


Drug Interactions of Beta-Blockers

  • Additive effects with other drugs that slow heart rate
    • Digoxin, some Ca2+ channel blockers
  • Beta agonists (e.g. salbutamol)
    • oppose effects
  • Antidiabetic Medications
    • Beta receptors involved in response to hypoglycaemia, promote glycogen breakdown to mobilise glucose
    • May also mask symptoms of hypoglycaemia


Beta-Blockers & Vasospasm

  • Caution in variant agina
    • cause vasospasm
  • Activation of beta-2 receptors causes vasodilation
  • Activation of alpha-2 receptors causes vasoconstriction
  • If block beta receptors, while alpha receptors remain unopposed
    • vessels susceptible to constriction


Describe Calcium Channel Blockers

  • Block L-Type Calcium Channels
    • blocks inward calcium current
      • cardiac muscle
      • cardiac conducting system
      • vascular smooth muscle
        • arterial > venous


Describe the role of Calcium Channel Blockers in Angina

  • Reduce myocardial O2 demand by:
    • decreasing afterload due to arteriolar dilatation
    • decreasing contractility and rate


What are the Two Types of Calcium Channel Blockers used in Angina?

  • Dihydropyridines (end with 'pine' e.g. nefedipine, amlodipine)
  • Non-dihydropyrodine (verapamil and dilltiazem)


What are the adverse effects of Calcium Channel Blockers?

  • Depend on type/properties of CCB
  • Headache, flushing, dizziness, peripheral oedema
  • Bradycardia
  • Constipation, dyspepsia
  • Most CCBs are susceptible to CYP3A4 mediated drug interactions


Describe Organic Nitrates

  • Glyceryl trinitrate (nitroglycerin)
  • Isosorbide mono/dinitrate
  • Chemically converted in vivo to release nitric oxide (NO) in vascular smooth muscle
  • Reduce myocardial O2 demand
    • dilate veins therefore decrease preload
    • at higher doses dilate arteries therefore decrease afterload


Describe the Metabolism of Organic Nitrates

  • Nitroglycerin (a.k.a glyceryl trinitrate)
    • low oral bioavailability as reductase in liver converts to dinitrate
      • use sublingual or transdermal or iv formulations
  • Isosorbide dinitrate (ISDN)
    • poor bioavailability 
      • ISMN (metabolite) is 100% bioavailable


What are adverse effects of Organic Nitrates?

  • Used in acute angina and as preventative
  • Common ADRs:
    • headache 
    • flushing
    • dizziness
    • orthostatic hypotension
    • reflex tachycardia


Describe the interaction of Organic Nitrates with Phosphodiesterase 5 Inhibitors

  • PDE5 inhibitors e.g. sildenafil (viagra) are used for erectile dysfunction
    • PDE5 breaks down cGMP
    • inhibiting this, increases smooth muscle relaxation of corpus cavernosum, also PDE5 in vascular smooth muscle
  • If given with nitrates
    • severe hypotension
    • can occur if taken within 24hr of each other


Describe Pharmalogical Tolerace of Organic Nitrates

  • Nitrate free interval of at least 8hrs required
  • Normal dosing with GTN patch
    • apply patch 1st thing in the morning and remove patch before bed
  • Normal dosing with IDN tablet
    • take immediate release tablet 3xdaily
  • Normal dosing with IMN tablet
    • take CR tablet 1st thing in the morning
    • high bioavailability and long t1/2 produces periods of increased and decreased nitrate levels
    • nitrate levels are low but not zero


Describe K+ channel activators - Nicorandil

  • Opens K+ channels of vascular smooth muscle
    • K+ moves out of cell
    • Hyperpolarisation
    • Muscle contraction inhibited
  • Also a nitrate donor
  • Reduce myocardial O2 demand by:
    • dilation of primarily of arteries (decreases afterload)
    • some venodilation (decreases preload)


What are the Precautions and Adverse Effects of K+ channel activators (e.g. nicorandil)?

  • Headache, flushing, dizziness, hypotension
  • Interacts with PDE inhibitors
  • May cause formation of ulcers and fistulas


Describe Ivabradine

  • Blocks Na+ channels in the sinoatrial node
    • decreasing heart rate
    • reduces myocardial O2 demand
  • Metabolised by CYP450


What are the Adverse Effects of Ivabradine?

  • Heart (predictable) = e.g. bradycardia, arrhythmias
  • Eye - luminous effects


Describe Perhexiline

  • Inhibits enzyme involved in long-chain fatty acid metabolism in the heart
    • glucose metabolism predominates
      • oxidation of glucose requires less oxygen than oxidation of fatty acids = reduces myocardial oxygen requirements


Describe the Adverse Effects of Perhexiline

  • Neurotoxicity
  • Hepatoxicity


What is perhexiline metabolised by?

Describe the effects of perhexiline having a narrow TI?

  • Metabolised by polymorphic CYP2D6
    • large inter-individual variation in dose required
  • Narrow TI
    • requires therapeutic drug monitoring
    • non-linear pharmacokinetics


Describe Acute Management of STEMI

  • Treatment to assist with reperfusion
    • Percutaneous Coronary Intervention (PCI)
    • Fibrinolytics (thrombolytic) drugs e.g. tenecteplase & alteplase


Describe Percutaneous Coronary Intervention (PCI)

  • Blocked vessel can be opened via balloon angioplasty
    • blood flow is restored to artery
  • Stent = metal scaffold
    • can be inserted to hold vessel open while heals
      • bare metal stent
      • drug eluting stent
        • release antiproliferative drug to prevent restenosis, blocking of vessel due to excessive tissue growth


What is Fibrinolysis?

Describe Fibrinolytics (Thrombolytic) drugs (e.g. tenecteplase & alteplase)

  • Fibrinolysis = process that occurs in the body to breakdown blood clots
  • During fibrinolysis, plasmin catalyses breakdown of fibrin
  • Plasminogen in clot activated to form plasmin as needed
  • Fibrinolytic drugs activate plasminogen


What is Heart Failure?

  • A complex syndrome that can result from any disorder of the heart that affect the ability of the ventricle to fill with or pump out blood


What are the two subtypes of Heart Failure?

  • Left ventricular dysfunction
  • Right ventricular dysfunction


What are the two types of Left Ventricular Dysfunction?

What are they differentiated by?

  • Heart failure with Reduced Ejection Fraction (HFREF)
    • a.k.a HF with left ventricular systolic dysfunction (HF-LVSD)
  • Heart failure with Preserved Ejection Fraction (HFPEF)
    • a.k.a HF with left ventricular diastolic dysfunction
  • They are differentiated by left ventricular ejection fraction (LVEF)
    • usually 55%-70% in health person


What is Systolic BP?

  • Pressure of the blood against the artery walls when the heart contracts


What is Diastolic BP?

  • Pressure against the artery walls when the heart relaxes between beats


Describe Left Ventricular Dysfunction - HFREF (reduced ejection fraction - systolic dysfunction)

What are the causes?

  • Heart is failing as a pump due to decreased myocardial contractility
    • impaired 'squeeze' during systole
  • Causes:
    • usually due to coronary artery disease
    • systemic arterial hypertension
    • valvular heart disease


Describe Left Ventricular Dysfunction - HFPEF (Preserved ejection fraction - diastolic dysfunction)

What are the causes?

  • Heart is failing to pump due to decreased ability of ventricle to relax
    • impaired filling during diastole
    • reduced end diastolic volume
    • increased diastolic left ventricular stiffness
  • Cardiac contractility not impaired
  • Causes:
    • coronary artery disease (and subsequent myocardial ischaemia)
    • long-standing hypertension


Describe Right Ventricular Dysfunction HF and what are the causes?

  • Right ventricle fails to pump effectively
  • Causes:
    • usually due to pulmonary hypertension secondary to lung disease
      • right ventricle has to work harder to pump blood to lungs
    • left ventricular dysfunction
    • tricuspid valvular disease
    • congenital heart disease
    • ischaemia heart disease affecting right ventricle


What is Congestive Heart Failure (a.k.a chronic heart failure) and what are the types of Heart Failure?

  • General term used for HF and associated congestion
  • Types:
    1. Right sided heart failure
      • back-ups in the area that collects 'used' blood
    2. Left-sided heart failure
      • failure to properly pump out blood to the body
    3. Congestive heart failure
      • fluid collects around the heart


What is ejection fraction?

Proportion of blood in the ventricle of the heart pumped out at the end of each contraction


Describe the Compensatory Mechanisms activated in Heart Failure

  • When cardiac output does not meet needs for organ perfusion body activates compensatory mechanisms
  • Include:
    • increased sympathetic tone
    • activation of RAAS
    • sodium and water retention
    • other neurohormonal adaptation
    • cardiac remodelling
  • In the long term, these mechanisms can worsen cardiac function as they increase myocardial Orequirements


Describe Cardiac Remodelling (compensatory mechanism)

  • Months-years before symptoms occur
  • Cardiac dilation:
    • most evident in systolic dysfunction
    • ventricles fail to pump adequate amount of blood with each contraction
    • blood accumulates in ventricles, myocardial fibres are stretched and ventricles become dilated
  • Cardiac hypertrophy:
    • increase in muscle mass
    • increase in muscle wall thickness


What are the signs and symptoms of heart failure?

  • Dyspnea (breathlessness)
  • Orthopnea (breathlessness when lying flat)
  • Paroxysmal nocturnal dyspnea
  • Reduced exercise tolerance
  • Cough with frothy sputum
  • Fatigue
  • Poor urine output or nocturia
  • Loss of appetite
  • Impaired cognitive function
  • Ankle oedema


What are the Aims of Heart Failure Treatment?

  • Reduce symptoms
  • Improve exercise tolerance
  • Prevent hospitalisation
  • Reduce mortality


Angiotensin Converting Enzyme (ACE) inhibitors

  • Reversibily inhibit ACE
  • Renin converts angiotensinogen to angiotensin I, which is converted to angiotensin II by ACE
    • angiotensin II has multiple effects to:
      • increase preload and afterload
      • increase myocardial oxygen needs
      • this can ultimately worsen HF
  • e.g. captopril, enalapril, perindopril, ramipril


Angiotensin II receptor blockers (ARBs or 'sartans')

  • Work on the same physiological system as ACE inhibitors
    • antagonist at the angiotensin II AT1, receptors
    • overall same effect as ACE inhibitors
  • Don't inhibit breakdown of Bradykinin as ACE inhibitors do
  • Increase in bradykinin contributes to vasodilator effects of ACE inhibitors


Describe Neprilysin Inhibitors

  • Targets neprilysin, a metalloprotease enzyme that cleaves and inactivates naturetic proteins
    • naturetic proteins are released in response to cardiac wall stress


Describe Beta-Blockers

  • Activation of sympathetic nervous system is a compensatory mechanism in heart failure
    • initially beneficial, but long term activation is detrimental
  • Beta-blockers competively antagonise beta receptors
    • reduces heart rate, contractility and afterload
    • inhibits renin release from kidney (via b1) to reduce preload
    • slows ventricular remodelling
  • May initially worsen heart failure and cause hypotension
    • unoccupied b receptors exert basal activity of b-receptors
      • negative inotropic effects


What are inotropes?

  • A drug that alters the force of muscular contractions
    • Positive inotropes increase the strength of muscular contraction
    • Negative inotropes decrease the strength of muscular contraction


What are the functions of the kidneys?

  • Removal of waste products from the body, specifically:
    • urea: formed through breakdown of amino acids
    • creatinine: breakdown product of muscle metabolism
    • uric acid: form through recycling of nitrogen bases from RNA 
  • Also critical for homeostatic regulation of volume and solute concentration of blood


Describe the Nephron

  • Urine produced by nephrons (cortical or juxtamedullary)
  • Nephron consists of:
    • renal corpuscle
      • glomerulus and glomerular capsule
    • renal tubule
      • proximal convoluted tubule, loop of Henle, distal convoluted tubule


Describe the Proximal Convoluted Tubule (PCT)

  • Active transport of Na+, K+, CO2-, glucose, amino acids e.t.c. from the filtrate to the bloodstream
  • Solute concentration of filtrate decrease, osmosis pulls water from tubules to peritubular fluid and blood stream
  • Resorbs 60-70% volume of renal filtrate


Describe the Loop of Henle

  • Thin descending limb permeable to water but not solutes
  • Thick ascending limb impermeable to water and solute but has active transport mechanisms 
  • Na+ and Cl- pumped out of thick ascending limb, osmosis pulls water out of thin descending limb
  • High concentration filtrate increases Na+ and Cl- transport out of ascending limb 
  • Resorbs 15-20% volume of renal filtrate


Describe Distal Convoluted Tubule (DCT)

  • Active transport of Na+ and Cl- out of tubular fluid
  • Also contains pumps that reabsorb Na+ in exchange for K+
    • aldosterone stimulates synthesis and incorporation of these Na+ channels
  • Resorbs approx. 5% volume of renal filtrate


What is the function of diuretics?

  • Increase water and sodium excretion in kidney
    • reduces intravascular volume = reduced preload
    • reduces fluid retention related symptoms
      • peripheral and pulmonary oedema
  • Primarily use loop diuretics (most potent)


Describe Loop Diuretics

  • e.g. Furosemide
  • Inhibits reabsorption of Na+ and Cl- in ascending loop of Henle
  • Increased Na+ delivery to DCT, increases activity of Na+/K+ pump
    • can cause low K+ (hypokalaemia)


Describe Aldosterone Antagonists (e.g. spironolactone)

  • Promotes reabsorption of Na+ and H2O in the distal tubule of nephron
  • Weak diuretic effect
    • competitive antagonists
    • reduce preload
    • reduce aldosterone - induced myocardial or vascular damage
  • No increase in K+ loss


What are the Adverse Effects of Aldosterone Antagonists?

  • Act on progesterone/androgen receptors
    • can cause gynaecomastia, menstrual disorders, testicular atrophy
  • Increase in K+


Describe Digoxin

  • Inhibits the Na+/K+ ATPase (transport pump) in myocardial cell membrane
    • increase intracellular Ca2+ in myocytes = positive inotrope
    • increases ejection fraction and cardiac output
  • Inhibits Na+/K+ ATPase in vascular smooth muscle
    • depolarisation = vasoconstriction
    • overal vascular resistance decreases as cardiac output increases, causing a reduction in compensatory mechanisms


What are the Adverse Effects of Digoxin?

  • GI: anorexia, nausea, vomiting
  • Ocular: blurred/altered vision
  • CV: arrhythmia, bradycardia, AV block
  • Neurologic: fatigue, confusion
  • It also has a Narrow TI
    • drug monitoring


Describe Drug Interactions & Precautions with Digoxin

  • Caution with other drugs that reduce heart rate
    • used for arrythmia lower atrioventricular conduction to decrease heart rate
    • risk of bradycardia and heart block
    • pharmacodynamic interaction
  • P-glycoprotein substrate concentration may be affected by - gp inducers or inhibitors
    • pharmacokinetic interaction
  • Risk of arrythmia with digoxin
    • low K+ exacerbates K+ loss from myocardial cells, increasing effects/toxicity
  • Largely renally cleared (70%) 
    • caution in renal impairment


What are Other Positive Inotropes used in Heart Failure?

  • Milrinone
    • selective inhibitor of PDE3
    • prevents breakdown of cAMP = calcium influx and uptake by sarcoplasmic reticulum
    • leads to greater contractility and vasodilations
    • doesn't increase myocardial O2 requirements
    • only used short-term in severe, refractory heart failure
  • Dobutamine


What are Other Drugs used in Heart Failure?

  • Vasodilators
    • nitrates
      • venodilators - reduce preload
    • hydralazine
      • potent arterial vasodilator - reduce afterload
      • results in reflex activation of sympathetic nervous system
    • ivabradine
      • reduces heart rate


What are the Cells in the Heart?

  • Pacemaker cells
  • Non-pacemaker cells


Describe the Function of Pacemaker Cells and where they are Located

  • Generate spontaneous action potentials
  • Display automaticity
    • The ability to depolarise above a threshold voltage in a rhythmic fashion
  • Found in the SA node, AV node, Bundle of His, Purkinje Fibres


Describe the Function of Non-Pacemaker Cells and where they are located

  • Do not normally generate spontaneous action potentials
  • Stimulated by a wave of depolarisation initiated from nearby pacemaker cells
  • Contract in response to depolarisation
  • Atrial and ventricular myocytes


Describe Action Potentials in Pacemaker Cells (SA node [native pacemaker])

  • Phase 4
    • Slow spontaneous depolarisation
    • Inward current, mainly Na+, through non-specific cation channels
  • Phase 0
    • Rapid depolarisation
    • Voltage gated L-type Ca2+ channels open
  • Phase 3
    • Repolarisation
    • Ca2+ channels close, K+ channels open
    • Membrane potential drops to -60mV and channels open again causing inward current


Describe Action Potentials in Contractile Cells (Ventricular Myocytes)

  • Phase 0
    • Rapid depolarisation
    • Fast Na+ channels
  • Phase 1
    • K+ channels open
  • Phase 2
    • The plateau 
    • Slow Ca2+ channels open, outward K+ current
  • Phase 3
    • Rapid repolarisation, outward K+ current
  • Phase 4
    • Resting Potential


Describe Electrical dysfunction in the Heart

What is it described by?

  • Abnormalities of the electrical rhythm are known as arrhythmias
  • Described by
    • Site of origin
      • supraventricular, ventricular
    • Rate
      • tachycardias, bradycardias


What are the causes of arrhythmias?

  • Ischaemia/MI
    • Tissue necrosis
    • Electrolyte imbalance
    • Alter autonomic activity
  • Electrolyte imbalance
  • Drug toxicity
  • Surgery
  • Congenital defects


Describe Mechanisms of Arrhythmias

  • Altered impulse formation
    • Altered automaticity of SA node
    • Abnormal automaticity
    • Triggered activity
  • Altered impulse conduction


Describe Altered Impulse Formation (Altered Automaticity)

  • Increased SA node automaticity
    • sympathetic stimulation
  • Decreased SA node automaticity
    • reduced sympathetic stimulation/incl. parasympathetic activity
    • can lead to escape beats
  • Increased automaticity of latent pacemakers
    • faster than SA node
    • ectopic beats


Describe Abnormal Automaticity (Altered impulse formation)

  • Atrial or ventricular myocytes initiate impulses


Describe Triggered Activity (Altered Impulse Formation)

[incl. early and delayed afterdepolarisations]

  • Afterdepolarisations
    • a normal AP triggers additional abnormal APs
    • Early afterdepolarisations
      • Develop when AP duration is increased or QT interval prolonged on ECG
    • Delayed afterdepolarisations (torsades de pointes)
      • Often develop due to high intracellular Ca2+


What are the causes of calcium overload?

  • Catecholamines
    • MI
    • Heart Failure
  • Drugs
    • Digoxin


Describe Conduction Block (Altered Impulse Conduction)

  • Impulse fails to propagate because of an area of inexcitable tissue
  • Heart block


What is rentry?

  • Rentry is the mechanism by which there is repeated circular stimulation of a region of cardiac tissue


Describe Altered Impulse Conduction-Re-entry

  • Normally
    • Impulse travels via pathways 1 & 2
  • In re-entrant circuit
    • Conducted down pathway 1 only
    • Pathway 2 is blocked in one direction due to damage
    • Impulse gets to point b and continues back towards point a. But conduction from a to b is slowed because of the damage in the area
    • When the impulse reaches a the cells in pathway 1 have repolarised 
    • The circuit continues


What is Wolff Parkinson White Syndrome?

  • Additional abnormal pathways (accessory tract pathway)
  • Conduction in the Bundle of Kent is faster
    • Pre-excitation of ventricles
    • Can set up a re-entrant loop


What are the types of Ventricular Arrhythmias and Describe their Characteristics

  • Ventricular Fibrillation
    • common cause of death during MI
    • CO = zero
  • Ventricular Tachycardia
    • Emerge weeks to yrs after MI
    • Scar tissue leads to re-entry


Describe Atrial Fibrillation

  • Atria beat too fast and inefficiently
    • ectopic foci and re-entrant loops
  • Blood pools in the atria
    • risk of thrombi 


Describe Paroxysmal Supraventricular Tachycardias (PSVTs)

  • Begin and end suddenly 
  • AV nodal reentrant tachycardia


What are the Consequences of Arrhythmias?

  • Reduced Cardiac Output
    • Bradycardia
    • Tachycardia causes decreased filling time
    • Atrial fibrillation abolishes atrial contribution to ventricular filling
  • Increase Oxygen demand for Heart
    • tachycardia
  • Risk of thrombi
    • Atrial fibrillation causes pooling of blood in the atria
  • Death
    • Ventricular Fibrillation CO = Zero - Death


What are anti-arrhythmic agents?

  • Vaughan William Classification
    • Class I: Na+ channel blockers
    • Class II: B blockers
    • Class III: K+ channel blockers
    • Class IV: Ca2+ channel blockers
  • Digoxin


Describe Class I: Na+ Channel Blockers

  • Inhibit Na+ channels
  • Can slow
    • automaticity of SA node (Phase 4)
    • conduction in the ventricles (Phase 0)
  • Flecainide: marked Na+ channel block, slow dissociation
  • Lignocaine: mild Na+ channel block, rapid dissociation
  • Disopyramide: moderate Na+ channel block, intermediate dissociation (also prolong repolarisation by blocking K+ channels)


Describe Class II: beta blockers

  • Reduce the potential for arrhythmias to develop in response to catecholamines
  • Block beta 1 receptors in SA and AV node 


Describe Class III: K+ channel blockers

  • Blocks K+ channels
    • prolong the plateau and repolarisation
    • increases the refractory period
      • decreases the incidence of re-entry
  • amiodarone 


Describe Class IV: Calcium channel blockers

  • Act primarily on SA and AV node
    • these tissues require Ca2+ for phase 0 depolarisation
    • slow rate and conduction
  • dihydropyridines (nifedipine, amlodipine)
  • non-dihydropyridines (verapamil, diltiazem)


Describe Mixed class II/III

  • Sotalol
    • beta blocking activity (II)
    • also prolongs the AP (III)
    • ind: supraventricular and ventricular arrhythmias


Describe Digoxin in use of Arrhythmias

  • Indication: supraventricular tachycardias
  • Descreases HR
    • CNS and PNS effects resulting in increased parasympathetic input to the heart
  • Decreased conduction through the AV node
    • direct effect
  • Also increases contractility