Cardiovascular System Flashcards Preview

Pharmacology 2 > Cardiovascular System > Flashcards

Flashcards in Cardiovascular System Deck (146):
1

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

2

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

3

Describe the characteristics and key roles of Triglycerides

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

4

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

5

What is the role of Cylomicrons?

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

6

What is the role of VLDL?

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

7

What is the role of LDL?

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

8

What is the role of HDL?

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

9

What are the functions of Apolipoproteins?

  • Structural
  • Ligands
  • Activate enzymes

10

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

11

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

12

What is Primary Dyslipidaemia caused by?

  • Caused by genetic defects in lipoprotein metabolism

13

What is Secondary Dyslipidaemia caused by?

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

14

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

15

What is Atherosclerosis?

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

16

What are the Consequences of Atherosclerosis?

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

17

What is the Development of Atherosclerosis?

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

18

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

  • Inflammatory cells move from lumen to intima

19

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

20

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

21

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

22

What are Treatment Strategies of Atherosclerosis?

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

23

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

24

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

25

What are other pharmalogical effects of statins?

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

26

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

27

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

28

What are the Adverse Effects associated with Fibrates?

  • Mainly GI
  • Photosensitivity (rare)

29

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

30

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

31

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

32

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

33

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

34

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)

35

How may bile acid binding resins interact with other drugs?

  • May bind to and alter absorption of other medications

36

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

37

What are the adverse effects of Nicotinic Acid?

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

38

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

39

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

40

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

41

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

  • GI upsets
  • Fishy aftertaste

42

Dietary Interventions for Dyslipideamia etc.

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

43

What is Ischaemic Heart Disease?

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

44

What is the Classification of Ischaemic Heart Disease?

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

45

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

46

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

47

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

48

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

  • ACS unstable angina
  • ACS myocardial infarction (MI)

49

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

50

What are the causes of ACS?

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

51

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

52

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

53

What is MI classified based on?

Changes to ST segment of ECG

54

Describe NSTEMI

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

55

Describe STEMI

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

56

If there is an ST elevation what does that mean?

  • More severe damage
  • Causes changes in conduction of heart

57

Cardiac Ischemia Pathophysiology: > 8-10secs ischaemia

  • O2 reserves used up 
    • build up of metabolites

58

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

59

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

60

Cardiac Ischemia Pathophysiology: Later Changes

  • Injured myocyte replaced with fibrous tissue
  • Ventricular Dilation

61

Treatment to Prevent Angina Attacks

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

62

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 ✓

63

Beta-blockers MOA

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

64

Beta-blockers Differ in Terms of:

  • Cardio-selectivity
  • Lipophilicity
  • Intrinsic sympathomimetic activity

65

Adverse Effects of Beta-Blockers?

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

66

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

67

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

68

Describe Calcium Channel Blockers

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

69

Describe the role of Calcium Channel Blockers in Angina

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

70

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)

71

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

72

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

73

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

74

What are adverse effects of Organic Nitrates?

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

75

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

76

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

77

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)

78

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

79

Describe Ivabradine

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

80

What are the Adverse Effects of Ivabradine?

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

81

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

82

Describe the Adverse Effects of Perhexiline

  • Neurotoxicity
  • Hepatoxicity

83

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

84

Describe Acute Management of STEMI

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

85

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

86

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

87

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

88

What are the two subtypes of Heart Failure?

  • Left ventricular dysfunction
  • Right ventricular dysfunction

89

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

90

What is Systolic BP?

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

91

What is Diastolic BP?

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

92

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

93

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

94

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

95

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

96

What is ejection fraction?

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

97

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

98

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

99

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

100

What are the Aims of Heart Failure Treatment?

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

101

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

102

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

103

Describe Neprilysin Inhibitors

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

104

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

105

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

106

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

107

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

108

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

109

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

110

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

111

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)

112

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)

113

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

114

What are the Adverse Effects of Aldosterone Antagonists?

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

115

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

116

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

117

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

118

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

119

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

120

What are the Cells in the Heart?

  • Pacemaker cells
  • Non-pacemaker cells

121

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

122

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

123

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

124

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

125

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

126

What are the causes of arrhythmias?

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

127

Describe Mechanisms of Arrhythmias

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

128

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

129

Describe Abnormal Automaticity (Altered impulse formation)

  • Atrial or ventricular myocytes initiate impulses

130

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+

131

What are the causes of calcium overload?

  • Catecholamines
    • MI
    • Heart Failure
  • Drugs
    • Digoxin

132

Describe Conduction Block (Altered Impulse Conduction)

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

133

What is rentry?

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

134

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

135

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

136

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

137

Describe Atrial Fibrillation

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

138

Describe Paroxysmal Supraventricular Tachycardias (PSVTs)

  • Begin and end suddenly 
  • AV nodal reentrant tachycardia

139

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

140

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

141

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)

142

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 

143

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 

144

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)

145

Describe Mixed class II/III

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

146

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