Pharmacology of congestive cardiac failure and coronary ischaemic syndromes and lipid lowering drugs

Question 1

Differentiate systolic HF and diastolic HF

Answer 1

Systolic = reduced systolic function, HFrEF
= impaired pumping ability of the ventricle leading to reduced CO
- LVEF < 40%

Diastolic = preserved systolic function, HFpEF
= impaired ventricular cardiac filling
- leads to ventricular hypertrophy and stiffening
- EF is normal but CO is reduced

Question 2

Demographic systolic and diastolic HF?

Answer 2

Systolic
- men > women
- > 65 years

Diastolic
- rare in young patients and those without hypertension Hx
- women > men

Question 3

Risk factors for systolic (2) and diastolic (5) HF?

Answer 3

Systolic
1 hypertension
2 IHD

Diastolic
1 hypertension
2 CHD
3 diabetes
4 vascular disease
5 LVH

Question 4

HF compensatory mechanisms (3)

Answer 4

RAAS
SNS
Vasopressin, BNP/ANP, others

Question 5

Non pharmacological treatment measures (9)

Answer 5

1 Weight management
2 Diet - salt intake
3 Fluid restriction
4 Sodium restriction
5 Patient education and counselling
6 Regular exercise
7 Smoking
8 Alcohol restriction
9 Influenza, pneumococcal and COVID vaccination

Question 6

List pharmacological treatment of systolic HF (9)

Answer 6

ACE inhibitors
Angiotensin II antagonists
Neprilysin inhibitors
Diuretics
Beta blockers
Spironolactone
Ivabradine
Digoxin
SGLT2 inhibitors

Question 7

Action of aldosterone

Answer 7

increases sodium reabsorption and water

increase potassium excretion

Question 8

Action of angiotensin II

Answer 8

Vasoconstriction (increase TPR)

Aldosterone release

Question 9

Initial therapy systolic HF

Answer 9

ACE inhibitors - lowers BP - reduces preload and afterload

Shown to:
- reduce mortality
- slow progression of disease
- reduce hospitalization
- improve exercise tolerance, QOF and overall prognosis

Question 10

What is a common side effect of ACE inhibitors

Answer 10

Dry cough
- ACE normally breaks down bradykinin into inactive products
- ACE inhibitors means there is a build up of bradykinin in the respiratory system

= vasoactive peptide leasds to bronchoconstriction

Question 11

Process of ACE inhibitor administration

Answer 11

• initially, low dose and increase gradually to target dose
• ## monitor renal function and potassium levels (expect decreased renal function and increased potassium levels)

Question 12

Example of ACE inhibitor

Answer 12

perindopril

Question 13

Example of angiotensin II antagonist

Answer 13

candesartan

Question 14

MOA angiotensin II blockers

Answer 14

Similar to ACE inhibitors, further down the line

Avoids respiratory side effect so is used when ACE inhibitors aren’t tolerated

Reduces preload and afterload

Question 15

ACE inhibitors and angiotensin II antagonists effect on renal function (renal vessels) compare to normal

Answer 15

Prostaglandins vasodilate afferent arteriole

Angiotensin II vasoconstricts efferent arteriole

Acts to preserve GFR

ACE inhibitors and angiotensin II antagonists reduce GFR = reduce renal function.
- increased excretion of water and sodium and reduced excretion of potassium = may lead to hyperkalaemia

Question 16

What triggers release of natriuretic peptides - ANP/BNP/CNP?

Answer 16

Released when atrial and ventricular chambers of the heart are distended e.g. HF

Question 17

What is the outcome of natriuretic peptides release? (5)

Answer 17

vasodilation
diuresis and natriuresis
inhibition of renin and aldosterone
reduce SNS
anti hypertrophic / fibrotic effects = reduce cardiac remodelling

Question 18

What is neprilysin? What is an example of an inhibitor of this?

Answer 18

An enzyme that breaks down natriuretic peptides

Sacubitril - inhibits the enzyme

Question 19

Actionof neprilysin inhibitors ?

Answer 19

Inhibits the breakdown of natriuretic peptides = prolongs their actions
- also breaks down bradykinin

Beneficial in HFrEF…
- vasodilation
- diuresis and natriuresis
- inhibition of RAAS
- reduce SNS
- reduce preload and afterload

Question 20

Drug interaction: sacubitril and what other drug? Potential complication? Washout period?

Answer 20

Sacubitril = neprilysin inhibitor
AND
ACE inhibitor

Angioedema
- both ACE and neprilysin break down bradykinin

36hrs

Question 21

Treatment and prevention of stable angina (3) + treatment of underlying conditions (3)

Answer 21

Treatment/prevention:
1 organic nitrates e.g. GTN
2 calcium channel blocking agents e.g. amlodipine
3 beta adrenoreceptor blocking agents e.g. metaprolol

Tx underlying conditions
1 antiplatelet medications e.g. low dose aspirin
2 bp control e.g. ACEi
3 lipid control e.g. HMG-CoA reductase inhibitors (statins)

Question 22

3 examples of organic nitratyes

Answer 22

GTN
isosorbide mononitrate
isosorbide dinitrate

Question 23

MOA nitrates (6)

Answer 23

1 metabolised to NO
2 activates guanylyl cyclase
3 enzyme converts GTP to cGMP
4 produces protein kinase G (PKG)
5 reduces contractility and inhibits Ca+ entry
6 smooth muscle relaxation and vasculodilation in arteries and veins

Question 24

Main effects of nitrates on CVS (3)

Answer 24

1 decrease preload
- venous dilation
- reduces cardiac workload

2 decrease afterload
- reduces PR
- reduces cardiac workload

3 dilate coronary vessels
- increases coronary blood flow, particularly to ischeamic areas
- increases myocardial oxygen supply

Question 25

downside organic nitrates? solution?

Answer 25

too frequent or continuous use leads to... development of tolerance = reduced therapeutic effect nitrate free period restores activity

Question 26

ADR organic nitrates (3) and drug interactions (1) explain

Answer 26

ADR 1 dizziness 2 postural hypotension 3 headache Drug interactions 1 PDE5 inhibitors e.g. tadalafil (used in treatment of ED - PDE5 inhibitors prevent the breakdown of cGMP in muscle cells - inhibited breakdown plus increased production of cGMP = big increase intracellular cGMP = results in severe hypotension and CV collapse

Question 27

characteristics GTN (2) linked to practical outcome

Answer 27

1 - high first pass metabolism - inactive if taken orally therefore, sublingual administration 2 - tablets are relatively unstable - spray avoids problems

Question 28

What is the voltage gated calcium channel for contraction of smooth and cardiac muscle?

Answer 28

L type channels

Question 29

Ca+ channel blockers and blood vessels

Answer 29

vascular smooth muscle relaxation = reduction in peripheral vascular resistance = drop BP Artery specific! Dilate coronary vessels Reduce afterload

Question 30

Examples of Ca+ channel blockers used in treatment of angina (4) and when used?

Answer 30

Amlodipine Nifedipine Diltiazem Verapamil Regular basis for prophylactic angina (not acute)

Question 31

Side effects Ca+ channel blockers (5)

Answer 31

1 hypotension, headache, flushes 2 bradycardia e.g. diltiazem 3 peripheral edema - arteriole dilation and increased permeability of post capillary venules 4 constipation e.g. verapamil 5 drug interactions

Question 32

Angina Tx Beta blockers: e.g. non selective vs cardio-selective

Answer 32

non selective e.g. propanolol cardio selective cardio selective (b1) e.g. atenolol, metoprolol

Question 33

beta blockers MOA in treatment of angina (4)

Answer 33

1 reduce SNS effects on heart 2 reduce HR, contractility and cardiac work 3 reduce cardiac work and oxygen demand 4 reduce afterload by reducing BP

Question 34

Side effects beta blockers (4)

Answer 34

1 may precipitate wheezing and acute asthmatic attacks in asthmatic patients (blocking effects of adrenaline which keeps airways open) 2 bradycardia, fatigue, reduced exercise tolerance 3 sleep disturbances, nightmares, impotence 4 aggravation of Raynaud's disease

Question 35

beta blockers and diabetes

Answer 35

may reduce some signs of hypoglycaemia and prolong hypoglycaemia

Question 36

beta blockers and withdrawal

Answer 36

abrupt withdrawal may be dangerous and can result in: - servere angina - cardiac arrhythmias - MI - rebound hypertension in susceptible patients

Question 37

Plasminogen activators: example, MOA, use, procedure and side effects

Answer 37

Alteplase - serine protease tissue plasminogen activator in presence of fibrin Binds to fibrin in a thrombus and converts the entrapped plasminogen to plasmin = initiates local fibrinolysis = clot fragmentation Used in acute treatment of occlusive coronary artery thrombi and STEMI Initiated ASAP and within 12 hrs of onset of symptoms may produce bleeding and haemorrhage, may be life threatenting (e.g. intracranial, GIT)

Question 38

Drug medications for acute and post treatment MI (with example)

Answer 38

1 Plasminogen activators e.g. alteplase 2 anticoagulants e.g. heparin 3 antiplatelet medications e.g. aspirin 4 organic nitrates e.g. GTN 5 strong analgesics e.g. morphine 6 beta blockers e.g. metaprolol 7 ACEi e.g. ramipril/ARB 8 statins e.g. simvastatin

Question 39

What do lipoproteins transport?

Answer 39

cholesterol and triglycerides

Question 40

Medications in control of lipids and examples

Answer 40

1 statins (HMG CoA inhibitor) e.g. simvastatin 2 ezetimibe - block git absorption 3 PCSK9 inhibitors e.g. alirocumab = LDLR 4 fibrates e.g. fenofibrate (primarily decrease triglycerides and raise HDL) 5 ion exchange resins e.g. cholestyramine

Question 41

MOA statins (2), effect, side effects, contraindications and compliance

Answer 41

1 inhibit HMG CoA reductase 2 increase number of LDL receptors on surface of hepatocytes - increased uptake of LDL Effect: reduced TC and LDL Myopathy, muscle pain, tenderness, weakness, rhabdomyolysis (very rarely) Pregnancy < 50% at six months

Question 42

Atorvastatin/simvastatin: drug interaction and cytochrome P450 system Outcome?

Answer 42

Statins = substrates clarithromycin/erythromycin/itraconazole = inhibitors of CYP3A4 Elevated serum concentration statins

Question 43

Consequence of dose response curve: statins? Greater response required?

Answer 43

Flat dose response curve >8-% of cholesterol lowering effects can be achieve with 50% of maximum dose Greater dose required: Add a second agent to a lower statin dose rather than increase the statin dose to a maximum with possible increase in side effects

Question 44

Ezetimibe: characteristics, moa, outcome, ADR

Answer 44

undergoes enterohepatic recycling inhibits intestinal absorption of dietary and biliary cholesterol - acts at brush border of SI reduction in cholesterol absorption reduces hepatic stores of cholesterol and increases uptake from blood myopathy, increase creatine kinase levels and rarely rhabdomyolysis

Question 45

What transporter does Ezetimibe inhibit?

Answer 45

sterol transporter: Niemann-Pick C1-Like 1

Question 46

Combination for lipid lowering drugs and describe dual action

Answer 46

Ezetimibe and statins statins inhibit cholesterol synthesis and ezetimibe inhibits intestinal absorption or dietary and biliary cholesterol

Question 47

What is PCSK9?

Answer 47

Proprotein convertase subtilisin/kexin type 9 (PCSK9) = proprotein convertase involved in degredation of LDL receptors in liver = tags LDL receptors for destruction

Question 48

Examples of PCSK9 inhibitors and MOA

Answer 48

alirocumab and evolocumab bind to and inhibit the action of PCSK9 (which labels LDL receptors for destruction)

Question 49

PCSK9 Inhibitors: outcome, half life?, administration, ADR, use

Answer 49

Reduce TC and LDL Long T1/2 Subcutaneous injection every 2-4 wks respiratory tract symptoms, influenza like illness, hypersensitivity reactions (some patents develop antibodies) and muscle pain Used to treat - Familial hypercholesterolaemia since mutations in PCSK9 gene can cause this disease

Question 50

Fibrates: examples, moa and outcome, use, ADR

Answer 50

Fenofibrate and gemfibrozil Stimulate peroxisome proliferator-activated receptor type alpha (PPARalpha) nuclear receptors in the liver - decreased triglyceride - increased HDL synthesis Used in type 2 diabetes May cause myopathy, increase creatine kinase levels - may cause severe muscle damage and rhabdomyolysis with statins

Question 51

What are cholestyramine (name of drug is?) and colestipol (name of drug is?). Moa and outcome

Answer 51

Cholestyramine: questran Colestipol: colestid = ion exchange resins which inhibit the reabsorption of bile acids from the intestine As cholesterol is a precursor of bile acids, that causes more cholesterol from the blood to be taken up by the liver to be broken down to bile acids = net decrease in serum cholesterol levels

Question 52

Drug interactions of cholestyramine (questran) and colestipol (colestid)? solution? ADRs

Answer 52

may inhibit GIT absorption e.g. digoxin, warfarin give drugs 2 hrs before or 4-6 hrs after cholestyramine or colestipol constipation, nausea, flatulence, reflux

Question 53

Summary of treatment guidelines according to calculated absolute risk of CVD

Answer 53

High: BP lowering and lipid lowering medications (unless clinically inappropriate or contraindicated) as well as lifestyle interventions Moderate: treated initially with lifestyle interventions. BP lowering and/or lipid lowering medications should be considered if their risk remains elevated after 3-6 months Low: lifestyle interventions