Pharmacology of congestive cardiac failure and coronary ischaemic syndromes and lipid lowering drugs Flashcards
Differentiate systolic HF and diastolic HF
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
Demographic systolic and diastolic HF?
Systolic
- men > women
- > 65 years
Diastolic
- rare in young patients and those without hypertension Hx
- women > men
Risk factors for systolic (2) and diastolic (5) HF?
Systolic
1 hypertension
2 IHD
Diastolic
1 hypertension
2 CHD
3 diabetes
4 vascular disease
5 LVH
HF compensatory mechanisms (3)
RAAS
SNS
Vasopressin, BNP/ANP, others
Non pharmacological treatment measures (9)
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
List pharmacological treatment of systolic HF (9)
ACE inhibitors
Angiotensin II antagonists
Neprilysin inhibitors
Diuretics
Beta blockers
Spironolactone
Ivabradine
Digoxin
SGLT2 inhibitors
Action of aldosterone
increases sodium reabsorption and water
increase potassium excretion
Action of angiotensin II
Vasoconstriction (increase TPR)
Aldosterone release
Initial therapy systolic HF
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
What is a common side effect of ACE inhibitors
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
Process of ACE inhibitor administration
- initially, low dose and increase gradually to target dose
- ## monitor renal function and potassium levels (expect decreased renal function and increased potassium levels)
Example of ACE inhibitor
perindopril
Example of angiotensin II antagonist
candesartan
MOA angiotensin II blockers
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
ACE inhibitors and angiotensin II antagonists effect on renal function (renal vessels) compare to normal
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
What triggers release of natriuretic peptides - ANP/BNP/CNP?
Released when atrial and ventricular chambers of the heart are distended e.g. HF
What is the outcome of natriuretic peptides release? (5)
vasodilation
diuresis and natriuresis
inhibition of renin and aldosterone
reduce SNS
anti hypertrophic / fibrotic effects = reduce cardiac remodelling
What is neprilysin? What is an example of an inhibitor of this?
An enzyme that breaks down natriuretic peptides
Sacubitril - inhibits the enzyme
Actionof neprilysin inhibitors ?
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
Drug interaction: sacubitril and what other drug? Potential complication? Washout period?
Sacubitril = neprilysin inhibitor
AND
ACE inhibitor
Angioedema
- both ACE and neprilysin break down bradykinin
36hrs
Treatment and prevention of stable angina (3) + treatment of underlying conditions (3)
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)
3 examples of organic nitratyes
GTN
isosorbide mononitrate
isosorbide dinitrate
MOA nitrates (6)
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
Main effects of nitrates on CVS (3)
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
downside organic nitrates? solution?
too frequent or continuous use leads to…
development of tolerance = reduced therapeutic effect
nitrate free period restores activity
ADR organic nitrates (3) and drug interactions (1) explain
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
characteristics GTN (2) linked to practical outcome
1
- high first pass metabolism
- inactive if taken orally
therefore, sublingual administration
2
- tablets are relatively unstable
- spray avoids problems
What is the voltage gated calcium channel for contraction of smooth and cardiac muscle?
L type channels
Ca+ channel blockers and blood vessels
vascular smooth muscle relaxation = reduction in peripheral vascular resistance = drop BP
Artery specific!
Dilate coronary vessels
Reduce afterload
Examples of Ca+ channel blockers used in treatment of angina (4) and when used?
Amlodipine
Nifedipine
Diltiazem
Verapamil
Regular basis for prophylactic angina (not acute)
Side effects Ca+ channel blockers (5)
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
Angina Tx
Beta blockers: e.g. non selective vs cardio-selective
non selective e.g. propanolol
cardio selective
cardio selective (b1) e.g. atenolol, metoprolol
beta blockers MOA in treatment of angina (4)
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
Side effects beta blockers (4)
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
beta blockers and diabetes
may reduce some signs of hypoglycaemia and prolong hypoglycaemia
beta blockers and withdrawal
abrupt withdrawal may be dangerous and can result in:
- servere angina
- cardiac arrhythmias
- MI
- rebound hypertension in susceptible patients
Plasminogen activators: example, MOA, use, procedure and side effects
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)
Drug medications for acute and post treatment MI (with example)
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
What do lipoproteins transport?
cholesterol and triglycerides
Medications in control of lipids and examples
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
MOA statins (2), effect, side effects, contraindications and compliance
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
Atorvastatin/simvastatin: drug interaction and cytochrome P450 system
Outcome?
Statins = substrates
clarithromycin/erythromycin/itraconazole = inhibitors of CYP3A4
Elevated serum concentration statins
Consequence of dose response curve: statins?
Greater response required?
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
Ezetimibe: characteristics, moa, outcome, ADR
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
What transporter does Ezetimibe inhibit?
sterol transporter: Niemann-Pick C1-Like 1
Combination for lipid lowering drugs and describe dual action
Ezetimibe and statins
statins inhibit cholesterol synthesis and ezetimibe inhibits intestinal absorption or dietary and biliary cholesterol
What is PCSK9?
Proprotein convertase subtilisin/kexin type 9 (PCSK9) = proprotein convertase involved in degredation of LDL receptors in liver
= tags LDL receptors for destruction
Examples of PCSK9 inhibitors and MOA
alirocumab and evolocumab
bind to and inhibit the action of PCSK9 (which labels LDL receptors for destruction)
PCSK9 Inhibitors: outcome, half life?, administration, ADR, use
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
Fibrates: examples, moa and outcome, use, ADR
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
What are cholestyramine (name of drug is?) and colestipol (name of drug is?).
Moa and outcome
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
Drug interactions of cholestyramine (questran) and colestipol (colestid)? solution? ADRs
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
Summary of treatment guidelines according to calculated absolute risk of CVD
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
