Drugs used in IHD

Question 1

What are Beta blockers?

Answer 1

Competitive antagonists at beta receptors e.g. atenolol, bisoprolol, metoprolol and varvedilol.

B1 effect= negative inotropes and chronotropes, causing less myocardial oxygen demand and increased coronary artery perfusion time (more time in diastole), improving the balance of supply and demand.

All B blockers have some action at B2= side effect of bronchospasm.

Cardioselective B blockers have 20x the affinity for B1 (atenolol, bisoprolol, esmolol and metoprolol.

Question 2

Side effects of beta blockers

Answer 2

Bradycardia
Bronchospasm
Depression, fatugue
Heart block
Impotence
Peripheral vasoconstriction
Postural hypotension
Masking of hypoglycaemia
Potential to precipitate heart failure

Question 3

What cautions should be taken with beta blockers?

Answer 3

Caution with combination with verapamil or diltiazem due to the potential for developing worsening of HF, excessive bradycardia and/or AV block.

Should be continued throughout the perioperative period if a patient is normally on a beta blocker.

Question 4

Calcium channel blockers

Answer 4

Reduce calcium entry through L type calcium channels. L type channels are widespread in the CVS, notably in myocardial, nodal and vascular smooth muscle tissue. They are responsible for the plateau phase of the cardiac AP.

Question 5

Non-dihydropyridine CCBs

Answer 5

Heart-rate lowering CCBs: verapamil and diltiazem.

Risks of bradycardia, heart block and heart failure.

Diltiazem is better tolerated due to less negative inotropy.

Anaesthetic effects: additive myocardial depressant effect with volatile anaesthetics and prolongation of NDNMBs. To continue throughout periop period.

Question 6

Dihydropyridine CCBs

Answer 6

Amlodipine. Long half-life and good tolerability. As an antianginal it is effective with a Bblocker.
Ankle oedema.

Question 7

Nitrates

Answer 7

Vasodilation via the production of NO. NO activates guanylate cyclase, increasing cGMP and decreasing calcium available for contraction by preventing influx into the cell and increasing uptake by the smooth ER.

This decreases venous return, end diastolic pressure and wall tension. Reduces O2 demand and increases blood flow to subendocardial regions.

SEs: hypotension, headache (cerebral vasodilation) and flushing.

Can continue peri-op

Question 8

Contraindications to nitrate therapy

Answer 8

HOCM
Severe aortic stenosis
Coadministration of phosphodiesterase inhibitors: sildenafil
Coadministration of riociguat (stimulator of guanylate cyclase and treatment for pulmonary HTN)

Question 9

Glyceryl trinitrate

Answer 9

400mcg spray taken every 5 mins. If pain after 3 doses or 15 mins then needs attention

Question 10

Long-acting nitrates for angina prophylaxis

Answer 10

Isosorbide mononitrate, isosorbide dinitrate. 3rd line therapy.

Prolonged administration provokes tolerance with loss of efficacy. Need a nitrate free or nitrate low interval of 10 to 14 hours.

ISDN bioavailability depends on inter-individual variability in hepatic conversion and is generally lower than its metabolite ISMN which is 100% bioavailable.

Taper is discontinued to avoid rebound angina.

Question 11

Nicorandil

Answer 11

Nitrate derivative of nicotinamide with antianginal effects similar to those of nitrates or B Blockers. Acts via K channel activation.

Side effects include nausea, vomiting and ulcerations (oral/ intestinal)

Can continue peri-op

Question 12

Ranolazine

Answer 12

Selective inhibitor of the late inward Na current.

Side effects include dizziness, nausea and constipation.

Increases QTc

Question 13

Trimetazidine

Answer 13

Inhibits beta oxidation of fatty acids, improving myocardial glucose utilisation, optimising cellular energy production.

Trimetazidine appears to have a haemodynamically neutral side effect profile.

It remains contraindicated in Parkinson’s disease and motion disorders, such as tremor (shaking), muscle rigidity, walking disorders, and restless leg syndrome.

Question 14

Aspirin

Answer 14

Acts via irreversible inhibition of platelet COX-1 and thus thromboxane production, which promotes vasoconstriction and platelet aggregation.

COX-1 inhibition is consistent and predictable in adherent patients. No monitoring needed.

Withhold 7 days prior to theatre if needed.

Central neuraxial blockade is safe with aspirin monotherapy.

Question 15

Oral P2Y12 inhibitors

Answer 15

Block the platelet P2Y12 receptor, which plays a key role in platelet activation and the amplification of arterial thrombus formation.

Preferable to wait until completion of at least 6 months of DAPT before proceeding to surgery.

Question 16

Clopidogrel

Answer 16

Mechanism of blockade at P2Y12: Irreversible via active metabolites.

Cheap but variable metabolism due to variants in CYP2C19 (omeprazole inhibits this).

7 days prior to surgery.

Question 17

Prasugrel

Answer 17

Mechanism of blockade at P2Y12: Irreversible via active metabolites.

Faster onset than clopidogrel and is more predictable.

Increased bleeding risk.

7 days prior to surgery.

Question 18

Ticagrelor

Answer 18

Mechanism of blockade at P2Y12: Direct and reversible.

Most predictable P2Y12 inhibition. Rapid onset and offset.

Dyspnoea- short lived.
Metabolised by CYP3A and levels affected by inhibition or induction (clarithromycin, dlitiazem, verapamil and grapefruit juice).

5 days prior to surgery

Question 19

Statins

Answer 19

Competitively inhibit HMG CoA reductase, en enzyme involved in cholesterol synthesis. They reduce the risk of cardiovascular events independently of serum cholesterol concentration.

SEs: myalgia, myopathy, myotitis and rhabdo.

Question 20

ACE inhibitors

Answer 20

Prevent the formation of angiotensin 2, a potent vasoconstrictor.
Also prevent the breakdown of bradykinin, a known vasodilator. Excess bradykinin results in the common side effect of a dry cough.

Can precipitate AKI in those with renal artery stenosis and angioedema.

ARBs oppose the binding of angiotensin 2 to the angiotensin receptor.

Question 21

Neprilysin inhibitors

Answer 21

A newer class of related antihypertensives inhibit neprilysin.

Neprilysin is an endogenous enzyme that degrades vasoactive peptides such as bradykinin and natriuretic peptides. This leads to enhanced diuresis, natriuresis, myocardial relaxation, and antiremodelling and a reduction in renin and aldosterone secretion (Fig 1).

The first in class is LCZ696 (entresto), which combines valsartan and sacubitril (neprilysin inhibitor) in a single pill. It should be withheld on the day of surgery.

Question 22

Fibrinolytics- reperfusion

Answer 22

The treatment of acute STEMI is reperfusion, and this should be offered to patients within 12 hours of symptom onset.

This takes the following two forms:

Primary PCI is the treatment of choice if the time from diagnosis to stent is less than 120 minutes.
Fibrinolysis can also be used if the time to PCI is greater than 120 minutes (although the patient should receive fibrinolysis within 10 minutes of diagnosis).
The main risk to the patient is haemorrhagic stroke and this is more likely with advanced age, lower weight, female sex, previous cerebrovascular disease and systolic and diastolic hypertension on admission.

Question 23

Streptokinase

Answer 23

Streptokinase is an enzyme produced by group C beta-haemolytic streptococcus. It forms a complex with plasminogen, converting further plasminogen to plasmin, which in turn breaks down fibrin.

The main side effect is uncontrolled bleeding, however it is also incredibly antigenic.

It should not be readministered within twelve months due to the high risk of anaphylaxis.

Question 24

Alteplase

Answer 24

Recombinant tissue plasminogen activator. Activated only when bound to fibrin, converting plasminogen to plasmin.
Systemic fibrinolysis occurs to a lesser degree than with streptokinase.

Question 25

Absolute contraindications to fibrinolysis

Answer 25

1. Previous intracranial haemorrhage or stroke of unknown origin.
2. Ischaemic stroke within 6 months.
3. Recent major trauma/ surgery/ head injury (1 month).
4. GI bleeding within the last month.
5. Known bleeding disorder.
6. Aortic dissection.
7. Non compressible punctures in last 24 hrs eg. liver biopsy, LP

Question 26

Relative contraindications to fibrinolysis

Answer 26

1. TIA preceding 6 months
2. Oral anticoagulants
3. Pregnancy or within 1 week postpartum
4. Refractory HTN (S>180/D>110)
5. Advanced liver disease
6. Infective endocarditis
7. Active peptic ulcer
8. Prolonged or traumatic resuscitation