Overview
This lecture covers two classes of cardiovascular vasoactive drugs: L-type calcium channel blockers and organic nitrates. The calcium channel blocker half explains how L-type Ca2+ channels drive vascular smooth muscle and cardiac contraction, how the three chemical classes bind different sites on the channel to produce different tissue selectivity (vasoselective amlodipine versus cardioselective verapamil and diltiazem), and how that selectivity maps onto indications, adverse effects and pharmacokinetics. The nitrate half covers the endogenous NO pathway from L-arginine through cGMP to smooth muscle relaxation, how nitrodilators donate NO to mimic it, and the resulting effects on preload, afterload and myocardial oxygen demand in angina and heart failure, ending with tolerance, adverse effects and the fatal nitrate/PDE5 inhibitor interaction. The two classes meet at a shared theme: reducing cardiac work and oxygen demand by acting on vascular tone.
Calcium handling and L-type channels
Excitation-contraction coupling in the cardiac myocyte, as the lecture diagram shows it:
- Ca2+ enters through the sarcolemmal L-type Ca2+ channel (ICa), including at the T-tubule.
- This triggers Ca2+-induced Ca2+ release from the sarcoplasmic reticulum via ryanodine receptors (RyR).
- Released Ca2+ acts on the myofilaments to produce contraction.
- Ca2+ is removed by the SR Ca2+-ATPase (SERCA) taking it back into the SR, and by the Na+/Ca2+ exchanger (NCX) extruding it across the sarcolemma. Both processes require ATP.
The accompanying trace shows the temporal sequence: action potential (Em) first, then the Ca2+ transient ([Ca]i), then contraction.
Voltage-gated Ca2+ channel types are L, T, N, P/Q and R. The lecture concentrates on pharmacological blockade of L- and T-type.
- L-type (“long lasting”): abundant in cardiac and vascular smooth muscle and strictly important for both. Large sustained conductance, inactivate slowly, widespread in the cardiovascular system, responsible for the plateau phase (slow inward current) of the action potential, and may trigger release of internal Ca2+.
- T-type: found on neurons and pacemaker cells.
Calcium channel blockers: classes, sites and general mechanism
CCBs are chemically and pharmacologically heterogeneous. Their common property is that they all antagonise Ca2+ movement across cell membranes. Different binding sites on the channel result in tissue selectivity.
The three chemical classes:
- Dihydropyridines (vasoselective): amlodipine
- Phenylalkylamines (cardioselective): verapamil
- Benzothiazipines (cardioselective): diltiazem
The channel is built from α1, α2, β, γ and δ subunits with a disulphide-linked extracellular loop, and the lecture diagram marks three separate binding sites on it: an amlodipine site, a diltiazem site and a verapamil site, each at a different position, which is what produces the differing tissue selectivity.
General site and mechanism of action: inhibit Ca2+ influx through L-type calcium channels (LTCCs), acting on Ca2+ entry into:
- Vascular (arteriolar) smooth muscle: vasodilate by reducing vascular tone in coronary arteries and peripheral arterioles, but not veins
- Cardiac muscle: reduce force of contraction (negative inotrope)
- SA nodal tissue: reduce rate of contraction (negative chronotrope)
- AV node: decrease conduction velocity into the ventricles (negative dromotrope)
Cardiac actions of the cardioselective CCBs run down the conduction system in sequence: sinus node (impulse generation) gives heart rate down, with reflex tachycardia instead seen with high-dose amlodipine; AV node (impulse conduction) gives AV conduction down; ventricular muscle (electro-mechanical coupling) gives contractility down.
Tissue selectivity between CCBs
Relative potency (+ to +++++, ”-” = none):
| Drug | Peripheral and coronary vasodilation | Depression of cardiac contractility | Depression of SA node | Depression of AV node |
|---|---|---|---|---|
| Amlodipine | +++++ | + | + | - |
| Diltiazem | +++ | ++ | +++++ | ++++ |
| Verapamil | ++++ | ++++ | +++++ | +++++ |
What this shows: amlodipine is strongly vasoselective with minimal cardiac depression; verapamil is strong across all four effects (most broadly potent/cardioselective); diltiazem is intermediate, with its strongest effects on the SA and AV nodes.
Main therapeutic indications:
- Hypertension: dihydropyridines
- Arrhythmias: diltiazem
- Angina: verapamil/diltiazem
Class advantages: CCBs do not induce bronchoconstriction and do not adversely affect lipid profiles.
Amlodipine (dihydropyridine)
Mechanism: binds to and inhibits L- and T-type channels.
- Antihypertensive effect is due to vasodilation, acting primarily on arterial smooth muscle >> cardiac.
- Dilates peripheral arterioles, reducing total peripheral resistance (afterload) and cardiac O2 consumption.
- Little effect on most venous beds, so no effect on preload.
How vasoselectivity arises: amlodipine directly binds to and stabilises the inactivated state of the L-type channel. The channel cycles between hyperpolarised/closed (C), open (O) and inactivated (I) states via activation/deactivation, inactivation/depolarisation and recovery; amlodipine acts at the I state. Inactivated channels are more likely to exist in arterial smooth muscle because depolarisations there last longer than in cardiac muscle. The arterial smooth muscle channel also differs slightly from the cardiac isoform (alternative splicing of α1 subunits), which facilitates block.
Preload and afterload, as defined in the lecture:
- Preload: all of the factors that contribute to passive ventricular wall stress (or tension) at the end of diastole. Anatomically this is venous return (upper body via SVC, lower body via IVC) to the right atrium, ie blood volume.
- Afterload: all of the factors that contribute to total myocardial wall stress (or tension) during systolic ejection. Anatomically this is resistance to flow in the aorta and arteries (peripheral vascular resistance) plus the work required to open the aortic valve.
Caution in angina: high doses of fast-acting dihydropyridines can produce excessive peripheral dilation and marked hypotension, provoking reflex cardiac stimulation with tachycardia and increased inotropy, and so dramatically increased myocardial O2 demand. Some dihydropyridines are associated with peripheral oedema.
Amlodipine pharmacokinetics:
- Completely absorbed from the GI tract, unaffected by food; systemic availability ~64%.
- Slow onset of action, peak plasma 6-12 h.
- Steady state in ~7 days.
- Extensively hepatically metabolised, excreted as inactive metabolites mainly (~60%) in urine; only 10% excreted unchanged in urine.
- Once daily dosing achieves clinical BP control; renal failure has little effect on plasma levels of the active compound.
- Affected by CYP3A4 interactions.
Verapamil (phenylalkylamine)
Mechanism: binds the Ca2+ binding domain of the open cardiac L-type channel, and is therefore relatively cardioselective. It suppresses cardiac contractility, reducing cardiac work and oxygen consumption. It also acts as a vasodilator with selectivity for the arterial portion of the peripheral vasculature, and systemic vascular resistance is reduced usually without reflex tachycardia or hypotension.
How: verapamil interferes with Ca2+ ion binding, promoting the inactivated channel conformation and slowing channel recovery from inactivation. Binding increases the refractory period of the drug-bound channel, so channel inhibition increases at higher heart rates. Contrast with amlodipine, which acts at the inactivated state rather than the open state.
Verapamil is good for:
- Angina: reduces myocardial oxygen demand and reverses coronary vasospasm.
- Hypertension: antihypertensive effect from a combination of vascular and cardiac effects.
Verapamil is not good for:
- Heart failure, which should be avoided.
- Concomitant β-blocker use with a CCB, which produces a synergistic pharmacodynamic effect slowing heart rate and decreasing cardiac contractility.
- Existing bradycardias or conduction defects, where verapamil can further decrease heart rate and accentuate heart block.
Verapamil pharmacokinetics:
- Rapid and near-complete oral absorption.
- L-verapamil is metabolised rapidly by first pass, so the IV route avoids first pass and has a greater effect on cardiac action potentials.
- Substrate for CYP3A4 metabolism.
- Extensive first pass metabolism reduces bioavailability and is affected by liver viability, eg in aged or cirrhotic patients.
Diltiazem (benzothiazipine)
Mechanism: effective mainly by inhibiting Ca2+ influx during membrane depolarisation, primarily in cardiac and vascular smooth muscle. It interferes with the cardiac inward (depolarising) current in excitable tissue, which makes it suitable as an anti-arrhythmic. It is still not suitable for heart failure patients or in combination with β-blockers.
The SA node action potential (phases 4-0-3-4) carries the currents diltiazem is acting among: iK (repolarising, at the peak of the AP), iCa(L) (L-type calcium current, the phase 0 upstroke), iCa(T) (T-type calcium current) and if (funny current, phase 4 pacemaker depolarisation), with threshold marked. Diltiazem affects the depolarising Ca2+ currents.
Clinical uses:
- Antiarrhythmic in AF
- Angina, by reducing oxygen demand
- Reversal of coronary vasospasm
Pharmacokinetics: similar to other CCBs; highly absorbed (90%) and undergoes extensive first pass metabolism.
Drug interactions, both pharmacokinetic and pharmacodynamic. Diltiazem is affected by drugs acting on CYP3A4 in both directions, and is itself both a CYP3A4 inhibitor and a P-gp inhibitor, so it can also affect other drugs.
- CYP3A4 inhibition (eg erythromycin) leads to a potentiated effect of diltiazem: hypotension, bradycardia, AV block.
- CYP3A4 induction (eg rifampicin, carbamazepine) leads to loss of effect of diltiazem: hypertension, chest pain, supraventricular arrhythmias.
General adverse effects of CCBs
Mainly an extension of the drug action through relaxed vascular/smooth muscle, eg facial flushing and constipation.
Excessive dosing can lead to hypotension, bradycardia, AV block and heart failure.
Important
Do not use verapamil or diltiazem in conjunction with β-blockers: the combination causes cardiac depression. Caution also applies with other drugs.
Nitric oxide: physiology and the cGMP pathway
Endothelial-derived NO physiological functions:
- Relaxing vascular smooth muscle (vasodilation)
- Inhibiting platelet aggregation (anti-thrombotic)
- Inhibiting leukocyte-endothelial interactions (anti-inflammatory)
Many endogenous vasodilators (acetylcholine, bradykinin, histamine, ANP, ATP) act via NO production. NO is synthesised from L-arginine mainly by endothelial nitric oxide synthase (eNOS). NO is released from the endothelium and acts on vascular smooth muscle to cause vasodilation.
Endogenous synthesis, as the diagram sets it out:
- Ligand (ACh, bradykinin, ANP, histamine) binds its receptor on the vascular endothelial cell.
- Intracellular Ca2+ rises ([Ca2+]i up).
- Ca2+ combines with calmodulin to form Ca2+-calmodulin (eNOS activity is Ca2+ dependent).
- Ca2+-calmodulin activates inactive eNOS.
- Active eNOS converts L-arginine to citrulline + NO.
How NO causes vasodilation:
- NO, from the endothelium or from extrinsic sources such as nitrates, acts on vascular smooth muscle.
- It increases guanylate cyclase activity.
- cGMP is formed.
- cGMP activates cGMP-dependent protein kinases.
- These promote smooth muscle relaxation, by promoting Ca2+ efflux and uptake by SERCA.
- cGMP is terminated by phosphodiesterase (PDE5).
Nitrodilators: types and NO release
Nitrodilators mimic the vasodilatory actions of endogenous NO. They release NO in plasma or form NO within cells. Examples are sodium nitroprusside and the nitrates (eg GTN). Chemically, sodium nitroprusside is an iron-centred complex (Fe coordinated by five cyanide groups and one nitrosyl group, with 2 Na+ counterions, overall 2- charge), while an organic nitrate such as glyceryl trinitrate is a three-carbon backbone each carbon bearing an O-NO2 nitrate ester group.
Two routes of NO release:
- Enzymatic action, the organic nitrates: GTN, isosorbide di- and mono-nitrate. These require an enzymatic bioactivation step via a thiol/SH-containing intermediate, forming an S-nitrosothiol, before NO is released.
- Spontaneous releasing molecules: sodium nitroprusside, which releases NO directly.
Both converge on the vascular smooth muscle cell, where NO activates guanylate cyclase, raises cGMP and causes relaxation.
Types of nitrodilator by preparation:
- Glyceryl trinitrate (GTN), eg sublingual spray or sublingual/buccal tablet: treatment of acute angina, fast acting (2-5 min).
- Isosorbide mononitrate/dinitrate, oral delivery: longer onset and duration of action, more useful for long-term prophylaxis and management of coronary artery disease.
Haemodynamic actions and therapeutic applications of nitrates
Primary action:
- Main action is venous dilation, which reduces venous pressure and preload, and so reduces diastolic wall stress and cardiac work. Reduction of diastolic wall stress improves subendocardial blood flow, which is compromised in coronary artery disease.
- Systemic arterial dilation reduces afterload, enhancing cardiac output while at the same time reducing ventricular wall stress and oxygen demand.
Symptomatic relief of angina and MI, ie ischaemic pain due to decreased coronary flow and oxygen delivery to the heart:
- Nitrates vasodilate the venous circulation, so ventricular filling is reduced, reducing preload.
- They reduce systemic arterial resistance, reducing afterload and so LV wall stress.
- Reduced wall stress reduces cardiac work and consequently O2 demand, so chest pain is reduced.
- Collateral coronary circulation may be improved by reducing wall stress.
- At high concentrations nitrates may temporarily vasodilate large and medium sized coronary arteries (mainly epicardial), and may reverse vasospasm in Prinzmetal’s angina.
Acute or severe chronic heart failure:
- Reduction in afterload improves ejection fraction and stroke volume.
- Venous pressure reduction reduces oedema.
- Reduced O2 demand.
Other benefits:
- The antiplatelet effect of NO is beneficial.
- Acute hypertensive emergency, using sodium nitroprusside (ferricyanide) by infusion. Nitroprusside causes peripheral vasodilation by direct action on venous and arteriolar smooth muscle, reducing peripheral resistance. It is commonly given IV because of its rapid onset and short duration of action and is easily titratable to the desired effect, used in hypertensive crisis (eg aortic dissection) to produce controlled rapid hypotension in surgery. It must be given after IV administration of a beta-blocker to counteract the reflex tachycardia that occurs when nitroprusside is used alone; that response increases shear forces against the aortic wall and so increases dP/dt. The objective is to keep heart rate at 60-80 bpm. Nitroprusside is light sensitive.
Nitrate pharmacokinetics and routes
- Glyceryl trinitrate: 100% first pass metabolism, therefore given sublingually. Fast acting, effective in ~2 min, lasts about 30 min.
- Isosorbide mononitrate: ~100% bioavailability given orally, longer half life (2-6 h). Other forms of long acting nitrates have low bioavailability because of first pass metabolism.
- Isosorbide dinitrate: metabolised to form the mononitrate, with extended half-life.
Nitrates are given by many routes because these differ in onset of action and rate of elimination: sublingual tablet or spray, oral, topical ointment, transdermal patch, IV. The choice depends on the indication:
- Acute: something quick, eg sublingual or IV
- Chronic: needs to last longer, eg oral or transdermal
- Prophylaxis: sublingual, for predictable episodes
Tolerance: with frequent dosing nitrate tolerance develops and can decrease efficacy. The mechanism is not fully understood. Prevention is by providing a nitrate free interval, eg once-daily dosing regimens; with IV, dose escalation is required.
Nitrate adverse effects and drug interactions
Dose related effects, mainly due to vasodilatation, and may exacerbate hypotension:
- Flushing, headache, reflex tachycardia, palpitations
- Orthostatic hypotension, postural dizziness, nausea and occasionally bradycardia
- GTN may aggravate hypoxia by inhibiting hypoxic pulmonary vasoconstriction and worsening V/Q mismatch
- High doses of nitroglycerin may produce methaemoglobinaemia
- Topical nitrates may produce skin reactions
Facial flushing is illustrated in the lecture by a clinical photograph of pronounced bilateral facial erythema across the cheeks and chin.
Avoid abrupt nitrate withdrawal after prolonged use: it can cause rebound angina attacks or MI. Gradual withdrawal over 1-2 weeks is preferred.
Drug interactions: alcohol; other drugs that cause vasodilation or reduce blood pressure, including beta-blockers and calcium channel blockers; and phosphodiesterase inhibitors such as sildenafil.
PDE5 inhibitors
cGMP action is terminated by phosphodiesterases, of which PDE5 is one specific isoform, converting cyclic GMP to GMP.
Sildenafil (Viagra) inhibits PDE5, allowing NO-induced accumulation of cGMP and so sustaining relaxation. It is used to treat erectile dysfunction, producing sustained relaxation of penile vascular (corpus cavernosum) smooth muscle by preventing cGMP breakdown, and has also been trialled in the treatment of pulmonary hypertension.
Important
Sildenafil is contraindicated in conjunction with nitrates (a black box warning). In combination with GTN it exaggerates the impact of nitrates on cGMP, producing profound hypotension, and can be fatal.
Self-test
- Describe the steps of cardiac excitation-contraction coupling from L-type channel opening to removal of Ca2+.
- Distinguish L-type from T-type voltage-gated Ca2+ channels in terms of distribution and properties.
- Explain why the three CCB classes differ in tissue selectivity despite sharing a common property.
- List the four sites of CCB action on Ca2+ entry and state the effect at each.
- Rank amlodipine, diltiazem and verapamil for depression of the AV node, and state the relative potency of each.
- Explain how amlodipine achieves vasoselectivity.
- Define preload and afterload.
- Predict what happens when a high dose of a fast-acting dihydropyridine is given to a patient with angina, and explain why this is a problem.
- Describe verapamil’s mechanism at the channel and explain why its inhibition increases at higher heart rates.
- A patient on a β-blocker with known bradycardia and a conduction defect is prescribed verapamil. Explain what risk this creates.
- Contrast the clinical consequences of CYP3A4 inhibition versus CYP3A4 induction for a patient on diltiazem.
- Describe the steps of endogenous endothelial NO synthesis from ligand binding to NO release.
- Describe the steps by which NO causes vascular smooth muscle relaxation, and say what terminates the signal.
- Distinguish how sodium nitroprusside and organic nitrates release NO.
- Explain how nitrates relieve anginal chest pain.
- What is the onset and duration of sublingual GTN, and why can it not be given orally?
- Explain why nitrate tolerance matters and how it is prevented.
- List the dose-related adverse effects of nitrates.
- What is the risk of abrupt nitrate withdrawal after prolonged use, and what is preferred instead?
- Explain the mechanism of the sildenafil-nitrate interaction and its consequence.
- Both CCBs and nitrates are used in angina. Explain how each class reduces myocardial oxygen demand, and how their haemodynamic targets differ.
Answers
Reveal answers
- Ca2+ enters through the sarcolemmal L-type channel (ICa); this triggers Ca2+-induced Ca2+ release from the SR via ryanodine receptors; released Ca2+ acts on the myofilaments to produce contraction; Ca2+ is then removed by SERCA back into the SR and by the Na+/Ca2+ exchanger across the sarcolemma, both requiring ATP.
- L-type (“long lasting”) are abundant in cardiac and vascular smooth muscle, have large sustained conductance, inactivate slowly, are widespread in the cardiovascular system, produce the plateau phase (slow inward current) of the action potential and may trigger release of internal Ca2+. T-type are found on neurons and pacemaker cells.
- All CCBs antagonise Ca2+ movement across cell membranes, but they are chemically and pharmacologically heterogeneous and bind at three distinct sites on the channel (separate amlodipine, diltiazem and verapamil binding sites), and these different binding sites produce the tissue selectivity.
- Vascular (arteriolar) smooth muscle: vasodilation by reducing tone in coronary arteries and peripheral arterioles but not veins. Cardiac muscle: reduced force of contraction (negative inotrope). SA nodal tissue: reduced rate (negative chronotrope). AV node: decreased conduction velocity into the ventricles (negative dromotrope).
- Verapamil +++++, diltiazem ++++, amlodipine none (-).
- Amlodipine binds to and stabilises the inactivated state of the L-type channel. Inactivated channels are more likely to exist in arterial smooth muscle because depolarisations there are longer lasting than in cardiac muscle, and the arterial smooth muscle channel differs slightly from the cardiac isoform through alternative splicing of α1 subunits, which facilitates block.
- Preload is all of the factors that contribute to passive ventricular wall stress (or tension) at the end of diastole. Afterload is all of the factors that contribute to total myocardial wall stress (or tension) during systolic ejection.
- Excessive peripheral dilation and marked hypotension, which provokes reflex cardiac stimulation with tachycardia and increased inotropy, dramatically increasing myocardial O2 demand, the opposite of what is wanted in angina.
- Verapamil binds the Ca2+ binding domain of the open cardiac L-type channel and interferes with Ca2+ ion binding, promoting the inactivated conformation and slowing recovery from inactivation. Binding increases the refractory period of the drug-bound channel, so inhibition increases at higher heart rates.
- Concomitant β-blocker and CCB use is synergistic pharmacodynamically, slowing heart rate and decreasing cardiac contractility; with pre-existing bradycardia and conduction defects verapamil can further decrease heart rate and accentuate heart block.
- CYP3A4 inhibition (eg erythromycin) potentiates diltiazem, causing hypotension, bradycardia and AV block. CYP3A4 induction (eg rifampicin, carbamazepine) causes loss of diltiazem effect, with hypertension, chest pain and supraventricular arrhythmias.
- Ligand (ACh, bradykinin, ANP, histamine) binds its endothelial receptor; intracellular Ca2+ rises; Ca2+ combines with calmodulin to form Ca2+-calmodulin (eNOS activity is Ca2+ dependent); this activates inactive eNOS; active eNOS converts L-arginine to citrulline + NO.
- NO acts on vascular smooth muscle to increase guanylate cyclase activity, forming cGMP; cGMP activates cGMP-dependent protein kinases, which promote relaxation by promoting Ca2+ efflux and uptake by SERCA. The signal is terminated by phosphodiesterase, PDE5.
- Sodium nitroprusside is a spontaneous NO-releasing molecule and releases NO directly. Organic nitrates (GTN, isosorbide di- and mono-nitrate) require enzymatic action, via a thiol/SH-containing intermediate forming an S-nitrosothiol, to release NO.
- They vasodilate the venous circulation, reducing ventricular filling and preload, and reduce systemic arterial resistance, reducing afterload and LV wall stress. Reduced wall stress reduces cardiac work and O2 demand, so chest pain is reduced. Collateral coronary circulation may improve with reduced wall stress, and at high concentrations they may temporarily dilate large and medium epicardial coronary arteries and reverse vasospasm in Prinzmetal’s angina.
- Effective in about 2 minutes and lasts about 30 minutes. It cannot be given orally because it undergoes 100% first pass metabolism, hence the sublingual route.
- With frequent dosing tolerance develops and can decrease efficacy; the mechanism is not fully understood. It is prevented by providing a nitrate free interval, eg once-daily dosing regimens; IV use requires dose escalation.
- Flushing, headache, reflex tachycardia, palpitations, orthostatic hypotension, postural dizziness, nausea and occasionally bradycardia; GTN may aggravate hypoxia by inhibiting hypoxic pulmonary vasoconstriction and worsening V/Q mismatch; high doses of nitroglycerin may produce methaemoglobinaemia; topical nitrates may produce skin reactions. Effects are dose related and mainly due to vasodilatation, and may exacerbate hypotension.
- Rebound angina attacks or MI. Gradual nitrate withdrawal over 1-2 weeks is preferred.
- Sildenafil inhibits PDE5, which normally breaks cGMP down to GMP, so cGMP accumulates. Combined with a nitrate this exaggerates the nitrate’s impact on cGMP and produces profound hypotension, which can be fatal; sildenafil carries a black box contraindication with nitrates.
- CCBs reduce O2 demand by inhibiting Ca2+ influx: dihydropyridines dilate peripheral arterioles, reducing total peripheral resistance and afterload with little venous effect and so no change in preload, while verapamil and diltiazem additionally depress contractility, heart rate and AV conduction, reducing cardiac work, and both can reverse coronary vasospasm. Nitrates work through NO and cGMP, acting mainly on venous capacitance vessels to reduce preload and diastolic wall stress (also improving subendocardial flow), with arterial dilation reducing afterload at higher effect. So the CCBs act primarily on the arterial side and on the heart itself, whereas nitrates act primarily on the venous side.