There are 3 main types of calcium channel blocker (CCB). Some CCBs act on calcium channels found in vascular smooth muscle and others act on calcium channels found in the heart. The first group we’ll start will are dihydropyridines and these are the class of CCBs that include: amlodipine, nifedipine and nimodipine – basically any that end in ‘-pine’. And these are highly specific to vascular smooth muscle. So, let’s quickly review how they work. Now, normally in a vascular smooth muscle cell the propagation of an action potential down the sarcolemma (muscle cell membrane) triggers the opening of voltage-gated Ca2+ channels which causes an influx of Ca2+ into the cell and a gradual rise in intracellular Ca2+ concentration. It is not entirely important to understand the pathway that leads to muscle cell contraction but essentially, when intracellular Ca2+ concentrations increase this causes the muscle cell to contract helping to keep the blood vessel constricted. Now, if somebody is given a CCB (particularly a dihydropyridine) which are specific to vascular smooth muscle this decreases the intracellular Ca2+ concentration leading to smooth muscle cell relaxation and as you can see, this causes vasodilatation of the blood vessel. Vasodilatation of arteries leads to a reduction in arterial blood pressure and this is why CCBs are used to manage hypertension (high blood pressure). Now as well as dilating systemic arteries CCBs can also dilate coronary arteries. In patients with angina there is typically an atherosclerotic plaque ± a thrombus that reduces blood flow distal to the lesion. Patients experience angina when the coronary artery undergoes vasospasm around the thrombus or the plaque, leading to reduced coronary blood flow and myocardial ischaemia. Certain CCBs help to dilate the artery and partly restore coronary blood flow. This is what resolves the ischaemic chest pain. So that’s one way in which CCBs can be used for prophylaxis for angina – by dilating coronary arteries. But they can also dilate systemic arteries. Systemic arterial vasodilatation and reduction in systemic vascular resistance reduces afterload, and therefore the work required of the left ventricle. This reduces the myocardial O2 demand of the heart, meaning the myocardium is less likely to become ischaemic. At this point, it’s useful to point out some of the side-effects of CCBs – particularly the dihydropyridines Vasodilatation of systemic arteries includes cerebral arteries. When these vessels expand, it can cause a slight rise in intracranial pressure and patients may experience a throbbing headache. (Throbbing because it is thought to be due to pulsation of the meningeal arteries) As with any drug that lowers BP there is also a risk of severe and potential symptomatic hypotension that may cause dizziness, syncope or falls particularly in older patients who have a reduced baroreceptor response. On the topic of the baroreceptor response one important thing to mention is that short-acting potent CCBs, which cause vasodilatation can sometimes cause a significant hypotension that results in a reflex tachycardia. When arterial BP drops the physiological response is to increase heart rate in order to maintain cardiac output. This is mediated by the baroreceptor reflex where baroreceptors present in the aortic arch and carotid bodies detect a drop in BP such as that which occurs when you stand up from sitting and they send signals to a part of the brain that increases sympathetic activation, resulting in a reflex tachycardia increased heart contractility and vasoconstriction. Patients with IHD experience chest pain on exertion because their heart rate and contractility increases to a point where the coronary arteries that supply the myocardium cannot deliver sufficient oxygen to the tissue. So short-acting, potent CCBs which cause vasodilatation and a resultant reflex tachycardia can be harmful as they may exacerbate angina in patients with ischaemic heart disease. Therefore for patients with high BP slow-acting forms of CCBs are often given to prevent the occurence of a reflex tachycardia so they can be given to patients with concomitant IHD. The next type of CCB is verapamil. Whilst verapamil has small effects on vascular smooth muscle Ca2+ channels it mainly inhibits Ca2+ channels present in the heart. Cardiac myocytes are the main cells involed in contraction in the myocardium and like smooth muscle cells they contract in response to changes in intracellular Ca2+ concentrations. So, when an action potential is sent down the sarcolemma of a cardiac myocyte it causes the opening of voltage-gated Ca2+ channels which allow an influx of Ca2+ into the cell and a sharp rise in intracellular Ca2+ concentration. This enables the cardiac myocyte to contract. Now if someone is given a CCB, like verapamil which is specific to cardiac Ca2+ channels this decreases the intracellular Ca2+ concentration leading to reduced contraction of the cardiac muscle cell. Reduced contractility of the heart is referred to as negative inotropy and this is why verapamil acts as a negative inotrope. Verapamil is not only specific to Ca2+ channels present in the cardiac myocyte, but it also acts on Ca2+ channels in the cardiac pacemaker cells particularly at the sino-atrial node (SAN) and the atrio-ventricular node (AVN). The SAN determines the rate of the heart so normally these pacemaker cells in the heart generate action potentials, firstly using Na+ channels and Ca2+ (T-type) channels to cause a slow depolarisation, followed by the opening of Ca2+ channels (L-type) which cause a more rapid depolarisation and hyperpolarisation which triggers the propagation of the action potential K+ outflux then causes repolarisation If somebody with a tachycardia takes verapamil this blocks some of their L-type Ca2+ channels, meaning it takes slightly longer to generate an action potential this slowing the heart rate. By slowing action potential conduction at the SAN this reduces heart – AKA negative chronotropy. This is why you may have heard the term: ‘rate-limiting CCBs’, of which verapamil is one. At the AVN and further down the conduction pathway, CCBs can reduce the velocity at which the action potentials travel and this reduction in conduction velocity is referred to as negative dromotropy. These 2 actions of verapamil in causing negative chronotropy and negative dromotropy explain why it is used to treat certain cardiac arrhythmias e.g. SVT. N.B. Patients with slowed conduction velocity e.g. heart block rate-limiting CCBs are absolutely contraindicated as they may cause cause complete (3rd degree) heart block. So, that pretty much covers the cardiac effects of CCBs, particularly verapamil which is specific to those channels. Finally we have diltiazem and that lies between dihydropyridines and verapmil in that its half specific to vascular smooth muscle cells and half specific to cardiac calcium channels This means diltiazem can cause hypotension so it can reduce BP, however it can also reduce heart rate as well, so thats good for patients with angina because it prevents that reflex tachycardia that was discussed earlier.