Many arrhythmia patients have concerns about their medication and the drugs they are prescribed. We have recently had presentations introducing us to how drugs work and what happens when they are in the body. Details of this presentation follow and we hope to add further information later. Our grateful thanks to Nick Butler for preparing the material and allowing it to be placed on our web site
Cardiac Drugs -Nick Butler, Pharmacy Manager, Gloucester Royal Hospital
1. How drugs work
Receptors. Many drugs act on receptors within the tissues, as either blockers or ‘antagonists ‘or as stimulators or ‘agonists’ of given physiological functions. The family of Beta-blockers are particularly relevant as they block the receptors that stimulate the heart to beat faster, thereby slowing the drive. These generally end in ‘ol’, and include atenalol, bisoprolol, sotalol. Other important blocking drugs are the ‘sartans’, which antagonise the action of angiotensin. These have been quite recently introduced and work by reducing resistance of the cardiovascular system to circulating blood and thus lowering blood pressure – candasartan is an example.
Neurohumoral. Neurohumoral transmitters are the natural chemicals within the body that allow nerve impulses to pass across junctions between tissues, and families of drugs have been developed that can either sustain the action of transmitters (allowing impulses to continue to pass), or to inhibit such chemicals, thereby inhibiting nervous transmission. These types of drugs are particularly effective for mental health disorders.
Enzymes. There is a broad family of drugs that act by inhibiting the actions of specific enzymes. Probably the most salient one for heart disease is aspirin. This acts by inhibiting an enzyme called cyclo-oxygenase, thereby affecting the production of agents in the tissues called prostaglandins and subsequently reducing the blood-clotting properties of blood platelets. ACE-inhibitors affect the action of Angiotensin Coverting Enzyme, thereby controlling levels of angiotensin. Statins, that are used to control cholesterol levels in the blood, have the function of inhibiting the action of one of the important enzymes in the synthesis of cholesterol by the liver.
Others. A variety of drugs act by blocking ‘channels’. There are numerous channels or molecular gateways through cell membranes , the purpose of which is allow a variety of agents such as calcium, sodium, potassium or hydrogen ions to pass. These are often known as ion pumps. Numerous drugs can block calcium- , sodium- or potassium- channels across heart cell membranes, thereby affecting polarization of membranes and thus the electrical impulses regulating heart beat. Amiodarone is a well-known example. Hydrogen-ion/proton pump inhibitors are also popular (eg omeprazole) for the control of stomach acidity.
2. What happens to drugs in the body
Absorption of drugs is very important, and generally depends upon the amount of food in the stomach. It is important to avoid ingestion of alcohol, antacids and specific dietary ingredients at the same time as taking medications. The instructions provided by the pharmacist on when to take a given drug in relation to meals are important to overall drug efficacy.
Distribution via the blood to the target tissues is a critical factor. Patients with heart failure (ie a compromised circulation may have slower distribution rates. Also, fluid balance and exercise can influence this.
Metabolism. Some drugs might need to be modified by the body to make them water-soluble. Others might need to dissolve in tissue membranes and build up their levels before they can exert their action. This is why some drugs need ‘build-up’ doses early on to become effective – warfarin is an example. Some drugs are rapid-acting, and so may require dosages of more than once-daily. Others are longer-lasting, resulting in different dosage prerequisites.
Elimination. Many drugs are eliminated via the urine, by mechanisms involving the liver, where they may first be deactivated, and then the kidneys, where they are filtered from the blood into the urine. Some drugs (amiodarone is well-known here) take many months to be excreted from the body. Some drugs also can influence negatively kidney function.
The overriding facts are that despite the tremendous advances made by pharmaceutical companies in recent years, there will always be a balance between desired efficacy and mitigation of adverse effects. Moreover, we are all different in the way we metabolise and clear drugs from our bodies – this is why it is important to iterate with one’s GP or cardiologist to identify appropriate drugs and dosages for a given arrhythmia.
3. Cardiac Drugs
The main way to control abnormal heart rhythms is by influencing the electrical system that controls the heart beat – the pathway from the sino-atrial node to the atrio-ventricular node and then the subsequent electrical conduction pathways around the ventricles - by interfering with the firing mechanisms that initiate heart muscle contractions (ie beating). Drugs can do this by reducing the conduction of electrical impulses through the heart, or by prolonging the recovery period of the heart muscle cells after they have contracted to make the heart beat (known as the refractory period). Either way, it is possible to slow down a heart beat that otherwise might rapidly increase to dangerous levels
A convenient way of addressing the various drugs available is via the Vaughan-Williams classification, introduced some 40 years ago. Though this classification has limitations (eg, several popular medicines fall into several of the categories), it is a useful means to describe the overall problems that arrhythmia patients encounter, and how clinicians try to control them with drugs.
Class I drugs control the natural body chemicals that constantly pass in and out of the heart muscle cells during heart beating – particularly sodium ions. These enter and leave the cells via ‘channels’. Controlling sodium through gateways in these channels reduces the ‘action potential’ or energy required to make the heart beat. Typical Class I drugs include dysopyramide, procainamide, flecainide and lignocaine.
Class II drugs control the parasympathetic nervous system, ie the release of hormones in response to stress, trauma or threats. These are also known as beta-blockers. They work by reducing the rate of electrical conduction through the heart muscle, lowering the rate of heart beat and blood pressure. Common examples are atenolol, bisoprolol, propranolol, carvedinol.
Class III drugs influence potassium passing through the heart muscle cells after contraction. These slow down the repolarisation of the cells, so that it takes longer before the muscle contracts again, thereby controlling fast rhythms. Amiodarone is an example (and this drug also falls into classes (I, II & IV), as is sotalol (which also has beta-blocking actions as well).
Class IV drugs influence the flow of calcium, thereby slowing conduction of electrical impulses through the heart and thus heart rate. Verapamil is an example.
Class V. This is a collection of drugs that work by a variety of other mechanisms to control heart rate, and include adenosine and digoxin.
Some of these drugs are also used in hospital tests to help the cardiologist to diagnose precisely the nature of an arrhythmia.
The cardiologist will choose the particular drugs, depending upon the characteristics of a patient’s arrhythmia (and every one is different!). Generally ICD patients will be on a cocktail of several drugs, which work in concert to reduce the chances of the heart speeding up and going into ventricular tachycardia (very fast heart beating, above 200 beats per minute) or ventricular fibrillation, where the muscle ceases to beat and circulate blood around the body and merely quivers.
Also, because of other underlying conditions, a person might have (such as: following heart attack; asthma, angina, diabetes; fluid retention, depression, etc.), the nature of the drug cocktail can be quite complex, and characteristic side effects are then more common (tiredness/fatigue/ sleep disturbance/black-outs or dizziness if jumping up too quickly, coldness of hand and feet). Under such conditions it is probably best to talk to the cardiologist about options available to the patient.
Of all of these drugs, amiodarone is seen as the ‘Domestos’ of the arrhythmia world, as it has a variety of very effective, important controlling functions. A point about its use is that it takes several weeks before it can exert its full function, as levels need to build up the membranes of the cells it influences. Moreover, when coming off the drug, it can take weeks before the last traces are lost from the body. Another drawback is that this also has some side effects. Amiodarone contains iodine and this can often affect the thyroid gland (either speeding it up or slowing it down) – the solution to this has been well worked out, however. Amiodarone can also cause visual disturbances, which usually disappear when one stops taking it. It is also a photosensitizer, meaning that exposed skin will go red when exposed to sunlight. The use of Factor 25/30 sun filter products (available on prescription) is recommended to all amiodarone users. In rare cases, amiodarone can also affect lung and kidney functions.
Recently, the manufacturer of amiodarone has launched a new drug, dronedarone, that has many of the functions of amiodarone, but does not contain iodine and so has fewer potential adverse side effects. This is currently under test for patients with atrial fibrillation and its results are promising. It is hoped that soon this will be licenced in this country for use with people with the propensity to go into ventricular fibrillation – ie the ICD recipients.
One thing that is being encouraged these days is for the ‘patient’ to become more involved with the clinical staff in decisions being made on medication. This is strongly influenced by the availability of information on the Internet, as well as the stories and articles that appear increasingly in the popular press, (but beware, some of which may be eye-catching and dramatic, but at the expense of inaccuracy). It is well-known, for example, that warfarin users should avoid certain fruits and vegetables (spinach; cranberries) as they contain agents that interfere with warfarin’s action on blood clotting; statin users are told not to take grapefruit juice, as this inhibits the ability to reduce cholesterol production; people with susceptible kidney function might be advised not to use ACE inhibitors.
One final note: though traditionally many arrhythmia patients who receive ICDs are also placed on drug therapy as well, in order to reduce the dependency upon the ICD, thereby prolonging its battery life and thus the time between device replacement, such is the sophistication that is now being built into ICD and similar device technology, it may be that dependence on all of such drugs might be reduced as the devices can exercise the control better.
These are fascinating times for the arrhythmia patient, and it behoves all of us to increase our understanding of what is happening, and how the treatments we receive do their job.
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