What is pharmacology?

Simply, it is the study of medicines and their interaction with the body. Information is needed from the moment the drug enters the body and, indeed, how it got there, how it travels to the site of action, the physiological actions and their consequences, and how it is metabolised and excreted.

When talking about a drug, the typically accepted method is as outlined in Table 4.1.

This is all you need to know about ibuprofen for the adult in one paragraph, simple!

However, this chapter herein avoids using this method for two reasons:

Why would I, a physiotherapist or a student, want to know about this?

If you have a detailed understanding of the action of the drugs in question you may understand how long it takes to act, how some drugs may have multiple uses, why doses of drugs may differ significantly when taken via different routes and how the drugs may be altering the patient’s perception of pain. You will also appreciate how your practice impacts upon the uptake of drugs, for example the application of heat near a transdermal patch or the use of relaxation.

The clinical picture, as previously mentioned, needs to be complete; poor medical knowledge may lead the clinician to jump to erroneous conclusions.

These are all quite natural assumptions – ones that would be enforced by looking at the British National Formulary (BNF); however, metformin may be used for polycystic ovary syndrome, amitriptyline for sleeping problems and neuropathic pain, and gabapentin for neuropathic pain. So, when you read the past medical history: don’t be sold a kipper – understand the possibilities.

On the ward, you must know your patient’s past medical history; for example morphine may influence certain respiratory techniques; spinal anaesthetics may make one think twice about mobility assessments; a patient’s dizziness may be caused by certain antibiotics, for example streptomycin, etc.

It is common for people to go to their local shop and buy some over the counter (OTC) medication. However, they don’t always take these appropriately – you need to know if they are over- or under-dosing and advise appropriately. Also, are they contraindicated by any of the prescribed medication? Does the medical prescriber know what the patient is taking? This point is particularly pertinent when the patient is taking herbal medications – asking them to chat to their family doctor regarding this is always recommended.

Picking up on these pharmacological red flags is as important as picking up any other type of red flag. So, the next time a patient tells you that they are taking three 500 mg of paracetamol six times per day or St John’s wort to help with their depression, you might decide to advise the patient to discuss these issues with their general practitioner.

So, as a physiotherapist, you should care and the profession as a whole should embrace pharmacology for the sake of patient safety.

How may drugs get to their destination?

Drugs must be absorbed, i.e. they have to get from the outside in. The main routes of administration are:

The ionic status of a drug molecule is significant when considering membrane transit. To traverse the lipid bilayer, a molecule should be non-polar and unionised (without charge). As many drugs are weak acids or bases, this presents a complication. The pH of the environment will alter the ratio of ionised to unionised molecules, thus influencing the diffusion of the drug across the membrane. Simply, an environment (pH = acidic or basic) that pushes up the relative number of unionised species will increase its ability to permeate the membrane, thus more drug will be absorbed. If the drug is an acid, A^–, (e.g. aspirin) in an environment with a low pH (e.g. the acidic gastric juices of the stomach, pH = 3) it will gain a hydrogen ion, H⁺, and thus become unionised, AH, and cross the membrane. To clarify, an acidic drug is better absorbed in an acidic environment and a basic drug is better absorbed in an alkaline environment. It begins to stretch the scope of this chapter to delve any deeper, but for a better understanding see the Henderson-Hasselbalch equation and dissociation constant (kP_a) in any good pharmacology/clinical physiology book.

Blood flow may be influenced in your practice as a physiotherapist via heat, relaxation, massage, chest percussion, acupuncture, electrotherapy, etc. If the area to which the drug has been delivered has a good blood supply, for example gut, skin, mucosa, it will be absorbed more rapidly. Also, a drug that enters the systemic circulation but acts locally, for example ibuprofen, may have a higher concentration in the injured area if the blood flow is enhanced. It is always worth considering if you wish to influence this mechanism of drug absorption. An often-quoted scenario is the patient who has a transdermal morphine patch and is advised to apply heat to their shoulder. In doing so, the patient’s uptake of the drug was enhanced and experienced associated side effects.

The sympathetic response is part of the ‘fight or flight’ reaction. Part of the sympathetic effect is to decrease the gastric blood flow in favour of skeletal muscle and reduce peristalsis (this is the fight or flight response which is explained in exquisite clarity in Payne’s Handbook of Relaxation Techniques: A Practical Guide for the Health Care Professional). By encouraging relaxation you will allow the parasympathetic nervous system to resume control and allow normal absorption of drugs and food from the gut (Figure 4.2).

Inhaled drugs (including oxygen), bronchodilators and cystic fibrosis transmembrane regulator therapy require the lungs to be operational enough to utilise the vast surface area and be clear enough so that excessive secretions are not blocking the epithelial transport of the drugs. The surface area and the capillary network allow rapid uptake of the drug, which makes inhalational therapy very useful indeed. Localised drug actions, such as dilating bronchioles, are useful as the lungs also expel the drug rather effectively, thus minimising the systemic effects. This is arguably the biggest influence that a physiotherapist can have on drug delivery, as not only can you mobilise secretions, you can facilitate the musculature to enable deeper breaths and expand more lung.

Metabolism and excretion – the body gets hostile

Drug elimination is achieved by either metabolism (change of the molecular shape and function) or excretion (through urine, exhalation, faeces, etc.).

Once a drug has made its perilous journey from outside of the body to within, the body sets about changing it: the liver is the main site of metabolism. The main process of metabolism is mediated by cytochrome P450 – a large group of enzymes that alter the molecule of the drug and the product (metabolite) may be totally inactive, active in a completely different way or even more potent. Drugs that are given for the purpose of being metabolised into an active drug are called ‘prodrugs’.

A drug taken orally must pass into the portal circulatory system from the intestines. This is a direct line to the liver and therefore it undergoes pre-systemic metabolism (also known as first-pass metabolism). It is essential to understand that this happens as the amount of available drug in the plasma is a fraction of the amount given orally (the actual fraction is called ‘bioavailability’). The result is that the drug which undergoes extensive first-pass metabolism must be given in a higher dose orally than another route.

Other ways that the drug is eliminated is through excretion via urine. The clearance of a drug depends on many factors, including plasma binding, glomerular filtration, lipid solubility and pH, etc.

A note on dosing

All of the above needs to be calculated for efficacious delivery of the drug. The dose needs to be enough to ‘work’ in the therapeutic window but not too much to create side effects.

Figure 4.3 is a basic representation of delivery of i.v. morphine. An initial bolus dose is given until analgesia is achieved and then a top-up is given, perhaps by a patient-controlled analgesia device. This ensures that the plasma concentration is always in the therapeutic window.

It is important to convey the information to the patient in an accessible way because they may not understand why they need to take some medications regularly when they only occasionally get symptoms, and some medications as and when required.

The heart and vascular systems

You should be aware of cardiac physiology as part of your course. Normal function of the heart depends on the rate, rhythm, contractility, blood supply and autonomic control. Drugs acting on the heart fall into three main groups:

Anti-dysrhythmic drugs are typically applied during emergency cardiac events in adjunct to, or in place of, physical treatments, such as electrical cardioversion (e.g. defibrillator). They include drugs that block voltage-sensitive sodium channels thus inhibiting the action potential, for example lidocaine (a local anaesthetic) will associate and dissociate within the time frame of a normal heartbeat, thus normalising the rate. It essentially pauses all electrical activity in order to allow normality to resume. It is delivered i.v. as it has a very low bioavailability (see above). It is metabolised rapidly, giving a short half-life, thus allowing rapid alteration of plasma concentration to avoid the central side effects of drowsiness and convulsions. Another action is that of β-adrenoceptor antagonism which effectively reduces sympathetic expression on the heart by increasing the refractory period of the atrioventricular (AV) node (i.e. slowing the heart’s pacemaker). These drugs, such as propanolol and atenolol, have the unfortunate side effect of bronchospasm, fatigue and bradycardia, but in the absence of lung disease the risk is relatively low. Another class of anti-dysrhythmic drugs are calcium antagonists and are discussed below in more detail.

Increasing cardiac contraction may require poison. The extract of the foxglove (genus Digitalis) is used as a cardiac glycoside (e.g. digoxin). The effects are reduction of conduction, increased force of contraction and disturbance of rhythm. They enhance vagal activity and inhibit the Na⁺/K⁺ pump, thus increasing the twitch tension in cardiac muscle. It is given orally (i.v. in emergencies) but unfortunately the clinical risk of such drugs is the fine line between effectiveness and toxicity. It is excreted via the kidneys which poses a problem in patients with less effective renal function in terms of maintaining plasma concentrations at a safe level.

Angina is an important symptom which indicates insufficient oxygen supply for cardiac activity. It is controlled by either increasing perfusion or reducing demand (or both). Two important drugs that you may encounter are glyceryl trinitrate (GTN) and isosorbide mononitrate. These organic nitrates are metabolised into nitric oxide which initiates a cascade of effects resulting in relaxation of vascular muscles and therefore reduced central venous pressure (and thus preload and afterload of the heart), reducing stroke volume and metabolic demand. The relaxation of coronary arteries will enhance the oxygen delivery to the myocardium. GTN is given orally by spray or sublingual tablet (owing to extensive first-pass metabolism it is ineffective if swallowed). It acts within minutes and is rapidly metabolised by the liver and effectively eliminated in half an hour, hence its usefulness in acute situations. Isosorbide is similar, but is taken as a tablet and lasts longer in the system which makes it a useful prophylaxis for angina.

Calcium antagonists block entry of Ca²⁺ to the cell by acting on voltage gated channels. Drugs such as verapamil and diltiazem are used occasionally for their anti-dysrhythmia action, but this group of drugs is more commonly used for hypertension (e.g. amlodipine and nifedipine). The action on the heart is generally a complicated balancing act but the effects of the arterial and arteriolar smooth muscle is relaxation, thus reducing peripheral resistance (and hence blood pressure). They are well-absorbed and thus taken orally, for example amlodipine is taken once daily because of its long half-life.

The renin-angiotensin system is of significant importance in terms of fluid volume and vascular tone. Renin is released by the kidneys and converts angiotensinogen into angiotensin I (AT₁) which is converted by ACE into the potent vasoconstrictor angiotensin II (AT₂). The ACE is a epithelial membrane-bound enzyme particularly abundant in the lungs and is the site of action for the anti-hypertensive ACE inhibitors (e.g. ramipril and captopril) whose action is simply to block the active site of the enzyme, thus preventing the formation of AT₂.

Statins help reduce the levels of low-density lipoprotein cholesterol (LDL-C) which adhere to damaged blood vessel walls as part of the athrogenesis chain reaction which ultimately results in significant vessel damage. The action is rather complex and involves an understanding of the mechanism of cholesterol transport and lipoprotein metabolism that exceeds the scope of this chapter. Suffice to say, they reduce circulatory HDL levels (see Chapter 20 of Rang and Dale’s Pharmacology for more detail). Examples of common statins are simvastatin, atorvastatin and pravastatin. As a physiotherapist, it is worth remembering that statins commonly cause muscle pain, so additional medical history may be required relating to how long they have been taking statins: does the pain correspond? Usually, by alerting the prescriber, the problem may be resolved by reducing the dose or changing the drug.

Diuretics increase NaCl excretion and thus water excretion. They are used to reduce oedema and decrease the load of the circulatory system on the heart. The most potent of these drugs are loop diuretics (e.g. furosemide), which inhibit transit of Na⁺, K⁺ and 2Cl⁻ ions in the loop of Henle. They are typically given orally or i.v. in acute pulmonary oedema. Another example is the thiazides (e.g. bendroflumethiazide), which are more often used to treat simple hypertension. They act on the distal tubule binding to, and inhibiting, the Na⁺/Cl⁻ transport system which increases the loss of NaCl. A caution with these diuretics is the loss of K⁺ ions which is important to monitor in patients who also have cardiac conditions requiring digoxin. An unwanted side effect of thiazides is erectile dysfunction. Potassium-sparing diuretics, such as spironolactone, are weak diuretics but they inhibit the secretion of K⁺. These are particularly important to monitor as hyperkalaemia (too much potassium) can quickly become fatal.