FLUJO DE EFECTIVO

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

Figure 4.3 The therapeutic corridor must be aimed for and maintained, otherwise the side effects are too great or the symptoms are not controlled.

Plasma concentra tion Time Symptoms Side effects Therapeutic window

of Rang and Dale’s Pharmacology for more detail). Examples of common statins are simvastatin, atorvastatin and prav- astatin. 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 excre- tion. 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 spironol- actone, are weak diuretics but they inhibit the secretion of K+_{. These are particularly important to monitor as hyper-} kalaemia (too much potassium) can quickly become fatal.

The lungs

Bronchodilators that you will mostly come across are known as β2-adrenoceptor agonists. They act on the β2- adrenoceptors and therefore relax the smooth muscle, enhance the ciliary clearance of mucus and reduce the pro-inflammatory action of mast cells. They are usually given by inhalation but oral tablets and injection prepara- tions are also available. For acute episodes, salbutamol and terbutaline are used because of their fast-acting nature and reasonable duration of approximately five hours. Sal- meterol and formoterol are used as a dose rather than in acute situations as they take a little longer to act, but typi- cally last much longer – approximately 8–12 hours. Other bronchodilators include xanthenes, such as theophylline or aminophylline (relaxation of smooth muscle but action is unclear), cysteinyl leukotrine receptor antagonists, such as montrelukast, and muscarinic receptor antagonists, such as tiotropium or ipratropium (increases acetylcho- line expression and reduces mucus secretion).

Anti-inflammatory drugs, such as glucocorticoids, reduce the formation of pro-inflammatory cytokines and COX-2. Steroids also reduce the allergic response in asthmatics by inhibiting the specific cytokine that is responsible for regu- lating mast cells – the eventual result is fewer mast cells in the respiratory mucosa. They are given as a daily dose, commonly by inhalation – known as a ‘preventer’ (beclom- etasone, fluticasone, etc.). The full required response is only achieved after weeks of continuous use, hence the Na+_/K+ _{pump, thus increasing the twitch tension in cardiac}

muscle. It is given orally (i.v. in emergencies) but unfortu- nately 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 insuf- ficient 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 relax- ation of coronary arteries will enhance the oxygen delivery to the myocardium. GTN is given orally by spray or sub- lingual 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 vera- pamil 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 comp- licated 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 abun- dant 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

Pharmacology

Chapter

Aminoglycosides are a particular type of antibiotic, the most commonly seen are gentamicin, streptomycin and neomycin. Usually given to treat Gram-positive cocci in aerobic conditions, they inhibit the process of protein synthesis from within the bacterium. Unfortunately, the aminoglycosides are ototoxic, i.e. they damage the sensory cells of the cochlea and vestibular systems which is irreversible and will result in vertigo, ataxia and dizziness, etc.