Section 6. Pharmacology
6.1: Pharmacokinetics and pharmacodynamics 392
6.2: Classification of drugs used in critical care 397
6.3: Drug calculations 419
6.4: Nurse prescribing 420
6.1 Pharmacokinetics and pharmacodynamics
Pharmacokinetic Process
Absorption
With the exception of IV drugs, drugs must be absorbed across a cell membrane before entering the systemic circulation. Oral drugs are absorbed in the upper small bowel because of its large surface area (Neal 2005).
■ Drugs absorbed from the GIT enter the portal circulation and some are extensively metabolized as they pass through the liver.
■ Drugs that are lipid soluble are readily absorbed orally and are rapidly distributed throughout the body water compartments.
■ Many drugs are bound to albumin, and equilibrium occurs between the bound and free drug in the plasma. The drug that is bound to albumin does not exert a pharmacological action.
■ Bioavailability – the fraction of the administered dose that reaches the systemic circulation – 100% in drugs administered IV.
Drugs administered orally have to overcome the physical barrier of the gut wall. The absorption process is affected by many factors:
■ Formulation
■ Stability to acid and enzymes
■ Motility of gut
■ Food in the stomach
■ Degree of first-pass metabolism (see later)
■ Lipid solubility
Distribution
Distribution around the body occurs when the drug reaches the circulation. It must then penetrate tissues to act. Factors that affect drug distribution:
■ plasma protein binding sites albumin – competition
■ specific drug receptor sites in tissues
■ regional blood flow
■ reduced in diabetes
■ enhanced flow, e.g. liver
■ lipid solubility
■ blood–brain barrier
■ membrane of GIT
■ highly water-soluble drugs, e.g. gentamicin
■ liver disease – low plasma protein levels
■ renal disease – high blood levels.
Metabolism
Metabolism of drugs occurs in the liver and involves a group of enzymes:
■ the microsomal mixed function oxidases (cytochrome P450 system of enzymes). These transform drugs into products that are more water soluble and easier to excrete. The majority of drug metabolism occurs in the liver. It involves two general types of reaction:
1. Phase I reaction – the biotransformation of the drug – oxidations are the most common reactions and these are catalysed by the mixed function oxidases.
2. Phase II reactions – drugs from phase I cannot be excreted efficiently by the kidneys and are made more hydrophilic by conjugation with compounds in the liver.
Metabolism also occurs in the gut lining, kidney and lungs. The majority of drugs that are metabolized are:
■ inactivated (propranolol)
■ activated (enalapril)
■ remain unchanged (atenolol)
■ the products of metabolism (metabolites) are longer acting than the original drug (diazepam).
Concomitant drug administration may influence metabolism:
■ phenytoin can induce liver enzymes – increasing the metabolism of other drugs
■ cimetidine can inhibit liver enzymes – reducing metabolism
■ these can have serious consequences if the patient is already on other drug therapies.
Other factors can affect drug metabolism:
■ age (including elderly and paediatrics)
■ alcohol consumption
■ disease (impaired liver function, dose reduction may be necessary for drugs metabolized in the liver), e.g. chlormethiazole
■ smoking
The first-pass metabolism
Drugs absorbed from GIT pass into the blood stream – some drugs are inactivated the first time they pass through the liver and this affects drug doses given by different routes. For example, propranolol, if given IV, is given in a dose of 1 mg, but if administered orally the dose is 40 mg.The first-pass metabolism can also affect possible routes of administration such as glyceryl trinitrate (GTN) as this cannot be given orally except by by-passing the liver, e.g. sublingually.
Excretion
Main route of excretion is the kidney in the urine. Excretion can occur in the faeces, whereby it first circulates from the small intestine to the liver then passes into the bile and into the GIT. If renal or liver impairment is present – reduced dose may be required (digoxin or gentamicin). Can be re-absorbed and re-enter the liver. Metabolism has been reversed (by enzymes present in the gut or by gut microflora) – converts the drug so that it can be re-absorbed. This can lead to a cycle known as the enterohepatic re-circulation and accounts for the prolonged effect of some drugs. Excretion varies with age and can lead to discoloration of the urine or faeces.
Frequent blood samples may be required for some drugs; in order for some drugs to be effective a certain blood level has to be obtained. Drugs are generally poisonous and at higher blood level concentrations can lead to serious consequences, even death. For all drugs there is also a minimum effective concentration, below which there will not be a therapeutic effect.
Make sure that you are aware of the patient’s drug blood levels before administering drugs in patients with liver and/or renal impairment 
Factors affecting excretion:
■ Renal failure
■ Blood flow to the kidneys
■ Glomerular filtration rate (GFR)
■ Urine flow rate and pH which indirectly alters:
● passive re-absorption
● active tubular secretion.
Pharmacodynamics
This is the study of the effects of drugs on the body or the biological processes. It is concerned with the pharmacological effect of drugs at their site(s) of action and considers mechanisms of action for both therapeutic and adverse effects of the drug.
■ Pharmacological responses are initiated by the molecular interactions of drugs with cells, tissues or other body constituents.
■ Drug molecules must exert some chemical influence on one or more cellular constituents to produce a pharmacological response.
■ To affect functioning of cellular molecules, the drug must approach the molecules closely.
■ Another requirement is that the drug must have some sort of non-uniform distribution within the body or the chance of interaction if the drug molecules are distributed at random would be negligible. This means that a drug must bind in some way to constituents of the cell to produce an effect.
■ For most drugs the site of action is at a specific biological molecule – the receptor. A receptor is the primary site of action of a drug.
■ Various types of receptor exist, and each responds to a different chemical or hormone, e.g. histamine, acetylcholine, adrenaline and dopamine.
■ Many endogenous hormones, neurotransmitters and other mediators exert their effects as a result of high-affinity binding or specific macromolecular protein or glycoprotein receptors in plasma membranes or cell cytoplasm.
■ When these receptors are bound to a certain chemical, this directs a change to occur in the cell, which then alters an activity of the cell.
The commonest ways in which drugs produce their effects
Not all drugs work via receptors for endogenous mediators and many drugs exert their effect by combining with other regulatory proteins and interfering with their function:
■ Ion channels – physical blocking of channel by the drug molecule – sodium channel blocking by local anaesthetics or by binding to accessory sites to facilitate opening of channels.
■ Enzymes – many drugs are targeted in this way:
● acting as competitive inhibitors, either reversible inhibitors (neostigmine on acetycholinesterase) or irreversible inhibitors (aspirin on cyclo-oxygenase), known as substrate analogues.
● many act as a false substrate – fluorouracil replaces uracil and blocks DNA synthesis.
● some drugs are pro-drugs and need enzymic degradation to convert them to the active form, e.g. diamorphine to morphine.
■ Transport proteins – drugs may interfere with the uptake of ions or small molecules across the cell membrane:
● cocaine interferes with the re-uptake of noradrenaline
● digoxin interferes with the sodium/potassium pump.
■ Other cellular macromolecules – these do not involve regulatory proteins:
● Chemical action, e.g. antacids (magnesium hydroxide)
● Drugs which act by physical action – osmotic diuretics (mannitol)
● Drugs which act by a physicochemical action – inhaled anaesthetics which act by altering the protein of cell membranes.
Most drugs produce their effects by acting on specific protein molecules usually located in the cell membrane. These proteins are called receptors and normally respond to endogenous chemicals in the body. A chemical that binds to a receptor is known as a ligand. Many drugs cause their effects by combining with these receptors and either are:
■ Agonists interact with a receptor mimicking the effect of a natural mediator – adrenaline is a beta-receptor agonist which stimulates the cardiac beta-receptors – increases heart rate
■ Partial agonists – maximal response falls short of the full response; block access of the natural agonist, e.g. pindolol, oxprenolol
■ Antagonists block a receptor to prevent such an effect – atenolol is a beta-receptor antagonist – slows heart rate by blocking the cardiac beta-receptors and reducing physiological stimulation. Selective but not specific (they act on more than one receptor – produce side effects) amitriptyline (tricyclic antidepressant) blocks cholinergic and histamine receptors which leads to dry mouth, blurred vision, constipation and drowsiness.
Potency of drugs
The interaction between a drug and the binding site of the receptor depends on the ‘fit’ of the two molecules. The closer the fit and the greater the number of bonds the stronger will be the attractive forces between them:
■ If a drug has a high potency it is a consequence of high affinity for a specific receptor.
■ Affinity is the tendency to bind to receptors.
■ Efficacy is the ability, once bound, to initiate changes that lead to effects.
■ If a drug is specific small changes in drug structure lead to profound changes in potency or cause a change from agonist to antagonist:
● Selectivity is the phenomenon that allows drugs to be useful; a drug must act selectively on particular cells and tissues.
● Specificity is reciprocal – individual classes of drug bind only to certain targets, and individual targets only recognize certain classes of drug.
● No drug acts with complete specificity – will only produce an effect.
■ Potency is independent of efficacy and efficacy is usually more important than potency when selecting a drug for clinical use.
■ The lower the potency of a drug and the higher the dose needed, the more likely that sites of action other than the primary one will assume significance:
● This is often associated with the appearance of unwanted side-effects, of which no drug is free – varies from trivial to fatal.
● Pharmaceutical companies try hard to manufacture drugs that are more selective and thus less dangerous to other tissues.
Mode of action
■ If the basic mode of action of a drug is via a receptor then it is likely that:
● It will be potent
● It will have biological specificity and may produce opposite effects on apparently similar tissue type
● It will have chemical specificity, and changes in the chemical structure of a drug molecule may have a large or small effect on its pharmacological activity
■ Specific antagonists abolish the effects of the drug on the tissue
■ If plasma concentration of the drug is too high (outside the therapeutic range) toxicity will occur
■ If plasma concentration is too low treatment will fail
■ The aim of treatment is to keep the plasma concentration within the therapeutic range
■ The plasma levels of certain drugs are measured in practice for these reasons
Drug interactions
Drugs are chemicals and may interact with one another. When this happens, a drug’s action may be:
■ Suppressed
■ Rendered completely inactive
■ Increased.
The therapeutic action of one drug may interfere with the therapeutic action of another – either cancelling out or amplifying effects
Combinations of drugs must be carefully considered to avoid drug interactions. As the number of medications prescribed for a patient increases (polypharmacy) so does the potential for drug interactions. With so many drugs given at the same time and so many drugs available, it is impossible to predict the interactions that can occur. Any adverse reaction needs to be reported to the appropriate authorities. The British National Formulary (BNF) contains lists of known interactions, and these should always be consulted before drug mixtures are administered. Some produce minor problems, others can be fatal. The types of drug interactions that occur are:
■ Outside the body – generally due to storage conditions, too much light, oxygen or moisture, interactions with containers whereby the chemicals contained within the drug are prone to degradation.
■ In the GIT – some food chemicals may react with drugs.
■ After absorption – where the most known interactions take place, usually when more than one drug is administered concurrently.
Pharmacogenetics
After taking into account all the issues related to pharmacokinetics and pharmacodynamics, and the age, level of nutrition, occupation, state of health of the patient, there are still the individual differences in drug metabolism. This is described in terms of a person’s genetic make-up. How some patients metabolize or inactivate drugs and facilitate their excretion is to a large extent determined by inheritable traits – our genes. In addition, different ethnic groups show different pharmacokinetic profiles for a number of drugs.
There are many issues to consider when administering individual patient therapy.
A good understanding of the fundamental principles of drug therapy should help critical care nurses to optimize patient care. An increase in critical care nurses’ contribution to multidisciplinary care in relation to drug administration/therapy is currently being explored.
6.2 Classification of drugs used in critical care
The classification of drugs (Table 6.1) is massive and is thus too huge to do it justice. The classes of drugs outlined in this section are brief. However, there are many texts (Galbraith et al 2007, Neal 2005; BNF, updated twice per year) that go into much more detail regarding the drugs used in critical care. For further information it is recommended that you use these and/or other sources for more in-depth information.
| Class of drug | Action of drug class |
|---|---|
| Anti-emetic | Nausea, vomiting |
| Anti-coagulant | Prevents or reduces clotting of the blood in blood vessels, e.g. heparin or warfarin. |
| Anti-platelet | Decreases platelet aggregation – aspirin and dipyridamole. |
| Antihypertensive | Used to reduce blood pressure – examples are beta-adrenergic antagonists (beta blockers) such as atenolol, ACE inhibitors such as captopril, calcium channel blockers, e.g. nifedipine and diuretics such as bendroflumethiazide. |
| Analgesic | Relieves pain. |
| Hypnotic | Induces sleep – dependency – producing, e.g. triazolam. |
| Anxiolytic | Relieves anxiety – used to alleviate acute and severe anxiety states, e.g. diazepam. |
| Anaesthetic | Insensible stimuli – loss of sensation. Local anaesthesia – sensory nerve impulses are blocked and the patient remains alert. General anaesthesia – loss of consciousness and patient is unaware of and unresponsive to painful stimulation, can be maintained by inhalation of anaesthetic gases. |
| Antibiotic | Anti-bacterial – length of treatment depends on the nature of the infection and the response to treatment, e.g. penicillin, ampicillin, erythromycin, metronidazole and vancomycin. |
| Antacid | Neutralizes the acidity of the gastric juice, given in dyspepsia, gastritis, peptic ulcer and oesophageal reflux. |
| Anti-arrhythmic | Given to prevent or reduce cardiac irregularities of rhythm, e.g. digoxin, amiodarone. |
| Antihistamine | Blocks the release of histamine – released in an allergic reaction, used for insect bites and stings to reduce irritation and inflammation. |
| Antispasmodic | Relaxes smooth muscle as found in the gut – useful in abdominal colic and distension as in irritable bowel disorder. |
| Antidepressant | Relieves depression – these may be tricyclics such as amitriptyline and imipramine or monoamine oxidase inhibitors. |
| Antipyretic | Reduces temperature – such as aspirin, paracetamol. |
| Anti-epileptic | Epilepsy control – to prevent the occurrence of seizures, only one drug and combinations to be avoided, e.g. phenytoin, sodium valproate, carbamazepine. |
| Bronchodilator | Dilates airways – relaxes the bronchial smooth muscle and causes dilatation of the air passages, e.g. salbutamol, ipratropium bromide. |
| Cytotoxic | Used in the treatment of cancer, e.g. methotrexate and vincristine. |
| Corticosteroids | Synthetic steroid hormones synthesized by the adrenal cortex – anti-inflammatory and suppress the immune system. |
| Diuretic | Increases urine output – best given in the morning, e.g. furosamide, bendroflumethiazide, reduces the circulating volume in heart failure and hypertension. |
| Fibrinolytic | Digests fibrin in blood clots – used to dissolve the blood clot and restore circulation to the heart following myocardial infarction, e.g. streptokinase. |
| Immunosuppressive | Suppresses the immune system and used in autoimmune disorders or following transplantation to reduce rejection of the donor organ, e.g. azathioprine. |
| Inotrope | Affects the contraction of the heart muscle, e.g. digoxin. |
| Laxative | Promotes a softer or bulkier stool or encourages a bowel action and given for constipation, e.g. lactulose |
| Miotic | Constricts the pupil of the eye – used in glaucoma to open up drainage channels, e.g. pilocarpine. |
| Muscle relaxant | In conjunction with general anaesthetics to produce complete muscle relaxation, prevent muscles from contracting, stop respiration for ventilation, e.g. atracurium and vecuronium. |
| Neuroleptic | Acts on nervous system; antipsychotic. |
| Vasodilator | Dilates blood vessels reducing BP. |
| Hypoglycaemic agent | Glucagon to treat hypoglycaemic states. |
| Hyperglycaemic agent | Insulin for intravenous and subcutaneous use in type I diabetes. Oral drugs for use in type II diabetes. |
Adrenergic Drugs
These drugs are within the domain of sympathetic nervous system function. In the peripheral nervous system only the sympathetic postganglionic fibres are adrenergic (a nerve that releases noradrenaline). Adrenaline affects adrenergic receptors. Stimulants that induce effector responses of a ‘flight’ or ‘fight’ character are sometimes referred to as sympathomimetics (drugs which mimic the sympathetic nervous system), while blocking agents prevent these responses and are termed sympatholytics (drugs which block or inhibit sympathetic stimulation).
Sympathomimetics (adrenergic receptor stimulation/agonist)
■ Direct-acting – they act directly on beta 1 adrenoreceptors – adrenaline, noradrenaline, isoprenaline, dopamine, dobutamine (Table 1.11):
● Increase rate and force of contraction of the heart, increase cardiac output and exact positive chronotropic and inotropic effects
● Increase level of lipid concentration in blood and convert into energy
● Depress digestion and gastrointestinal motility
● Release renin into the renal blood, resulting in the formation of angiotensin II, potent vasoconstrictor and increase glomerular filtration rate
■ Indirectly acting – by causing a release of noradrenaline from the stores at nerve endings (amphetamines)
● Preventing re-uptake of noradrenaline (tricyclic antidepressants – amitriptyline)
● Preventing destruction of noradrenaline – monoamine oxidase inhibitors
● Preventing the release of noradrenaline – guanethidine
● Causing nerve ending to synthesize a false transmitter – methyldopa
■ Prolonged use of local anaesthesia – causes vasoconstriction of the skin; this delays re-absorption from the injection site and prolongs the anaesthetic action
■ Acute anaphylactic reactions – gross swelling of the skin and mucous membranes; intramuscular adrenaline is effective as an emergency measure
■ Heart block – beta 1 agonists –isoprenaline
Adrenoreceptors (adrenergic receptor blocking/antagonists)
The uses of adrenoreceptor antagonists
■ These drugs act selectively on alpha and beta receptors, they do not usually act on both
■ Hypertension – phentolamine, phenoxybenzamine, prazosin and terazosin
Beta receptor antagonists
Block the beta receptors in the heart, peripheral vasculature, bronchi, pancreas and liver:
■ At rest they have little effect on heart rate, cardiac output or arterial pressure; they reduce the effect of excitement or exercise on these
■ Reduce coronary blood flow, but less than oxygen consumption; oxygenation is improved, important in angina
■ Reduce the force of cardiac contraction and slow the heart rate; can precipitate heart failure in patients with weak contractility
■ Anti-hypertension effect – produce a gradual fall in blood pressure over a period of several days
■ Increased airways resistance – dangerous in asthmatics and can produce severe asthma attacks.
Cardioselective beta-blockers
There is some selectivity possible now with cardioselective beta-blockers; however, these are not absolutely cardiospecific and still block the beta 2receptor to some degree. They have less effect on airway resistance but are not free from this effect. There is still a risk of inducing bronchospasm.
■ These drugs include:
● Atenolol
● Betaxolol
● Bisoprolol
● Metoprolol
● Acebutolol
■ Some beta-blockers have intrinsic sympathomimetic activity (ISA) – they are partial agonists, which stimulate as well as block the receptor, e.g. oxprenolol, pindolol and acebutolol cause less bradycardia and less coldness of the extremities.
■ Some beta-blockers are lipid soluble, some are water soluble (excretion by the kidneys reduced in renal impairment).
Some drugs are photosensitive so ensure that you take adequate precautions when they are being infused 
Use of beta-blockers:
■ Hypertension – may be combined with other drugs
■ Cardiac dysrhythmias – ventricular arrhythmias
■ Cardioselective beta-blockers should be used in diabetics as others may precipitate hypoglycaemic attacks
■ Angina – reduce cardiac work and so oxygen consumption
■ Thyrotoxicosis – propranolol
■ Anxiety states
■ Glaucoma
■ Migraine
Parasympathomimetic drugs
Action similar to that of the parasympathetic nervous system and act on cholinergic receptors (Table 6.2):
| Neurotrans-mitter | Receptor type | Major locations | Effects of binding |
|---|---|---|---|
| Acetylcholine | Nicotinic | Centrally in autonomic ganglia and the neuromuscular junction of skeletal muscles | Feeling of relaxation and well being; an increase in skeletal muscle tone; release of adrenaline and noradrenaline. |
| Muscarinic sub-types | Centrally and peripherally:
M 1 – brain and higher cerebral functions;
M 2 – stomach;
M 3 – visceral smooth muscle and exocrine glands
|
Pupil constriction; relations of GIT spincters, increased GIT motility and secretions; promotion of micturition and defaecation; promotes glycogenesis, gluco-neogenesis, increases insulin secretion; promotes tears; bronchoconstriction and mucus production. |
■ Carbachol – used in urinary retention, causes contraction of the bladder muscle.
■ Anticholinesterases potentiate the transmission of antcholinesterase at the neuromuscular junction:
● Physostigmine prevents the breakdown of acetylcholine by inhibiting the enzyme cholinesterase, causes contriction of the pupil, used in glaucoma, use replaced in myasthenia gravis by neostigmine.
● Neostigmine – synthetic substance, direct effect on the neuromuscular junction of voluntary muscle and less effect on the eye.
■ Muscarinic antagonists: a weak central stimulant but at high doses cause a tachycardia – atropine
General Anaesthetics
These drugs lead to the absence of sensation associated with a reversible loss of consciousness. Anaesthesia depresses all excitable tissues, including central neurones, cardiac muscle, smooth and striated muscle. However, it is possible to administer anaesthetic agents at concentrations that produce unconsciousness without unduly depressing the cardiovascular and respiratory centres of the myocardium:
■ Thiopental and propofol – unconsciousness occurs within seconds and is maintained by the administration of an inhalation anaesthetic such as halothane.
■ Halothane – unconsciousness maintained by this inhalation anaesthetic, replaced by less toxic agents such as desflurane and isoflurane
■ Nitrous oxide at concentrations of up to 70% oxygen is a widely used anaesthetic agent – causes sedation and analgesia but not sufficient alone to maintain anaesthesia.
Muscle relaxants
Anaesthetists in theatre and in intensive care use muscle relaxants to relax skeletal muscles during surgical operations and to prevent movement and breathing during mechanical ventilation. These drugs are given intravenously and distributed in the extracellular fluid.
Neuromuscular blocking agents compete with acetylcholine for muscle receptors but do not initiate ion channel opening; these include:
■ Pancuronium – long duration of action, has an atropine-like action on the heart and can lead to a tachycardia
■ Vecuronium depends on hepatic inactivation, and recovery takes 20–30 minutes; popular for short procedures
■ Atracurium – duration of action 15–30 minutes, only stable when kept cold and at low pH, at body pH and temperature it decomposes spontaneously in plasma and does not depend on renal or hepatic function for its elimination, good for patients with renal or hepatic disease.
Depolarizing blockers act on acetylcholine receptors, but trigger the opening of ion channels and are not reversed by anticholinesterases; the only drug of this type used is:
■ Suxamethonium – rapid onset and very short duration of action (3–7 minutes).
Always check that your patient is adequately sedated before administering a muscle relaxant 
Anxiolytics and Hypnotics
These groups of drugs are used for sleep disorders (hypnotics) and acute anxiety states (anxiolytics) dominated by the benzodiazepines which:
■ Induce sleep when given in high doses
■ Provide sedation and reduce anxiety when given in low, divided doses during the day.
Benzodiazepines used as hypnotics:
■ Short acting – temazepan or zopiclone preferred to avoid daytime sedation
■ Long acting – nitrazepam
■ Adverse effects – drowsiness, impaired alertness, agitation and ataxia
■ Dependence – a withdrawal syndrome may occur including anxiety, insomnia, depression, nausea
■ Intravenous infusion – diazepam and lorazepam
■ Midazelam is used as an intravenous sedation during endoscopic, dental and ventilation procedures
■ All have an amnesic action and patients have no recollection of an unpleasant experience.
Antidepressants
Used in patients with depression and anxiety; they are anxiolytic and do not cause dependence.
■ Amitriptyline
■ Moclobemide useful in phobic anxiety disorders
■ Citalopram – serotonin re-uptake inhibitor effective in panic disorders
Analgesic Drugs
Many medical or surgical conditions, e.g. wound(s), can stimulate pain receptors and lead to severe/moderate/mild pain. The role of the critical care nurse in this situation (if applicable) is to assess the level of pain using a pain assessment tool and administer prescribed medication. However, when there is severe pain together with other changes observed, narcotic analgesia may be prescribed. These drugs mimic endogenous opioids by causing prolonged activation of the opiate receptors. The body produces endogenous opioids which suppress centrally controlled pain mechanisms:
Centrally acting analgesics all act upon receptors within the CNS; there are at least four different receptors for these compounds (Table 6.3).
| Endogenous opioid | Receptor type | Major locations | Effects of binding |
|---|---|---|---|
| Not known | Delta | Limbic system – emotions | Behavioural changes Hallucinations |
| Enkephalin | Epsilon | Hippocampus Amygdala | Dysphoria Psychotic effects |
| Dynorphin | Kappa | Hypothalamus | Hypothermia Miosis Sedation Analgesia |
| Endorphin | Mu | Dorsal horn of spinal cord Thalamus | Analgesia Respiratory depression Euphoria |
This produces analgesia, respiratory depression, euphoria and sedation.
Assessment tools and patient controlled analgesia may be added as soon as the initial emergency is over.
Morphine
Morphine is an analgesic that can be used for severe pain, such as the pain following the injury caused by a coronary thrombosis and MI. Morphine not only relieves pain but also relieves the anxieties related to it and gives a sense of euphoria. The analgesic effects start within 20 minutes when given by subcutaneous injection and within 10 minutes of intravenous infusion. Morphine has a short half-life of about 4 hours, so frequent dosing is required. Therefore, morphine has been superseded by a more potent agent, diamorphine, which requires smaller doses.
Codeine
Related to morphine but less potent, codeine is partly converted into morphine in the liver. Approximately 10% of the population is lacking the enzyme responsible for this conversion (Galbraith et al 2007); this explains why some patients gain little pain relief from high doses of codeine. Thus codeine is not commonly used on its own, but it is prescribed as an antidiarrhoeal and enhances the analgesic activity of paracetamol and aspirin and is often combined with them.
Diamorphine
Depresses the exaggerated respiratory effort, reduces the patient’s distress and helps to redistribute some of the increased cerebral blood volume to the peripheries. Diamorphine is generally given intravenously for a rapid effect; orally it is less effective as it is almost completely converted into morphine. Diamorphine is generally the analgesic of choice for severe chest pain in MI or by subcutaneous syringe driver if oral MST can no longer be tolerated.
Pethidine
The analgesic effect of pethidine is not as strong as morphine, but it is widely used for moderate to severe pain as it causes less respiratory depression. Useful in labour as it does not suppress uterine contractions, but fetal respiratory rate can be affected. Pethidine is not recommended for long-term use because of its metabolite norpethidine, which can lead to serious convulsions.
Other narcotic analgesics
■ Methadone – used as a morphine or heroin substitute as it produces fewer withdrawal symptoms
■ Fentanyl citrate – commonly used as a neuroleptoanalgesic due to its short duration of therapeutic action, allows patients to recover quickly from the drug’s effects and popular in the use of maintenance of ventilation
Naloxone
Pure antagonist at the opioid receptors and can be used to reverse narcotic analgesia in the case of overdose. The result can be quite dramatic, but the drug has a half-life of only 1 hour, and therefore in cases of overdose the patient needs to remain under observation for a considerable time.
NSAIDs (non-steroidal anti-inflammatory drugs)
This group of drugs has in various degrees analgesic, anti-inflammatory and antipyretic actions. NSAIDs have the ability to inhibit cyclo-oxygenase and the resulting inhibition of prostaglandin synthesis is responsible for their therapeutic effects. Unfortunately, these drugs frequently result in gastric intestinal irritation.
■ Mild analgesic – ibuprofen and aspirin
■ Moderate analgesic – diclofenac and naproxen
■ Strong analgesic – indometacin
Other analgesic drugs available
■ Paracetamol – no anti-inflammatory action, usually tried first
■ Codeine and dihydrocodeine – stronger than paracetamol but more side-effects
■ Paracetamol + codeine phosphate (co-codamol, co-dydramol, co-proxamol)
■ Morphine sulphate for acute pain over short periods; MST (modified release formulation of morphine) not suitable for acute pain (12 hourly)
Inotropes
The positive inotropic effect of these drugs is to increase the contractility of the cardiac muscle and so improve cardiac function and increase cardiac output (Table 6.4).
| +, increased; =, unchanged; –, decreased; CI, cardiac index; DA, HR, heart rate; MAP, mean arterial pressure; SVR, systemic vascular resistance. | ||||||||
| Drug | DA | Alpha | beta-1 | beta-2 | HR | MAP | CI | SVR |
|---|---|---|---|---|---|---|---|---|
| Dopamine
Low dose
Moderate dose
High dose
|
+++ +++ +++ |
+ ++ +++ |
+ ++ ++ |
0 + + |
+/= + ++ |
+/= + ++ |
+/= + + |
+/= + ++ |
| Dobutamine | 0 | + | +++ | ++ | + | +/=/− | ++ | =/− |
| Dopexamine | ++ | 0 | + | +++ | ++ | =/− | + | =/− |
| Noradrenaline
Low dose
High dose
|
0 | ++ +++ |
+ + |
+ + |
−/= − |
+ ++ |
+/=/− =/− |
++ +++ |
| Adrenaline
Low dose
High dose
|
0 | + ++ |
+ + |
+ + |
−/= − |
+ ++ |
−/=/+ −/= |
++ +++ |
| Isoprenaline | 0 | 0 | + | +++ | ++ | − | + | − |
| Milrinone | 0 | 0 | 0 | 0 | + | − | ++ | − |
| IABP | 0 | 0 | 0 | 0 | = | +/=/− | + | − |
Inotropic drugs work by increasing intracellular calcium concentration by a variety of methods; the force generated by cardiac muscle is proportional to the amount of intracellular calcium present during contraction.
■ Dopamine – naturally occurring neurotransmitter, beta 1 receptors in cardiac muscle:
● increases cardiac contractility of heart with little effect on heart rate
● low dose acts on dopamine receptors in the kidneys and increases renal perfusion
● increased dose causes vasoconstriction and exacerbates heart failure
● increases systolic pressure
● titrated to blood pressure
● dosage is calculated in μg/kg/min
● the drugs should be changed if no satisfactory results.
■ Dopexamine – artificial, primarily effective on beta-receptors, improves renal blood flow, increases mean arterial blood pressure and cardiac output.
■ Dobutamine – artificially formulated beta 1 agonist; inotropic effect without increase in heart rate and makes the heart work faster, has a more inotropic effect than chronotropic effect, sometimes used in cardiogenic shock.
■ Isoprenaline – increases heart rate and contractility, used for short-term treatment of heart block and bradycardia.
■ Adrenaline – increases systolic blood pressure, heart rate, force of contraction.
■ Noradrenaline – contraction of all smooth muscles and receptors, causes reduced vascular compliance, increases central venous pressure and systemic vascular resistance and blood pressure.
■ The only inotrope used in cardiac failure is digoxin, which is also an anti-arrhythmic drug:
● Increases the force of cardiac contraction in the failing heart
● Particularly effective in heart failure caused by atrial fibrillation
● Can lead to drug toxicity
Ensure that you take extra care when changing infusions carrying inotropic drugs as there may be a considerable drop in your patient’s blood pressure – consider using a two-pump approach 
Anti-hypertensive Drugs
Angiotensin-converting enzyme (ACE) inhibitors
■ These drugs act by inhibiting the renin–angiotensin system by preventing the conversion of angiotensin I to angiotensin II by the angiotensin-converting enzyme therefore preventing the formation of angiotensin II. This process is overactive in heart failure:
● Captopril
● Enalapril
● Cilazapril
● Lisinopril
● Perindopril
● Quinapril
● Ramipril.
■ They also vasodilate which reduces the strain on the failing heart by reducing the pre-load and the afterload.
■ Proven beneficial in heart failure:
● Dyspnoea reduced
● Exercise tolerance increased
● Hospital care reduced
● Life expectancy is increased in moderate to severe heart failure.
■ Other potential value:
● Reduce left ventricular dilatation post MI
● Reduce the incidence of arrhythmias post MI
● May improve coronary blood flow at the same time as decreasing oxygen demand.
Adverse effects:
■ Hypotension
■ Renal damage – regular monitoring is essential
■ Cough – dry productive, worse at night
■ Skin rash
■ Aplastic anaemia – rarely.
Vasodilator Drugs
These drugs act directly on the smooth muscle of the blood vessels or block the calcium channels in the muscle membrane.
Calcium antagonists
These have actions on the heart by increasing the refractory period of the heart, lengthening the period of time calcium remains in the cardiac cell during depolarization. Relieve angina mainly by causing peripheral arteriolar dilatation and afterload reduction. Increasingly replacing hydralazine in the use of hypertension. The drugs include:
■ Nifedipine in patients who have a related bronchospasm or left ventricular failure
■ Diltiazem – only a slight negative inotropic effect; less potent than nifedipine
■ Verapamil – used in SVT in addition to angina.
Can lead to flushing, dizziness, headaches and oedema of the ankles.
Nitrates
Main effect is to cause peripheral vasodilation, especially in the veins, by a direct action on the vascular smooth muscle. A patient suspected of an MI or suffering from angina may be commenced on a nitrate infusion.
Glyceryl trinitrate (GTN)
Generally short-acting and lasts for about 30 minutes:
■ The aim is to diminish the infarction ischaemic zones and thus limit the size of infarct.
■ GTN is a rapid-acting drug that causes coronary vasodilatation and ventilation promoting more oxygen-rich blood to move towards the heart.
■ GTN by dilating both veins and arteries reduces the filling pressure of the heart as well as the resistance against which the heart has to pump; consequently, myocardial work and oxygen demand is reduced.
■ GTN suffers a very large first-pass effect when given orally and is thus given by other routes:
■ It has a very short duration of action, but onset of action is rapid – within 2 minutes.
■ There are nitrates that take longer to have an effect, e.g. onset of action is later than 30 minutes:
● Isosorbide mononitrate
● Isosorbide dinitrate.
Mechanism of action
■ Act by relaxing smooth muscle by converting nitrates into nitric oxide, which is a powerful vasodilator
■ Have their main effects on cardiovascular system
■ Veins are dilated more than arteries and this reduces preload
■ There is a reflex tachycardia but even so oxygen demand is reduced
■ Systemic arteries are dilated – reduces afterload
■ The collateral coronary arteries are dilated resulting in a better blood flow to the heart
■ In atherosclerosis of the coronary vessels, nitrates do not cause dilatation of these vessels; they do reduce myocardial oxygen demand by reducing cardiac output and arterial pressure, but more than this they divert the blood to the ischaemic area by dilating the collateral circulation
Adverse effects
■ The vasodilator effect of GTN can produce a headache and flushing – these can be severe
■ Palpitations and hypotension due to a reduction in peripheral resistance and may cause syncope – blood pressure should be continually monitored via an arterial line. If blood pressure falls the infusion rate can be altered according to the condition of the patient.
Nitroprusside
This is used for severe hypertension crisis; it acts directly by causing vasodilatation of smooth muscle, quick acting, reduces systemic vascular resistance of both veins and arteries.
Diuretics
Cause increased secretion of urine in the kidneys. They all produce their effect by decreasing the re-absorption of water and electrolytes by the renal tubules and thus allowing more to be excreted. The kidney filters about 100 litres of fluid per day, but only 1500 ml is lost as urine.
Useful in the following conditions:
■ Heart failure
■ Hypertension
■ Nephrotic syndrome
■ Cirrhosis of the liver
■ Acute pulmonary oedema
■ Oedema formation from heart disease and cirrhosis
■ Hypercalcaemia and occasionally in hyperkalaemia.
Types of diuretic
■ Water – (atrial natriuretic factor peptide) fails to work in heart failure.
■ Osmotic diuretics – mannitol increases osmotic pressure in filtrate and causes more water to be excreted, used in:
● Forced diuresis in drug overdose
● Cerebral oedema
● Maintain diuresis during surgery.
■ Xanthines – theophylline, caffeine, a weak diuretic action.
■ Thiazide diurectics – relatively weak diuretics, inhibit sodium/chloride re-absorption in the early segment of the distal tubule, chlorothiazide, hydrochlorothiazide, bendroflumethiazide. May lead to hypokalaemia, increased uric acid and cholesterol levels.
■ Loop diuretics – most powerful of all diuretics – capable of causing 15–25% of the sodium filtrate to be excreted. Action similar to thiazide, but sodium/chloride re-absorbtion takes place in the ascending loop of Henle, a very rapid onset of action but of fairly short duration, powerful and can cause electrolyte imbalance, dehydration and hypovolaemia, e.g. furosamide, bumetanide, ethacrynic acid.
■ Potassium-sparing diuretics – weak when used alone, but cause potassium retention, often given with a thiazide or loop diuretic to prevent hypokalaemia.
● Triamterene, amiloride – work on the distal tubule and the collecting ducts.
● Frumil is a combination of furosamide and amiloride.
● Spironolactone – an aldosterone antagonist.
Always check a patient’s urine output after giving diuretics and monitor their electrolytes 
Antiarrhythmic Drugs
The rhythm of the heart is generally determined by the pacemaker cells in the sinoatrial node, but it can be disturbed in many ways leading to discomfort to heart failure or even death (Neal 2005):
■ Serious arrhythmias, e.g. ventricular tachycardia, are associated with heart disease
■ Supraventricular arrhythmias arise in the atrial myocardium or atrioventricular node
■ Ventricular arrhythmias may be caused by ectopic focus, which starts firing at a higher rate than the normal pacemaker
■ Re-entry mechanisms can occur, where action potentials are delayed for some pathological reason, re-invade nearby muscle fibres leading to a loop of depolarization.
Many antiarrhythmic drugs are local anaesthetics or calcium antagonists, but they are generally classified into those which are effective in:
■ Supraventricular arrhythmias
● Adenosine – hyperpolarizes the cell membrane in the atrioventricular node and, by inhibiting the calcium channels, slows conduction in the atrioventricular node.
● Verapamil acts by blocking calcium channels and has powerful effects on the atrioventricular node; has a negative inotropic action; largely replaced by intravenous adenosine because it is safer.
■ Ventricular arrhythmias
● Lidocaine – given IV to treat ventricular arrhythmias, usually after an MI.
■ Both types
● Disopyramide – lengthens the refractory period of the action potential of cardiac cells; used to prevent recurrent ventricular arrhythmias; a negative inotrope and can cause hypotension and aggravate cardiac failure.
● Quinidine – use is limited due to the danger of cardiac and frequent non-cardiac side-effects.
● Flecainide – strongly depresses conduction in the myocardium; has a negative inotropic action.
● Amiodarone – blocks several channels; is often effective when other drugs have failed.
Ensure that patients receiving cardioactive drugs are being cardiovascularly monitored, e.g. ECG 
Bronchodilators
Beta-agonists
These drugs act on the beta-adrenergic receptors in bronchial smooth muscle. Currently available beta-agonists include salbutamol, formoterol (eformoterol), terbutaline, salmeterol and fenoterol. They are used both in asthma and in chronic obstructive pulmonary disease.
Stimulation of these receptors results in:
■ Bronchodilatation
■ Increased skeletal muscle excitability
■ Vasodilation of blood vessels in the brain, heart, kidneys and skeletal muscle
■ Stabilization of the membrane of mast cells, preventing the release of inflammatory mediators.
Beta 2-adrenergic receptor agonists:
■ are used to dilate the bronchioles and help breathing
■ are associated with cardiac acceleration, leading to a tachycardia, and may compromise heart function
■ are generally given by inhalation as this route causes less marked beta 1 cardiac stimulation
■ can be given systemically (oral or parenteral route) but this causes greater cardiac stimulation and systemic beta 2-agonists should therefore be used with caution.
Adverse effects include:
■ A fine tremor
■ Palpitations
■ Peripheral vasodilatation resulting in hypotension and headache
■ Increase in blood glucose level
■ Warm limbs
■ Decrease in serum potassium levels.
Anti-muscarinic agents
Muscarinic (M 3) receptor agonists are synthetic atropine-like agents, e.g. ipratropium bromid (Atrovent) and tiotropium, and block muscarinic receptors associated with the parasympathetic stimulation of the bronchial air passages. Onset is slower than with beta 2-agonists (maximum effect in 30–60 minutes) but the duration of the effect is prolonged (3–6 hours) (Galbraith et al 2007).
Adverse effects include:
■ Dry mouth
■ Constipation
■ Reduced gastric juice secretion
■ Urinary retention
■ Blurred vision.
Methylxanthines
These include theophylline and aminophylline and induce bronchodilation through a mechanism that bypasses interaction with an extracellular receptor, either adrenergic or cholinergic (Galbraith et al 2007). Methylxanthines are phosphodiesterase inhibitors that prevent the degradation of cyclic adenosine monophosphate (cAMP), which results in an increase in bronchial smooth muscle cell activity, leading to bronchodilatation.
Adverse effects:
■ Mainly related to nervous system overstimulation – insomnia, anxiety, nervousness, epigastric distress, nausea, vomiting and tachycardia
■ More serious and in higher doses – convulsions and dysrhythmias.
Glucocorticoids
Effectively increase the airway calibre in asthma; steroids act by reducing bronchial mucosal inflammatory reactions (e.g. oedema, mucus hypersecretion) and by modifying the allergic reactions of asthma and anaphylaxis. These include:
■ Hydrocortisone – can be given orally, more commonly used intravenously (shock, status asthmaticus) or topically (eczema)
■ Prednisolone – orally for inflammatory and allergic diseases.
Have many adverse effects:
■ Metabolic effects such as redistribution of fat to the face and trunk, tendency to bruise easily, disturbed carbohydrate metabolism may lead to hyperglycaemia and occasionally diabetes, wasting and weakness, osteoporosis
■ Fluid retention
■ Adrenal suppression
■ Infections due to immunosuppressive effects of glucocorticoids
■ Peptic ulceration.
Antihistamines
The term antihistamine is usually reserved for the H 1 blockers or antagonists (Table 6.5). Used in the treatment of:
| Receptor | Receptor abb. | Major locations | Effects of binding |
|---|---|---|---|
| Histamine | H 1 | Smooth muscle and exocrine glands and respiratory tract. | Used in the treatment of allergies and prevent release of histamine from mast cells, acid production. |
| H 2 | Parietal cells of the stomach. | Prevent the release of acid from the stomach H 2 antagonist. |
■ Allergies
■ Nausea
■ Symptoms of the common cold
■ Influenza
■ Topical treatment for skin allergies, or insect bites.
A common side-effect of these drugs is drowsiness; patients should be advised not to drive or operate hazardous machinery:
■ Astemizole, cetirizine, loratadine and terfenadine are less likely to cross the blood–brain barrier and lead to drowsiness
■ Promethazine and timeprazine are so good at promoting drowsiness that patients commonly use them as sedatives
■ Doxylamine – used in combination with analgesia.
Antibacterial Drugs
Antibiotics work in three different ways:
1. Inhibit nucleic acid synthesis:
● Sulphonamides
● Trimethoprim
● Rifampicin
2. Inhibit cell wall synthesis:
● Penicillin – benzylpenicillin, flucloxacillin, broad-spectrum (amoxicillin, ampicillin)
● Cephalosporins – cefadroxil (urinary tract infections), cefuroxime (prophylactic in surgery), ceftazidime and ceftriaxone
● Vancomycin – septicaemia or endocarditis; can cause renal failure and hearing loss.
3. Inhibit protein synthesis:
● Aminoglycosides – gentamicin, amikacin, netilmicin, streptomycin
● Tetracyclines
● Macrolides – erythromycin and clarithromycin
● Chloramphenicol
Antifungal and Antiviral Drugs
Fungal infections may be superficial or systemic, the latter occurring in immunocompromised patients such as AIDS patients.
Viruses are small and replicate by entering living cells as they lack independent metabolism and can therefore only reproduce themselves within living host cells. Vaccines are generally the major method for controlling viral infections (poliomyelitis, rabies, measles, mumps, rubella). Some effective antiviral drugs have been developed and act in two different ways:
1. Stop the virus entering or leaving the host cell
● Amantadine
● Zanamivir
2. Inhibit nucleic acid synthesis
● Aciclovir – selectively antiviral
● Antiretroviral drugs – used to suppress the replication of human immunodeficiency virus (HIV) in patients with AIDS.
Drugs Used on the Gastrointestinal Tract
Anti-emetic
■ Metoclopramide – a dopamine antagonist that stimulates gastric emptying, used to treat nausea and vomiting.
■ Prochlorperazine is a phenothiazine that is widely used as an anti-emetic; less sedative than chlorpromazine.
Antacids
These are all weak bases and rapidly combine with hydrochloric acid and neutralize it.
■ Antacids – raise the gastric luminal pH, provide effective but short relief of many dyspepsias and symptomatic relief in peptic ulcer, gastritis and oesphageal reflux and heartburn. These are usually basic compounds of:
● Aluminium hydroxide
● Magnesium carbonate
■ Omeprazole – can produce virtual reduction in acid production by blocking the H +/K +-ATPase, which pumps H +ions out of the parietal cells
Histamine H 2 receptor antagonists
■ Histamine H 2-receptor antagonists (Table 6.5) – cimetidine and ranitidine block the action of histamine on the parietal cells and reduce acid secretion.
■ Cimetidine has been found to slow down metabolism of many other drugs, resulting in enhancement of their effects.
■ There are others such as nizatidine and famotidine.
Sucralfate
A combination of sugar sucrose and aluminium compound, which only acts in the presence of acid. Once ingested it forms a thick paste-like substance which adheres to the gastric mucosa protecting it from acid. Effective in healing duodenal ulcers, with minimal side-effects, but can lead to constipation.
Antispasmodics
Cholinergic antagonists – pirenzepine with a relatively selective action on the gut – directly relax smooth muscle and reduce gastrointestinal motility, and are used to reduce spasm in irritable bowel syndrome (antispasmodics).
Antidiarrhoeal Drugs
■ Infectious diarrhoea is a common cause of illness or a complication of some interventions, e.g. antibiotics, enteral feeding
■ Antimotility drugs are used to provide symptomatic relief
■ Loperamide or imodium are generally used; codeine also reduces bowel motility
Laxatives
Laxatives are used to increase motility of the gut and encourage defaecation:
■ Bulk laxatives – increase the volume of intestinal contents stimulating peristalsis
■ Stimulant laxatives – increase motility by acting on mucosa or nerve plexuses, which can cause damage in prolonged use
■ Lubricants – promote defaecation by softening and/or lubricating faeces and assisting evacuation.
Anti-epileptics
Epilepsy is a chronic disease in which seizures result from the abnormal discharge of cerebral neurones. The seizures are classified empirically and the correct classification is important as it determines the choice of drug treatment. The aim of treatment is to control the seizures with one drug:
■ Phenytoin or carbamazepine – will control tonic-clonic and partial seizures
■ Valproate is an alternative agent
■ The benzodiazepines, e.g. phenobarbital and clonazepam also can be used but have a sedative effect.
Antiplatelet Drugs
In the instance where there is some formation of clotting disorder, it is possible to use drugs that interfere with blood coagulation processes and thus reduce or prevent further thrombus formation.
Aspirin
■ Used to reduce platelet aggregation, thus reducing the chances of increasing or causing clots in critical care patients with MI or at risk of MI and stroke.
■ Works by inhibiting the production of thromboxane produced by the platelets from prostaglandin precursors, which is a powerful inducer of both aggregation of platelets and vasoconstriction.
■ Can be used as an adjunct to fibrinolytic therapy and is effective in reducing the incidence of death in acute MI.
Fibrinolytic Agents
Critical care nurses may be involved in initiating, giving, assisting in the administration of or receiving patients from accident and emergency following fibrinolytic therapy. This treatment is given intravenously via infusion to break down clots that have led to the occlusion of coronary arteries and the MI.
Current fibrinolytic agents patients can receive include streptokinase, altepase (t-PA), anisoylated plasminogen-streptokinase activator complex (APSAC), and urokinase. Streptokinase is often the fibrinolytic therapy of choice. The use of APSAC and urokinase is restricted due to cost. Although their mechanism of action differs, they all function by producing active plasmin which dissolves fibrin clots and promotes vasodilatation.
Streptokinase
Streptokinase is an exotoxin from beta-haemolytic streptococci and a potent plasminogen activator, and when given in large doses as a short infusion it accelerates the conversion of plasminogen to plasmin. This breaks down fibrin within the clot forming soluble fibrin degradation products (FDP), leading to the dispersal of the thrombus.
The treatment must preferably be performed as soon as possible after the onset of infarction and can re-establish blood flow in approximately 3 minutes. It is administered via intravenous infusion over a period of 1 hour. Streptokinase has a half-life of approximately 20 minutes.
Patients may have antibodies to streptokinase from a streptococcal infection or if they have received streptokinase previously. There is a general agreement that streptokinase should not be administered again within 2 years. In 1–2% of patients, signs of an allergic reaction may develop, such as urticaria, wheezing or even hypotension and anaphylaxis.
Streptokinase is contraindicated in patients with severe hypertension and in those with a history of blood disorders or stroke. The main risk factor with treatment is the risk of bleeding as fibrinolysis is increased.
Altepase (t-PA)
Altepase is an endogenous enzyme found in vascular endothelium. Altepase activates plasminogen and is used to dissolve clots, salvage myocardium and hinder new thrombosis formation to help reduce mortality. The sooner it is given after the start of symptoms, the more likely it is to reduce the size and severity of the MI. The plasma half-life is 5–8 minutes and unlike streptokinase repeated dose is possible. Altepase is the agent of choice for patients who have previously received streptokinase.
When coronary flow is successfully restored by fibrinolytic therapy, ST segment elevation returns to baseline and creatinine kinase (CK) falls as it is washed out by reperfusion. Fibrinolytic therapy is generally followed by a course of intravenous heparin to prevent immediate vessel re-occlusion. However, in some cases re-perfusion after thrombolysis may fail to occur. Fibrinolytic failure has been associated with more complex plaques and with more extensive haemorrhage into the plaque. Other options after failed thrombolysis include:
■ rescue angioplasty
■ insertion of an intra-aortic balloon pump (only if there is severe left ventricular failure)
■ repeat thrombolysis (Davies & Ormerod 1998).
Fibrinolytic therapy is often followed by the administration of beta-adrenergic blockers. Early beta-blockade reduces mortality and decreases the incidence of ventricular fibrillation (VF), and infarct size. However, these drugs are contraindicated in severe heart failure, hypotension, bradycardia, second- or third-degree heart block or asthma.
There is an ongoing debate regarding which of the fibrinolytic therapies is more beneficial. Research evidence suggests that it does not necessarily matter which fibrinolytic agent is given compared to how soon it is administered. Fibrinolytic therapy can cause haemorrhage, particularly in females, older patients, those with low body weight and hypertension, and with fibrinogen depletion. Blood transfusion, heparin reversal and other corrective measures such as cryoprecipitate, fresh frozen plasma (FFP) and platelet transfusion may be needed.
Anticoagulants
Heparin
Heparin works faster than warfarin because it binds to plasma anti-thrombin III, which is a natural anticoagulant in the blood; in so doing it inactivates thrombin, plasmin and other serine proteases of coagulation, including factors IXa, Xa, XIa and XIIa. Heparin also inhibits additional coagulation by inactivating thrombin thus preventing the conversion of fibrinogen to fibrin. The amount of heparin required to produce anticoagulant effect depends on each individual and their activated partial thromboplastin time (APPT). A coagulation test is carried out to measure heparin activity. The normal APPT is 40 seconds. The concentration of heparin will prolong APTT from 2 to 2.5 times over the control value; this should be maintained and measured 6 hourly.
Some 10% of people on heparin suffer from haemorrhage, cotopnoea and hypertensive reactions. This means that patients on heparin therapy require regular measure of BP and heart rate. Urine and stools are closely monitored for any signs of blood. If over-coagulation of heparin occurs, the effect may be rapidly reversed by administration of protamine sulphate. The protein protamine sulphate neutralizes a heparin overdose. It combines with the heparin molecule to form a complex that suppresses the pharmacological activity of the anticoagulant. A combination is formed to dissociate the heparin and antithrombin III. This will reduce the anticoagulant action of heparin because protamine is a protein, and inactivates them.
Dalteparin
Dalteparin is a low-molecular-weight heparin (LMWH) which can be used for prophylaxis. It has been identified that the advantage of LMWH is that it does not need close monitoring of blood coagulation tests. It has a longer life and so requires once-a-day dosage.
Warfarin
Once the clotting stabilizes, warfarin may be started, because of the time it takes to be effective. Warfarin inhibits the synthesis of clotting factors produced by the liver from vitamin-K and thus active clotting factors decrease by binding to the albumin. This explains why it is given in low doses. Warfarin acts in the liver to prevent synthesis of vitamin-K-dependent clotting factors (i.e. factors II, VII, IX and X). Warfarin acts as an antagonist to hepatic use of vitamin K but it takes about 8–12 hours to deplete clotting factors. This is because its anticoagulant effect results from a balance between partially inhibited synthesis and unaltered degradation of vitamin K clotting factors. The resulting inhibition of coagulation is dependent on their degradation rate in circulation.
Degradation of vitamin K clotting factors of VII, IX, X and II to half-lives will take 6, 24, 40 and 60 hours respectively. This is why it takes warfarin to decrease the amount of vitamin-K-dependent coagulation factor synthesized in the liver by up to 50%. This highlights the need for warfarin to be started in conjunction with heparin in order to initiate warfarin in the system before taking the patient off heparin.
Warfarin is measured as a ratio against a standard PTT. A standard level represents 25% of the normal rate and this should be maintained for a longer-term therapy. Warfarin should be omitted if normal activity is less than 20% until activity rises to above 20%. The international normalized ratio (INR) represents the recommended target levels of between 2.5 and 3.5.
Blood tests need to be taken regularly to determine the maintenance dose prescribed. INR should be measured once monthly in long-term patients. Once a patient has suffered a PE, the risk of it recurring is high. Warfarin given after heparin therapy should continue for at least 6 months as recurrent multiple emboli may require life-long therapy.
Patients on warfarin need to be warned about bleeding disorders that may occur, especially with elderly patients. This is due to the reduced effect of platelets and coagulation factors. Occurrence of any of the above factors would mean a withdrawal from the drug, which restores normal clotting factors. For warfarin poisoning vitamin K is given slowly intravenously as an antidote. This reverse may take several hours; therefore, in urgent cases, fresh frozen plasma is given.
The primary result of excessive usage of the drug is bleeding of the gums when brushing teeth, excessive or easy skin bruising and unexplained nose bleeds. The vital signs the nurse has to look for include when a patient appears to be in shock or having difficulty in breathing and pain.
Immunosuppressants
Used to prevent tissue rejection after organ transplantation and to treat autoimmune diseases:
■ Prednisolone is used in combination with azathioprine.
■ Mycophenolate mofetil, ciclosporin and tacrolimus are potent immunosuppressants that are used with prednisolone.
These drugs have serious adverse effects and, like cytotoxic drugs, increase a critical care patient’s vulnerability to infection.
Hyperglycaemic and Hypoglycaemic Agents
Hyperglycaemic agents
Glucagon is used to treat drug-induced hypoglycaemic states where intravenous glucose cannot be administered. Nausea is a principal side-effect, and the preparation needs to be protected from light.
Hypoglycaemic agents
There are two different types, parenteral and oral:
1. Parenteral – insulin adminstered IV or subcutaneously – used in type I diabetes:
● The greater the concentration of zinc or the presence of protamine in the insulin preparation, the more prolonged the duration and delayed the action of the insulin itself.
● Types:
– Neutral insulin – is clear, generally short acting
– Lente or isophane – is cloudy and intermediate acting
– Mixed insulin suspensions of the two above to lengthen the action, and reduce the number of daily injections required
– Sources of insulin – bovine (ox), porcine (pig) and human (genetically modified for commercial use).
2. Oral hypoglycaemic agents – used in type II diabetes
■ Sulphonylureas
– Stimulate the release of insulin from the pancreas
– Inhibit the process of gluconeogenesis (forming glucose from amino acids and fatty acids) in the liver
– Increase the number of insulin receptors on target cells
– Adverse effects – hypoglycaemia overdose, allergy, depression of bone marrow and gastrointestinal disturbances
– Available – chlorpropamide, glibenclamide, gliclazide, glipizide, tolazamide and tolbutamide.
■ Biguanide (metformin)
– Acts by promoting glucose uptake into cells through enhanced insulin-receptor binding.
– Slows absorption of glucose from the gut
– Inhibits glucagon secretion and stimulates tissue glycolysis
– Adverse effects – drug tolerance and acidosis.
6.3 Drug calculations
In critical care there are cardiac support and other drugs which require careful and meticulous calculations to ensure that the correct dose is given to patients. Therefore I have included some of the common drug formulas and useful information.
IV and oral therapy are common administration routes for drugs in critical care. It is in your interest to use some of your time to observe and learn some of the drugs that patients are prescribed. In addition to this, in your role as a critical care nurse you will be expected to check and calculate the dosage, and draw up the drugs.
The following are some of the drug calculation formulae that may help you in this role:
1. 1000 μg in 1 mg
1000 mg in 1 gram
2. Ampicillin 500 mg diluted in 10 ml; you require 200 mg
{What you want/What you have got}× What it is in
{200/500}× 10 = 4 ml
3. Adrenaline comes in strengths of 1:1000 (1 mg per ml) and 1:10000 (1 mg per 10 ml)
(i) If you require 1.6 mg of 1:1000 strength adrenaline, using the formula:
{What you want/What you have got}× What it is in
{1.6/1} × 1 = 1.6 ml
(ii) If you require 2.5 mg of 1:10000 strength adrenaline, using the formula:
{What you want/What you have got }× What it is in
{2.5/1}× 10 = 25 ml
4. Lidocaine comes in either a 1% solution or a 2% solution; this means that:
(i) A 1% solution is equal to 1 gram in 100 ml
1000 mg in 100 ml
10 mg per ml
(ii) A 2% solution is equal to 2 grams in 100 ml
2000 mg in 100 ml
20 mg per ml
5. There are other drugs such as dopamine, adrenaline, dobutamine and noradrenaline which require to be calculated in μg/kg/min.
First calculate micrograms/ml
Then use the formula: μg required × kg × min/concentration in micrograms
Always check your calculations with someone more senior if you are unsure of your answer 
6.4 Nurse prescribing
Nursing is moving into the reality of nurse prescribing (Beckwith & Franklin 2007, Jones 2004). Any critical care nurse who is interested in the extension of nurse prescribing rights will appreciate the significance of the Crown Report. The Crown Report (Department of Health 1999) made three main recommendations:
■ The majority of patients continue to receive medicine on an individual patient basis
■ The current prescribing authority of doctors, dentists and certain nurses (in respect of a limited list of medicines) continues
■ New groups of professionals would be able to apply for authority to prescribe in specific clinical areas, where this would improve patient care and patient safety could be assured.
Independent prescribing
This is identified as someone:
Who is responsible for assessment of patients with undiagnosed conditions and for decisions about the clinical management required, including prescribing (Department of Health 1999, page 39)
Critical care nurses who are currently prescribing from the Nurse Formulary can continue to do so. However, these nurses and others not currently able to prescribe, who are in a position to undertake the assessment of patients with undiagnosed conditions, e.g. hypokalaemia, and make a prescribing decision, e.g. potassium added to fluids, can become a newly legally authorized independent prescriber. To undertake this role of nurse prescriber, a critical care nurse will have to undertake a relevant nurse prescribing course.
Dependent prescribing
Crown defines the dependent prescriber as someone who does not have the diagnostic and assessment ability to make a decision about an initial prescription, but will have sufficient knowledge to determine whether that prescription should be continued, or whether to alter the dosage. Furthermore, a dependent prescriber may still be able to prescribe a drug for the first time, but this would be within the parameters of clinical guidelines for a given condition, and the care plan of a patient. This is about protocol arrangement.
Critical care nurse practitioners who consider themselves working at specialist level could, by undertaking a recognized accredited nurse prescriber course, become an independent or dependent prescriber.
