Pharmacodynamics: how drugs act on the body.
Subject: Pharmacology (Analysis)
Author: Casey, Georgina
Pub Date: 10/01/2011
Publication: Name: Kai Tiaki: Nursing New Zealand Publisher: New Zealand Nurses' Organisation Audience: Trade Format: Magazine/Journal Subject: Health; Health care industry Copyright: COPYRIGHT 2011 New Zealand Nurses' Organisation ISSN: 1173-2032
Issue: Date: Oct, 2011 Source Volume: 17 Source Issue: 9
Accession Number: 271050295
Full Text: Nurses give drugs to patients every day. We have a professional responsibility to ensure comprehensive and current knowledge of the actions of these drugs.

An understanding of the underlying principles of drug action--pharmacodynamics--allows nurses to assess the impact of drug therapy on patients and their health problems, and to provide targeted information to clients about their therapy.

INTRODUCTION

The study of drugs--pharmacology--encompasses two key areas: pharmacodynamics, or the effect of a drug on the body; and pharmacokinetics--the way the body processes a drug.

An understanding of both these aspects of drug therapy provides the rationales for medication regimes and the use of individual drugs to treat specific disease processes.

The role of nursing in the use of medications is mandated by legislation and professional standards. While most nurses are unable to prescribe drug therapy, we are held to a high standard of practice in the safe administration, evaluation and education of patients, in relation to prescribed regimes. As health professionals, we may also be approached for advice about alternative and over-the-counter medications.

An understanding of the ways drugs exert their effects in the body allows us to:

* Look for and evaluate the effects of drugs (both desired and adverse) on an individual patient.

* Identify the usefulness of a drug or drug regime in the treatment of a patient's specific health conditions and consult with prescribers about this.

A drug is any chemical introduced to the body that affects physiological function. This description includes prescribed, over-the-counter, recreational or illicit drugs, and herbal, traditional and complementary, or alternative, remedies.

Drugs act by altering existing cellular activities; they do not create new functions or metabolic pathways in the body. There is a distinction between a drug's mechanism of action (how it interacts at a molecular level) and its effect--the physiological outcome of that action. To exert their effects, drugs must participate in a chemical interaction with biological molecules. With few exceptions (box 1, p25), the target molecules for drug action are proteins. (1)

Most drugs interact with protein molecules either on cell membranes or inside the cell. These regulatory proteins, also the targets for endogenous signalling molecules, can be enzymes, ion channels, transport proteins, or receptors. With the exception of those drugs described in box 1, all drugs for which the mechanism of action is known, interact with one of these targets.

Enzymes

An enzyme is a molecule that promotes chemical reactions without being involved in the reaction itself. In the body, enzymes are involved in all metabolic processes. Enzymes are very specific to the substrates (chemicals) on which they act, so drugs that target enzymes can be useful in disrupting specific physiological events.

Most drugs that target enzymes are inhibitors--they bind to the enzyme and prevent it from accessing its normal substrate material. A good example is the ACE-inhibitor drugs, eg captopril, which are reversible, competitive inhibitors of the angiotensin-converting enzyme (ACE).

The presence of an ACE-inhibitor drug blocks the conversion of angiotensin I to angiotensin If, reducing blood pressure by preventing the actions of angiotensin II on the cardiovascutar and renal systems. The reversible, competitive nature of ACE-inhibitor drugs means that if the normal substrate of ACE (angiotensin I) is increased, it will displace the drug from the ACE enzyme because the substrate and drug "compete" with each other for the enzyme-binding site. (1)

Other drugs are irreversible inhibitors of enzymes. Aspirin irreversibly inhibits the cyclooxygenase enzyme (COX). Following a dose of aspirin, synthesis of prostaglandins will be reduced until all the affected COX enzymes are replaced during natural turnover of these molecules.

Drugs can also act as false substrates: the chemotherapy agent fluorouracil acts as a false substrate for one of the enzymes in the synthesis of DNA. The resulting product cannot be used in the completed DNA molecule, so the synthesis pathway is disrupted and replication of malignant cells is prevented. (1)

Ion channels

Ions--sodium, potassium, chloride and calcium--are hydrophitic (water-loying) and lipophobic (lipid-hating) so cannot freely cross the lipid bilayer of the cell membrane. To cross membranes, they need to use water-filled protein pores that span the membrane and allow the ions to diffuse through (fig 1, p26). These ion channels are gated, to control diffusion, and are mostly specific to individual ions. Ion channels can open in response to cell membrane depolarisation (eg during an action potential) or following binding of a neurotransmitter. When opened, ions diffuse through according to their electrochemical concentration gradient. Drugs that target ion channels either physically block channels, or bind to and modify their activity. (1)

Local anaesthetic drugs (eg lidocaine--formerly lignocaine) cross to the interior of neurons and physically block the inner opening of sodium channels (fig 1). This prevents the entry of sodium ions, blocking depolarisation and stopping action potentials from travelling along the nerve.

Calcium channel blockers such as verapamil and diltiazem inhibit the opening of calcium channels, preventing entry of calcium into cardiac and smooth muscle cells. Because calcium is required for muscle contraction, these drugs cause reduced cardiac contactility and delayed conduction (antidysrrhythmic action) and vasodilation of arterioles (reducing blood pressure) and coronary blood vessels (increasing oxygen supply to the myocardium).

Binding of some drugs to ion channels can alter their structure so they are more likely to open or remain closed. Benzodiazepines (eg diazepam, lorazepam) bind to an accessory site on chloride channels in the central nervous system normally activated by gamma-amino butyric acid (GABA). When these ion channels are activated, chloride entry causes hyperpotarisation of the neuron, so GABA acts as an inhibitory neurotransmitter. Benzodiazepines, binding to their separate site on the same receptor, alter the shape of the ion channel and make it easier for GABA to bind and open the channel. Thus benzodiazepines facilitate the inhibitory effects of GABA in the nervous system. (1)

Transport proteins

Transporter proteins are required to move ions and other lipophobic molecules across membranes such as the renal tubules, blood-brain barrier and the intestine. They also pump sodium and calcium out of cells against their concentration gradients, and take up "used" neurotransmitter molecules or their constituents back into nerve terminals.

A key example of drugs that act on these transporter molecules is the selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine (Prozac), citalopram and sertraline. After release into the synapse, serotonin (5-hydroxytryptamine, or 5HT) is rapidly taken back up into the nerve ending by specific transport proteins. This limits the action of 5HT in the synapse and allows it to be recycled. By inhibiting transporter proteins, the SSRIs increase available 5HT in the synapse and this acts to relieve symptoms of depression. Tricyclic antidepressants such as imipramine and amitriptyline also inhibit 5HT reuptake but are much less specific, inhibiting other transport molecules as well. Venlafaxine and duloxetine are SNRIs--serotonin noradrenaline reuptake inhibitors. They are less selective than the SSRIs but are perceived as having greater therapeutic effect because of their action on noradrenaline as well. (1)

Receptors

Receptors are protein molecules that bind to endogenous chemical mediators, eg hormones, neurotransmitters, and inflammatory mediators such as histamine. Activated receptors alter cell functions via intracellular pathways that can lead to both rapid and long-term changes in cell function (fig 2, p27). Delayed responses in cellular activity, usually mediated by altered gene expression, mean that therapeutic effects of some drugs may not be seen for hours, days or sometimes weeks after treatment starts. (2)

Receptors can be found on the cell membrane, within the cell or inside the nucleus. Some receptors are linked directly to ion channels and control the opening or closure of these. Other receptors are linked to secondary pathways, such a G-receptor proteins or kinases. G-Proteins: G-protein coupled receptors are the most common cell membrane receptors in the body. Over 30 percent of all known drugs act via these receptor-protein complexes, although only 30 of the known 800 receptors have been identified as drug targets. (3) Examples of drugs that act via G-proteins are opioids, ranitidine (used to decrease acid secretion in the stomach), and beta-agonists such as salbutamol and adrenaline.

Binding of a drug to its protein receptor activates a G-protein on the inner surface of the cell membrane. Essentially the G-protein is a "go-between", carrying the message from an activated receptor to the molecules in the celt that actually generate the change in celt activity.1 Once attached to the "worker" molecule, the G-protein is inactivated and returns to its receptor to await further signals. The cholera toxin prevents the inactivation of G-proteins in intestinal cells, causing uncontrolled secretion of water and salts into the gastro-intestinal tract and severe watery diarrhoea.

The worker molecules that G-proteins target include ion channels, and cyclic adenosine monophosphate (cAMP) or phospholipase C second messenger systems. Second messenger systems can activate or inhibit cell activities such as enzyme reactions, secretion and contraction. Cell division, proliferation and differentiation are also affected via these pathways. (1) Protein kinases: Kinase-linked receptor proteins are more dominant in the regulation of cell division, growth and differentiation, tissue repair, programmed celt death (apoptosis), and inflammatory and immune responses. Receptors in this group are the targets of growth factors, cytokines and insulin. The majority of drugs acting on kinase-linked receptors modify immune or inflammatory responses and cell proliferation, ie anti-cancer agents. (4)

Trastumuzab (Herceptin) binds to and inactivates the HER2 kinase linked receptor that is over-expressed in some forms of breast cancer. Drugs in development include those targeting neuro-degenerative disorders and atherosclerosis. (1)

[FIGURE 1 OMITTED]

Intracellular and nuclear receptors: Lipid-soluble drugs, such as glucocorticoids and oestrogens, can freely cross the lipid bilayer of the cell membrane and bind to receptors in the cell cytoplasm. Once bound, the drug-receptor complex moves into the celt nucleus and activates or represses gene transcription, leading to the inhibition or synthesis of proteins that produce the drug's effects. This process takes up to several hours--the reason why corticosteroid therapy is not able to relieve acute asthma symptoms but must be taken regularly as a preventer. The effect of a single dose of the drug will last until the newly synthesised proteins have been removed from the cell. (2)

Other drugs act directly on receptors within the nucleus. Many of these receptors are involved in the regulation of lipid metabolism, activating in the presence of cholesterol and fatty acids, and are the target receptor for the fibrates. Others are the receptors that activate the synthesis of the drug-metabolising enzymes of the liver. Glitazones (pioglitazone), used in the treatment of type 2 diabetes, act via a nuclear receptor to induce synthesis of an array of proteins that alter insulin signalling pathways. (1)

DRUG ACTIONS

Drugs, and endogenous ligands such as hormones or neurotransmitters, bind to receptors and other targets according to concentration and affinity. Affinity is the tendency of a drug to bind to its target. Ideally, a drug will have high affinity, so that even at low concentrations, it readily binds to its target. The term for this is potency--the more potent a drug, the less of it is needed to exert a therapeutic effect.

Specificity or selectivity of a drug is of key importance in its ability to activate selected receptors and not others. No drug yet developed is 100 percent selective for its target. The less selective the drug, the more likely it will cause unwanted effects by binding to and activating (or blocking) other receptors. Furthermore, the less potent a drug is, the higher the dose required to exert an effect, and the more likely it is the drug will bind to other targets than the intended. (2)

The beta-blocker class of drugs is an excellent example of selectivity. Propanolol, the first beta-blocker to be widely used, is nonselective for beta-1 and beta-2 adrenoreceptors. Atenolol is beta-1 selective while labetalol blocks both alpha and beta-receptors. White atenolol is considered to be highly selective for beta-1 receptors, it should not be given to people with asthma because it retains some beta-2 antagonism. (1)

The degree to which a drug activates a receptor is termed efficacy. Agonist drugs--those that activate receptors--can be full (100 percent efficacy) or partial agonists. A good example of this is the difference in action between morphine and tramadol. Both these bind to and activate opioid receptors, but morphine has 100 percent efficacy, while tramadol is only a partial agonist, so has less analgesic effect. (1)

Drugs that bind to receptors but do not activate them have zero efficacy and are termed antagonists--they occupy the receptor so that other ligands cannot bind and activate them. Competitive antagonism occurs where an agonist drug or endogenous ligand is displaced from its receptors by an antagonist drug. To continue with the example of opioids, naloxone is an opioid antagonist (zero efficacy) and can be used to treat opioid overdose by displacing the agonist opioid from its receptor sites. The action of naloxone can be overcome by increasing the concentration of opioid agonist present. This is worth noting because the half-life of naloxone is much shorter than most opioid agonists. As the concentration of naloxone decreases, the agonists will displace it from opioid receptors and the risk of respiratory depression will recur. Often multiple doses of naloxone are required to overcome the effects of overdose. (1)

Other antagonist effects occur where: (1,2)

(1) Drugs bind to and inactivate enzymes, eg non-steroidal anti-inflammatory drugs inactivate the COX enzyme.

(2) The action of one drug is prevented by a second drug acting on a separate part of the signalling pathway, eg verapamil prevents entry of calcium into myocardial cells and will counter the effects of dobutamine (a beta-1 adrenoreceptor agonist).

(3) The physiological effect of one drug is counterbalanced by the action of a second drug acting via a separate mechanism, eg senna is a direct stimulant of GI motility used to treat constipation, while ioperamide is an opioid agonist that inhibits GI motility and is used to treat diarrhoea.

Tachyphylaxis and tolerance

Drug targets themselves are affected by drugs and endogenous activity, which can alter the therapeutic actions of the drug over time. Tachyphylaxis, or desensitisation, occurs rapidly and involves loss of drug effect though a change in the structure or function of the drug's target protein. Receptor function is restored once the drug is removed. Desensitisation to a drug may also occur if the drug requires endogenous chemicals for its action. Amphetamines and ephedrine induce the release of noradrenaline from nerve terminals in the central nervous system. As noradrenaline stores become depleted, effects of these drugs are reduced. (1)

[FIGURE 2 OMITTED]

Exposure to a drug may cause its receptors to be removed from the cell membrane (receptor internalisation). This process occurs over hours to days, and takes a similar time to recover. As a result, response to a drug may decrease with prolonged administration.

Prolonged administration of drugs can also cause an alteration in the numbers of channels, enzymes, receptors and second messengers present in the cell, due to alterations in gene activity. This up- or down-regulation of drug target numbers or function can be the basis of therapeutic effects seen, eg with antidepressant drugs four to six weeks after starting a course of treatment. This also accounts for physical dependence after prolonged therapy with drugs such as antidepressants and opioids, where function is affected by abrupt withdrawal either in the occurrence of rebound effects or abstinence syndrome. Down-regulation of drug targets can cause resistance to therapy that requires increasing doses of a drug to achieve the same therapeutic effect, ie tolerance. (2,5)

Therapeutic effects of drugs may also diminish over time due to increased metabolism of the drug (so it is removed from the body more rapidly) or to physiological adaptation. Homeostatic mechanisms can compensate for the actions of a drug and cancel out its therapeutic or adverse effects.

Therapeutic versus toxic effects

The effect of a drug does not increase continuously with increasing doses. At some point, the maximum effect of a drug is reached and increasing the concentration does not provide any further therapeutic effect. A drug that exerts maximum effect at low doses is more potent than one requiring high concentrations. Added to this is the issue of drug toxicity, where a higher dose of a drug causes poisoning. (5)

The therapeutic index of a drug is determined by looking at the difference in drug concentration between effectiveness and lethality. The point where a drug is effective for 50 percent of the (animal) study population is compared to the concentration of a drug that is lethal to 50 percent of the population. A drug with a high therapeutic index has a wide concentration difference between effect and toxicity, while a drug with a tow index (or narrow therapeutic window) has very little difference between therapeutic and lethal dose. Digoxin has a therapeutic index close to 1, meaning the effective and toxic doses are almost the same. (2)

While knowing the therapeutic index of a drug can indicate the need for caution in dosing and close observation of the person receiving the drug, it is not a reliable indicator of the safety of a drug. Thalidomide has a very high therapeutic index and this was the basis of its promotion as an anti-nausea treatment for pregnant women. The therapeutic index gave no indication of harmful effects of this drug, apart from the dose required to kill some rats. (1)

Many of the adverse effects of drugs, while dose-related, can occur at doses that are within or near the therapeutic range. Often these adverse drug reactions (ADR) do not become apparent until large-scale clinical trials are undertaken, or after the drug has been released on the market.

ADVERSE DRUG REACTIONS

Adverse drug effects are unintended and unpleasant responses to a drug and can range from mild and transient, to severe, immediate and life-threatening. Some may appear long after a person has started therapy, others can appear after the drug has been stopped (eg tardive dyskinesia associated with anti psychotic drugs). The incidence of ADRs increases with age, female sex, presence of multiple disease and the number of drugs being taken. (5) ADRS are distinguished from toxicity because they occur at normal therapeutic doses.

Between 1999 and 2008, the number of hospital admissions for ADRs in England increased by 70.8 percent, encompassing renal, cardiovascular and respiratory disorders as well as psychiatric and behavioural issues. (6) ADRs cause nearly 200,000 deaths each year in the European Union, with an annual social cost of 79 billion euros. (7)

In New Zealand, potential safety issues with a drug are detected through the use of spontaneous adverse reaction reports. These may be submitted to the Centre for Adverse Reactions Monitoring (CARM) by any health professional or consumer (although consumer awareness of this may not be great). They are analysed and reported to the Medicines Adverse Reactions Committee of Medsafe (the New Zealand Medicines and Medical Devices Safety Authority). This can be found at www.medsafe.govt.nz/profs/PUArticles/ AdverseReactionReportingSumary2010.htm.

New medicines to the market here in New Zealand are monitored more actively with the Intensive Medicines Monitoring programme (IMMP), to try to uncover adverse reactions that would not be seen prior to general release of a drug--rare, late, or unexpected ADRs, or those that closely resemble the condition being treated. (8)

Table 1 shows the classification of ADRs with examples.

Allergic drug reactions are classified as type B reactions, being unpredictable, at least the first time they occur for an individual. To cause an allergic reaction, a drug (or its metabolite) forms a complex with proteins in the body that in turn triggers an immune response. The response itself develops over one to two weeks, so a short course of, for example, penicillin, will not generate an allergic reaction but if a second course of the drug is prescribed, the allergic response may be severe. In contrast, prolonged administration of a drug could see an allergic response developing several weeks after therapy has begun. Drugs within the same chemical class can trigger an allergic reaction following prior sensitisation.

Allergic reactions are classified according to the types of antibodies and immune cells involved: (1,2,5)

* Type I (anaphylactic), eg penicillin

These reactions are immediate and can be life-threatening. IgE-mediated release of histamine and other mediators leads to urticarial rash, oedema, bronchoconstriction and hypotension.

* Type II (cytotoxic), eg haemolytic anaemia, agranulocytosis, thrombocytopaenia, aplastic anaemia.

Activation of the complement cascade by IgG and IgAf antibodies leads to destruction of circulating blood cells or of bone marrow.

* Type III (immune complex), eg serum sickness, Stevens-Johnson syndrome/Toxic epidermal necrolysis:

Activated IgG immune complexes block small blood vessels and cause local inflammation, destruction and sloughing of tissue, especially skin and mucous membranes. May cause urticaria, ulceration, joint pain, lymphadenopathy, fever, lung damage.

* Type IV (cell-mediated), eg contact dermatitis, other skin rashes:

Immune cells respond directly to the presence of the allergen, inducing localised inflammation, oedema and rash. Rashes can be mild or extensive, severe, exfoliating lesions. Can also trigger generalised autoimmune responses.

INDIVIDUAL RESPONSES TO DRUGS

Aside from pharmacokinetic considerations (the absorption and processing of drugs), individuals administered the same dose of a drug may show variable therapeutic effects. Differences in response can be evidenced by a smaller or larger effect, or that the drug acts for a shorter or longer time period. The main causes of pharmacodynamic variations in drug response are genetic factors, age and polypharmacy.

Genetic factors

Genetic factors, most often loosely assessed as ethnicity, (9) can affect the actions of, and responses to, drugs. A good example of ethnic variations in drug activity is found with the cardiovascular effects of propranolol. Chinese people are more sensitive to this drug than those of European descent, while African-Americans are less sensitive. (1)

Genetic variations in drug action are due to alterations in the structure or activity of drug targets, second messenger systems or downstream pathways. Genetic variations in the target enzyme Vitamin K epoxy reductase affect a person's therapeutic response to warfarin. Pharmacogenomics--research into the impact of genetic variation on drug therapy--is becoming increasingly valuable as a tool to individualised drug therapy so that maximum benefit for a patient can be achieved. Pharmacodynamics in infants and children Development stage is well recognised as having an impact on a child's ability to process and eliminate drugs. Much less is known about the role of developmental stage on the mechanism of action of drugs and differences in response to therapy that might arise form these. (10)

Differences in drug action during infancy and childhood may relate to alterations in drug target numbers or affinity, or development of second messenger systems. (11)

Adverse effects may occur during developmentally vulnerable periods in the child that are not apparent in adults. This is particularly true for nervous, endocrine, reproductive, immune and visual systems. (11) One example is the increased incidence of acute dystonia caused by metoclopramide in children, compared with adults.

The treatment of depression in children is believed to be affected by different developmental rates of the serotonin and noradrenergic neurotransmitter systems in the central nervous system. Drugs that target both of these systems are less effective than the selective serotonin reuptake inhibitors (eg fluoxetine).

GABA is inhibitory in adults, but excitatory in neonates and premature infants, where the distribution of GABA-A receptors in the brain is also altered. This may account for seizures that occur in neonates on exposure to benzodiazepines. Neonates are also more sensitive to the effects of opioids, due to an increased number of opioid receptors. (11)

Pharmacodynamics in the older adult

Age-related changes to cardiovascular, renal and hepatic function have a significant impact on an older adult's ability to process drugs. At the same time, sensitivity to the actions of drugs is altered. This may be due to changes in drug-target interactions, target numbers, or altered second messenger and downstream actions. In addition, reduced homeostatic function makes even healthy older adults more susceptible to the normal effects of drugs, while in the frail elderly, progressive organ failure increases vulnerability. (12) Drugs that affect the central nervous system often induce exaggerated effects in older people. Altered receptor sensitivity, declining function and increased penetration of drugs into the brain increase the risk of adverse effects from benzodiazepines, opioids and anaesthetic drugs in particular. (13)

Beta-adrenergic activity is decreased in older adults, making them less responsive to both agonist and antagonist drugs, including beta-2 agonists. This is due to decreased G-protein activity, rather than loss of receptors. (14)

Anticholinergic effects of many drugs can be particularly troublesome for older adults because of age-related decline in parasympathetic activity. Examples are tricyclic antidepressants, antipsychotic and some anti-Parkinson's drugs. There may be increased confusion and drowsiness, constipation, urinary retention, dry mouth and pastural hypotension. (15)

In one study, (6) most of the increase in reported ADRs occurred in adults aged over 65. This population is more vulnerable to the adverse effects of drugs for a number of reasons. Cognitive decline and the reduction in homeostatic functions make an older adult less likely to cope with the effects of normal doses of drugs, as compensatory mechanisms are reduced. Also, older adults are more likely to be taking multiple drugs which may interact with each other, causing increased or decreased therapeutic and adverse responses. ADRs may be attributed to ageing rather than drug effects, a supposition that may lead to further prescribing.

A good review of the risks of medication use in the elderly can be found here: www.bpac.org.nz/magazine/2008/february/why.asp.

MONITORING DRUG THERAPY

As students, nurses are taught the five rights of safe medication administration. As practising professionals, nurses must also reflect critically on the actions, purpose and effectiveness of medications we administer. When administering a drug, we should be asking ourselves: is this the right drug, at the right dose for this patient, at this time?

To answer this question, you should determine:

(1) Whether the intended therapeutic effect of the drug or drug regime is being achieved.

(2) Are there any observable ADRs? You should determine in advance what these are likely to be and how they should be assessed.

Whether this particular drug has special risks (eg narrow therapeutic window) that require specific monitoring.

(4) Is this patient tolerating/able to comply with the drug regime and its monitoring programme?

CONCLUSION

Up-to-date understanding of the actions of drugs is essential to safe, professional practice around medications. Nurses play a key role in supporting patients in the appropriate use of drugs to manage health conditions. Knowledge about pharmacodynamics allows nurses to provide appropriate education to clients and to evaluate the appropriateness of drug regimes in terms of effects, adverse effects and client safety.

LEARNING OUTCOMES

After reading this article and completing the accompanying online teaming activities, you should be able to:

* Describe the key targets for drugs in the body and the ways that drugs interact with these.

* Explain pharmacodynamic concepts that influence the actions and adverse actions of drugs.

* Describe types of adverse drug reactions.

* Discuss life-span considerations that influence the action of drugs.

* Outline nursing responsibilities in the monitoring of drug therapy.

Earn two hours of CPD

By reading this article and doing the associated online learning activities, you can receive a certificate for two hours of continuing professional development (CPD). Go to www.cpd4nurses.co.nz to complete the learning activities for this article. The online service costs $19.95 per article.

References

(1) Rang, H., Dale, M. & Ritter, J. et at. (2012) Rang and Dale's Pharmacology (7th ed). Edinburgh: Churchill Livingstone.

(2) Gutierrez, K. (2008) Pharmocotheropeutics: Clinical reasoning in primary care (2nd ed). St Louis MO: Sounders.

(3) Hill, S. (2006) G-protein-coupled receptors: Past, present and future. British Journal of Pharmacology; 147, S27-S37.

(4) Cohen, P. (2002) Protein kinases--the major drug targets of the 21st century. Nature Reviews Drug Discovery; 1, pp309-315.

(5) Begg, E. (2008) Instant clinical pharmacology (2nd ed). Oxford: Blackwell.

(6) Wu, T.-Y. & Jen, M.-H. et al. (2010) Ten-year trends in hospital admissions for adverse drug reactions in England 1999-2009. Journal of the Royal Society of Medicine; 103:6, pp239-250.

(7) Lierop, T.v. & Bunyan, C. (2008) Strengthening phurmacovigilonce to reduce adverse effects of medicines. Brussels: European Commission. http://ec.europa.eu/health/files/pharmacos/pharmpack_12_2008/ memo_pharmacovigitiance_december_2008 en.pdf. Retrieved 09/09/11.

(8) Ferbburg, C. (2010) Reflections on how to improve dug use. Pharmaceutical Management Agency Annual Review 2010. Wellington: NZ Government.

(9) Wadman, M. (2005) Drug targeting: Is race enough? Nature; 435, p1008.

(10) Kearns, G. et al. (2003) Developmental pharmacology--drug disposition, action and therapy in infants and children. New England Journal of Medicine; 349:12, pp1157-1167.

(11) Mulla H. (2010) Understanding developmental pharmacodynamics: Importance for drug development and clinical practice. Pediatric Drugs; 12:4, pp223-233.

(12) Hutchison, L & O'Brien, C. (2007) Changes in pharmacokinetics and pharmacodynamics in the elderly patient. Journal of Pharmacy Practice; 20:1, pp4-12.

(13) Bowie, M. & Slattum, P. (2007) Pharmacodynamics in older adults: A review. The Americon Journal of Geriatric Pharmacotherapy; 5:3, pp263-303.

(14) Corsonelle, A., Pedone, C & Uncalzi, R. (2010) Age-related pharmacokinetics and pharmacodynamics and related risk of adverse drug reactions. Current Medicinal Chemistry; 17, pp571-584.

(15) Merck Manual (2009) Drug therapy in the elderly, www.merckmanuals.com/professional/geriatrics/ drug therapy in the elderly/pharmacodynamics_in_the_elderly.html. Retrieved 09/09/11.

Georgina Casey, RN, BSc, PGDipSci, MPhil (nursing), is the director of CPD4nurses.co.nz. She has an extensive background in nursing education and clinical experience in a wide variety of practice settings.
Box 1. Drug targets other
than proteins

[ILLUSTRATION OMITTED]

Drugs that target the extracellular
environment

Some drugs do not attach to cell
receptors, but rather alter the external
environment of the cell in
some way. Examples are:

* Osmotic diuretics (eg mannitol).
These inert drugs are filtered by
the glomeruls but cannot be reabsorbed
in the kidney tubules. They
prevent passive water reabsorption
in the proximal tubules and collecting
duct and thus induce a diuresis.

* Lactutose is an osmotic laxative
formed from poorly absorbed disaccharide
molecules. By remaining in
the gut, it draws water across the
gastro-intestinal membrane, increasing
the rate of movement of intestinal
contents and keeping faecal material
well-hydrated.

* Bisphosphonates prescribed for treatment
of osteoporosis bind directly
to calcium in the bone and prevent
osteoclast action.

* Antacid drugs are salts of magnesium or
aluminium. They alter the pH
of the stomach by chemically reacting
with the hydrochloric acid. Alginate
antacids such as Gaviscon both buffer
and create a barrier between the
acid contents of the stomach and the
oesophageal wall.

* Some antibiotics (mitomycin), anticancer
agents (eg bleomycin and
nitrogen mustard derivatives) and ionising
radiation act directly on the
DNA of a cell.


Table 1. Adverse drug reactions

Classification       Features            Examples

Type A (augmented)   * Predictable       * Hypotension
Also called Type 1   (exaggeration       with anti
reactions            of drug's           hypertensive
                     expected            therapy.
                     therapeutic
                     effects or
                     predicted from      * Excessive
                     the mechanism       bleeding with
                     of action of        anticoagu
                     the drug)

                     * Dose dependent    La nts.
                     * Common            * Hypoglycaemia
                                         with insulin.

                     * Often (but not    * Drug
                     always) not         dependence with
                     serious             opioid anal

                     * May be            gesics.
                     reversible

                     * May be            * Osteoporosis
                     managed by          with prolonged
                     adjusting drug      use of
                     dosage              corticosteroids.

Type B (bizarre)     * Unpredictable     * Anaphylaxis
Also called Type 2   (arising from       with
reactions            allergic or         penicillins.
                     pseudo-             * Paradoxical
                     allergic            insomnia/
                     reactions,          anxiety with
                     genetic dif-        benzodiazepines.
                     ferences,
                     increased           * Agranulocytosis
                     sensitivity to      with thiazide
                     drug mechanism,     di uretics and
                     disease effects     sulphonylurea
                     or idiosyn-         antidiabetic
                     cratic causes)      drugs.

                     * Doseindependent   * Thrombocytopaenia
                     Uncommon            with heparin.
                     Often serious
                     A Usually need
                     to stop drug
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