Section 9. Other areas of pharmacology
9.2 Paediatric pharmacology 373
9.3 Drugs and the elderly 376
9.4 Topical drugs 380
9.5 Emergency treatment of poisoning 388
9.1. Herbal medicines
Regulation
A long overdue registration scheme for herbal medicines was introduced in late 2005. Registered products have to meet standards of safety, quality and consumer information but many unlicensed products are available. The Medicines and Healthcare products Regulatory Agency (MHRA) provides advice on using herbal medicines on its website: www.mhra.gov.uk.
Drug interactions
These are becoming much more important as the number of patients taking herbal medicines increases.
Warfarin is the most common cardiovascular drug involved in interactions. It was found by Izzo et al (2005) to interact with boldo, curbicin, fenugreek, garlic, danshen, devil’s claw, don quai, ginkgo, papaya, lyceum and mango to cause possible over-anticoagulation. It may react with ginseng, green tea, soy and St John’s wort to give a decreased anticoagulation effect.
Individual herbal medicines and their action
Chamomile
Daisy-like plant whose flower heads and oils are used. The oil is an ingredient of some shampoos, promoted as an agent to lighten and condition the hair.
▪ Chamomile is commonly used as a relaxing tea prepared by soaking the dried flowers, usually in teabags, in boiling water. It may also induce a deep sleep.
▪ When given in large amounts it often causes gastrointestinal colic and sometimes severe allergic reactions.
▪ Apigenin, an active component found in some chamomile extracts, has been shown to bind to the benzodiazepine receptor in the gamma-aminobutyric acid (GABA) receptor complex of the brain. This action could explain the sedative effect of chamomile.
▪ In Germany, chamomile is prescribed by general practitioners as a vaginal pessary to combat trichomoniasis and fungal conditions.
▪ In view of its coumarin content it should not be taken with warfarin.
▪ Chamomile should be avoided by those with a known hypersensitivity to members of the daisy family.
Cranberry juice
The cranberry or guelder rose, Viburnum opulus, bears red berries that are compounded into a juice known to have properties that help in urinary tract infections (UTIs).
▪ Cranberry prevents the adherence of the bacterium Escherichia coli (the commonest cause of UTIs) to the bladder and urethral wall.
▪ UTIs can cause serious kidney infections and cranberry juice is not usually recommended as a sole treatment.
▪ There is a possibility that cranberry may interfere with the metabolism of some drugs including warfarin. Cranberry juice contains various antioxidants, including flavinoids, which are known to inhibit cytochrome P450 enzyme activity and thus may interfere with drug metabolism.
Echinacea
▪ This is one of the few commonly used herbs that still carries its Greek name. The common name is coneflower.
▪ Used in infections such as colds, influenza and fungal infections of the skin.
▪ Evidence suggests that it is of little use in the prevention of the common cold, but it may be of help in treating and shortening the length of the infection.
▪ There is some evidence that incorporated in a gel for topical use it may suppress the itch and erythema associated with insect bites.
▪ Animal studies have shown that it may act as an immunostimulant on various parts of the immune system. In vitro studies have demonstrated some antibacterial (bacteriostatic) and antiviral properties.
▪ Should be avoided in chronic disease, such as tuberculosis, multiple sclerosis or HIV. It should also be avoided by individuals who have a known hypersensitivity to the daisy family, and by pregnant women.
▪ Should only be used for short periods as tolerance develops when used continually.
Evening primrose oil
Seeds of the evening primrose, Oenothera biennis, contain an oil which is high in both linoleic and γ-linolenic acid. These are essential fatty acids needed for prostaglandin synthesis.
▪ Used in many diverse diseases such as psoriasis, breast pain as may occur premenstrually and Parkinson’s disease.
▪ Some evidence of its efficacy in breast pain and dermatitis.
▪ Should be avoided in people with epilepsy or a past history of epileptic seizures, and it should be avoided in people with schizophrenia.
▪ Generally well tolerated but may cause mild gastrointestinal effects, such as nausea, indigestion and softening of stools.
▪ May cause headaches due to effect on cerebral blood vessels.
Feverfew
This is Tanacetum parthenium, commonly known as the tansy, and belongs to the daisy family. It is available as capsules to treat migraine ( Migraherb Hard®).
The feverfew group of plants includes the pyrethrum, which contains pyrethrins, commonly used in insecticide sprays. These are reportedly nontoxic to humans, but are a strong irritant to the eyes and mucous membranes. Hypersensitivity reactions can occur.
▪ The name suggests that feverfew leaf extract would be used to counteract fevers, and this was one of the original uses.
▪ Used as a migraine prophylactic and as an antiarthritic drug.
▪ Appears to have antiplatelet activity and should not be used in individuals on anticoagulant therapy.
▪ Long-term use and sudden discontinuation causes rebound headaches.
▪ Laboratory studies have shown some anti-inflammatory properties on the immune system, which would be useful in autoimmune conditions.
▪ Feverfew has some inhibitory action on the enzyme phospholipase A 2, involved in synthesis of chemicals involved in inflammation.
▪ Contraindicated in pregnancy because of the possibility of miscarriage.
Garlic
Garlic ( Allium sativum) is a member of the onion family. The pharmacologically active compounds derived from the clove contain sulphur and are responsible for the strong odours associated with garlic. The sulphides are excreted on the breath and in sweat and other body secretions, enabling us to recognise that someone has eaten food containing garlic! The term alliaceous describes anything with this type of smell.
▪ A diet high in members of the onion family has long been reputed to have cardioprotective properties and the principal use of garlic is in the treatment of cardiovascular disease where it is reported to decrease atheroma formation.
▪ Garlic has antiplatelet activity that is dose dependent and may also be fibrinolytic.
▪ Garlic was thought to lower plasma low density lipoprotein (LDL) cholesterol levels but not all research supports this.
▪ Some studies have shown a blood pressure-lowering effect.
▪ Shown in some studies to have a hypoglycaemic effect.
▪ Garlic is antioxidant and is said to protect against viral infections such as the common cold as well as some cancers, but there is no conclusive evidence for this although some antibiotic-resistant bacteria are susceptible to garlic extracts in vitro.
▪ Patients taking warfarin should not take garlic as it may increase the activity of warfarin and is antiplatelet.
▪ In therapeutic doses, garlic should be avoided in clients on hypoglycaemic therapies and anti-inflammatory agents, such as aspirin.
▪ Garlic should be avoided by pregnant women at doses exceeding those used in foods as it may cause miscarriage.
Ginkgo
Ginkgo comes from the leaves of the tree of the same name, Ginkgo biloba, commonly called the maidenhair tree and found in China. Chinese medicine has used ginkgo for centuries as a treatment for brain disorders.
▪ Extracts of ginkgo have antioxidant properties (contain bioflavinoids) and are able to scavenge free radicals in the body; this is a possible mechanism for its action.
▪ Many studies have shown that ginkgo can prevent tissue damage and increase the blood flow to various organs, especially the brain.
▪ There is evidence that ginkgo improves memory function in older people. In Germany it is used as a standardised extract to treat various dementias, including Alzheimer’s disease, seemingly with considerable success.
▪ Ginkgo is a good alternative to caffeine for promoting alertness without the adverse effects of sympathetic stimulation.
▪ Another use is in plastic surgery, where it is used to help in skin grafting and to promote the healing of skin flaps.
▪ Ginkgo is potentially of value in many circulation problems, and ongoing research is seeking to support its medicinal properties.
▪ Adverse effects are mild gastrointestinal upsets and headaches, both of which are uncommon. Diarrhoea, nausea, vomiting, irritability and restlessness may occur with high doses.
▪ Seeds of the tree, extracts of which are sometimes used to treat urinary incontinence, are considered to be quite toxic. The use of seed preparations is inadvisable.
Ginseng
Ginseng is available in a variety of preparations, from chewing gums to liquid elixirs. The origin of ginseng is in the Far East, mainly China and Korea. The active Korean form is prepared from the root of Panax ginseng. Ginseng is said to have many beneficial properties. The proposed active ingredients of ginseng are a group of steroid substances that may have slight androgenic activity.
The principal use of ginseng is as a substance that can increase stamina and wellbeing. It is also said to have aphrodisiac properties.
▪ The case for ginseng as a physical and mental stimulant remains unproven, but evidence to date provides some support for these effects.
▪ The preparations should not be taken at night, and the heavy use of caffeine-containing drinks should be avoided in case of insomnia.
▪ As with most of the herbs mentioned so far, the concurrent use of warfarin may be contraindicated.
▪ Ginseng should be avoided with stimulants, antipsychotic drugs or monoamine oxidase inhibitors and in those with any acute illness or hypertension.
▪ A course for a few days is said to give therapeutic benefit and a prolonged course of therapy is not recommended.
Red clover
Clover is a very common weed that has a symbiotic relationship with nitrogen-fixing bacteria and is an important part of the diet for many herbivorous animals. There are several hundred different species, but the main one of interest to herbalists is the red or purple flowering variety, Trifolium pratense.
▪ Extracts are used for a variety of conditions, including skin diseases, certain cancers and coughs.
▪ Clover is a rich source of isoflavones, potent antioxidants and free-radical scavengers. It is these properties that are being closely examined at present.
▪ All isoflavones have weak oestrogenic activity which may contribute to their therapeutic action.
▪ Recent publications show an increase in bone density in postmenopausal women taking red clover isoflavones and they may have protective effect on the development of postmenopausal cardiovascular disease.
▪ Red clover should be used cautiously in individuals susceptible to bleeding problems or who are receiving anticoagulants.
Saw palmetto
This has been used for various urogenital conditions, from infections to impotence, but its main use relates to its effect on the enlarged prostate gland.
▪ The condition of benign prostatic hypertrophy (BPH) is very common in elderly men and can cause urinary retention.
▪ Saw palmetto supposedly causes a decrease in the size of the prostate gland, and many studies have shown that it is equivalent to finasteride (see section 7.4) in action but without the adverse effects.
▪ Contains many fatty acids and sterols. One of these, sitosterol, inhibits the conversion of testosterone into its active form, dihydrotestosterone.
▪ Could be beneficial in baldness, acne and female hirsutism.
▪ Adverse effects, if they occur, are mild and may include headaches or gastrointestinal upsets.
▪ Drug interactions are so far unknown, but it would be sensible not to use it with oestrogens such as the oral contraceptive pill or hormone replacement therapy.
St John’s wort ( Hypericum perforatum)
This herb is used as an antidepressant and preparations are standardised according to their hypericin content. It is actually prescribed in Germany four times more often than standard antidepressants.
▪ Some studies have shown the herb to be as good as tricyclic or selective serotonin reuptake inhibitor (SSRI) antidepressants without so many unwanted effects.
▪ Probably acts by modifying the dopaminergic, noradrenergic or serotonergic receptor activity in the brain and benefit may not be seen for 3–4 weeks following commencement of therapy.
▪ Should not be used in combination with other antidepressants, sedatives or alcohol.
▪ Photosensitivity may occur and precautions should be taken in the sun.
▪ Should be avoided in pregnancy as it has abortificant and teratogenic properties in high doses.
9.2. Paediatric pharmacology
This is a specialist area and there is a British National Formulary (BNF) for children available online at www.bnfc.org. The reader is referred to this text for details of drug dosages in children. This is a complex area where age may range from premature babies at 24 weeks’ gestation to adolescents. Many drugs in the adult BNF are not licensed for use in children. Occasionally paediatric specialists may use unlicensed drugs if there is no alternative.
Medicines are not given to children unless absolutely necessary and following the discussion of treatment options with the parents or child’s carers.
Licensing of medicines
Many manufacturers write disclaimers that their products should not be used in children.
Some medicines do have proven problems but it is usually due to a lack of clinical trials in paediatrics (ethically difficult and additional cost to manufacturer may not be recouped). Increasing pressure on the pharmaceutical companies may change this.
Some medicines are used unlicensed (off-label) and it is not unusual for babies in neonatal units to receive at least one unlicensed medicine during their hospital stay. Over 50% of drugs used in children may not have been studied in this age group and the BNF does include advice on the use of off-label medicines.
The MHRA also has a section on medicines for children available at www.mhra.gov.uk where they emphasise the need for more trials so that safe dosages and the correct formulation may be supplied for medicines in children. There is now a Paediatric Committee within the European Medicines Agency and EU regulation on paediatric medicines that was adopted at the end of 2006. There is also a European database of clinical trials.
Paediatric dosage considerations
▪ Dose administered to a child is never equivalent to that administered to an adult and the relationship between adult and paediatric doses is not linear.
▪ Doses based on age bands are used for drugs with a wide therapeutic index.
▪ Age and body weight may be used to calculate dosage (Table 9.1). Body surface area is a more reliable indicator as it reflects cardiac output, renal function and fluid requirements better than weight. In practice, surface area is only occasionally used for drugs with a low therapeutic index such as cytotoxic agents.
| Preterm newborn infants | Born at less than 37 weeks’ gestation |
| Term newborn infants | 0–27 days |
| Infants and toddlers | 28 days to 23 months |
| Children | 2 to 11 years |
| Adolescents | 12 to 16–18 years |
▪ The recommended dose has usually been calculated by the manufacturer and is in the BNF for children, taking into account all the above factors.
Pharmacokinetic factors in children
There are age-related differences in the body’s handling of drugs and this may lead to different dose requirements.
Absorption and drug action
▪ In the first 6 months of life there is slower peristalsis and gastric emptying allowing greater drug absorption and sometimes higher plasma levels.
▪ Activity and concentration of gastric secretions is less in the newborn. Gastric pH at birth is between 6 and 8. It remains relatively high until falling to adult levels by about age 2–3. This means there is reduced absorption of acidic medicines e.g. phenytoin.
▪ Low levels of bile in the newborn may impair absorption of some fat-soluble drugs.
▪ Topical administration in the very young may lead to high drug absorption as their skin has less waterproof and protective layers.
Distribution and drug action
▪ Lower concentration of plasma proteins and therefore a higher concentration of unbound drug available.
▪ Capacity of plasma proteins to bind drug is well below adult levels for about 2 years.
▪ Bilirubin can be displaced from albumin by drugs that strongly bind. This is especially important in the neonatal period because the blood–brain barrier is not yet fully developed and bilirubin may enter the brain.
▪ Levels of body fluid decrease with age and the levels of fat increase.
▪ Total body water in the premature neonate is 92% and 75% in the term newborn baby.
▪ Fat content in preterm babies in very low at about 3%. In full-term babies it is 12%, in 1-year-olds it is 30% and in adults it is about 18%.
▪ Level of extracellular fluid will affect the level of the drug actually reaching the receptor. This will be a lower concentration in the neonate and a diminished response will result.
▪ Fat-soluble drugs will accumulate less in fat reservoirs in the young and will tend to have a faster but briefer action because of this.
Metabolism and drug action
▪ The activity of drug-metabolising enzymes does not reach adult level until about 3 years of age.
▪ Before this, the capacity of neonates and young children to metabolise drugs is poor. Hepatic clearance is reduced and half-lives increase.
▪ May mean some drugs are administered only once daily in newborns, instead of twice daily.
▪ Some metabolic pathways may be different e.g. paracetamol metabolism.
Excretion and drug action
▪ Rates of glomerular filtration and renal blood flow are lower in the neonate than the adult.
▪ Clearance of drugs dependent on the renal route is lower and extended dose intervals may be required.
▪ Renal function usually reaches adult level after about a year.
Administration of medicines
The child should be involved in decisions about medication where age and circumstances allow this. Obtaining co-operation is essential and more likely if a parent or friend is giving the medicine.
There may be difficulty taking the medication as the correct formulation may not be available. Liquid forms of many medicines do not exist.
An oral syringe is supplied when the dose is less than 5 ml and is used to calculate doses accurately and to administer in a controlled manner.
Care must be taken when trying to disguise the taste of a medicine as some drugs may interact with various foods. It is better to give a drink after the medicine has been taken if possible.
Sugar-free medicines should be provided when possible to prevent dental caries. If the medicine is not sugar free, parents should be advised on dental hygiene in long-term use.
The intravenous route is usually preferred if a drug cannot be given orally.
Intramuscular injections should be avoided when possible, but certain drugs e.g. vaccines are only administered intramuscularly.
9.3. Drugs and the elderly
The elderly form an increasingly large percentage of those requiring healthcare. Chronic conditions often warrant long-term pharmacological therapy but you may not be aware of the extent of prescribing to the elderly. Although those over 65 years of age make up about 20% of the UK population, they receive nearly half of all prescribed medication with about one third taking three or more different medications.
▪ Polypharmacy is the norm, not the exception. Possible reasons include:
▪ multiple pathologies
▪ increasing range of drugs available
▪ inappropriate prescribing
▪ lack of medication review
▪ increased emphasis on preventative treatments.
The increased availability of over-the-counter (OTC) drugs must also be remembered and the elderly could well be taking herbal remedies and vitamin preparations that may interact with their prescribed drugs. An example is cranberry juice. This is very popular for its antiseptic properties within the urinary system and its antioxidant properties but there is a possibility that it may interfere with the metabolism of warfarin, making the latter less effective (see section 5.7).
There is a correlation between increasing age and adverse drug reaction (ADR) rate (Routledge et al 2004). The elderly are more susceptible to ADRs because of:
▪ exposure to more medication
▪ age-related physiological changes in pharmacokinetics
▪ age-related changes in pharmacodynamics
▪ increased pathological changes due to disease processes
▪ impaired homeostasis
▪ poor compliance that may be due to poor memory, failing sight, bad hearing, declining dexterity and decreased mobility.
It is a challenge for those in healthcare to provide appropriate treatment for multiple conditions while minimising side effects and the risk of iatrogenic disease.
New signs and symptoms in the elderly should always be regarded as possible adverse reactions to medication already taken e.g. thiazide-induced gout, phenothiazine-induced parkinsonian tremor, increased incidence of falls due to hypnotics or antihypertensives (Box 9.1).
Box 9.1
Drugs in the elderly
• Doses need to be tailored to the client – often a lower dose is needed
• Repeat prescriptions should be reviewed regularly and unnecessary drugs withdrawn
• Drugs that are needed should not be withheld e.g. aspirin as secondary prevention for a myocardial infarction, warfarin for atrial fibrillation
• Start low, go slow, is good advice but sometimes drugs are underprescribed and so do not control the condition e.g. angiotensin converting enzyme inhibitors in heart failure, tricyclics for depression
Changes in pharmacokinetics
All pharmacokinetic parameters – absorption, distribution, metabolism and elimination – may be significantly altered. These changes should be taken into account and are even more important if a drug has a narrow therapeutic window.
Absorption
We may expect this to be impaired due to:
▪ reduced gastric acidity
▪ reduced surface area for absorption
▪ reduced blood flow to the gastrointestinal tract
▪ reduced gastrointestinal motility
▪ delayed gastric emptying.
Although the overall absorption may be slightly lower, these effects are rarely important.
Distribution
May be influenced by the following changes:
▪ Significant decrease in the lean body mass – standard dose of drug therefore provides a greater amount of drug per kg of body weight.
▪ Total body water may decrease by as much as 15% – distribution of water-soluble drugs therefore decreased e.g. digoxin, theophylline, antibiotics, leading to higher plasma concentrations.
▪ Body fat is increased so lipid-soluble drugs may have a larger volume of distribution and this may prolong their half-lives e.g. benzodiazepines, psychotropics.
▪ In general, standard doses of drugs may need reduction.
▪ Plasma albumin is normally well maintained, but may be reduced by up to 25% in chronic disease – resulting in higher levels of drugs normally protein bound e.g. warfarin, phenytoin, diazepam, furosemide.
Metabolism
Hepatic metabolism is reduced in the elderly due to:
▪ loss of liver mass
▪ reduced blood flow to the liver.
Other disease states will further reduce liver blood flow e.g. heart failure.
First-pass metabolism of drugs with a high extraction ratio e.g. propranolol is impaired. A dose reduction of between 30 and 40% may be needed for such drugs.
Liver enzyme activity may also be impaired and so it is necessary to monitor drugs with a narrow therapeutic index especially carefully e.g. digoxin, warfarin, theophylline.
Renal elimination
This is the most important age-related change in pharmacokinetics.
▪ Renal function deteriorates with age. Glomerular filtration rate decreases by approximately 1% per year over the age of 40 years.
▪ Reduced clearance of renally excreted drugs may lead to accumulation and toxicity.
▪ Renal impairment may not be obvious as decreasing muscle mass means that plasma creatinine levels may be normal.
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