Safe and effective pharmacotherapy is one of the greatest challenges in clinical geriatrics. Drugs have been clinically employed to ameliorate the infirmities of old age and have been advocated to prolong life span but in both cases success obtained so far is meager. Medical research has identified problems in the effective use of drugs in this population. Elderly patients are less likely to receive treatments indicated by guidelines. The most common cause of iatrogenic illness is adverse drug reactions which cause 10-15% of hospital admissions in patients aged sixty and above.

As the age advances and disease becomes established, clinically important changes occur in the way that the body is able to handle drugs. Aging alters pharmacokinetics and pharmo-dynamics affecting the choices, dose and dosing frequency of many drugs. The geriatric prescriber must know of these changes, so that due allowance is made in the choice of drug, dose employed, the therapeutic response to be expected and risk of adverse drug reactions to be considered.

A number of age related physiologic changes occur that potentially could affect drug pharmacokinetics and pharmacodynamics in old age. The changes that are important to prescribers are:

• Decrease in total body mass.
  
• Increase in body fat stores.
  
• Decrease in total body water.
  
• Decline in lean body mass.
  
• Decline in liver mass.
  
• Decline in hepatic blood flow.
  
• Decline in glomerular filtration.

Altered Pharmacokinetics

The time course, by which body absorbs, distributes, metabolizes and excretes drugs.

Absorption: In general there is little change in absorption of drugs in elderly.

Distribution: Total body water decreases by 10-15% between the ages of 20-80. In contrast, the percentage of body weight that is body fat, is increased from 18-36% in men and from 33-45% in women. Therefore, water-soluble drugs such as paracetamol, digoxin, cimetedine and ethanol will have decreased volume of distribution and so higher serum concentrations, necessitating reduced doses. Conversely high lipid soluble drugs will be distributed very extensively resulting in prolonged plasma half-life and action which can be a problem in the event of an adverse reaction. For example, diazepam (which is highly lipid soluble) may have prolonged elimination half-life of up to 100 hours in the elderly.

Plasma proteins decrease with age, particularly in the context of poor nutrition, chronic illness and disability. This may cause an increase in free concentration of extensively bound drugs. It can increase toxicity in clinical practice with diazepam, phenytoin, Warfarin and salicylates.

Metabolism:With advancing age hepatic mass and hepatic blood flow decreases. However, this is not reflected in liver functions, which remain normal. In the elderly, first pass metabolism of some oral drugs (propranalol, labetalol, and verapamil) is reduced, increasing their serum concentration and bioavailability. Consequently initial dose of drugs should be reduced by about 30%.

Hepatic clearance of drugs metabolized by cytochrone P 450 system (phase 1 reaction e.g. diazepam, amitryptaline, chlordiazpoxide) is often reduced in the elderly. Many drugs produce active metabolites in clinically relevant concentrations. Accumulation of these metabolites increase the risk of toxicity due to age related decrease in renal clearance, particularly in patients with renal disease e.g., benzodiazpines, tertiaryamine anti-depressants and opioid-analgesics.

Renal Clearance

Renal function deteriorates with age, falling by 10% after the age of 40 years. However, serum creatinine tends to remain stable due to a concomitant decline in muscle mass turnover.
The general effect of pharmacokinetic changes in the elderly is to;
· Increase the duration of action of many drugs.
· Increase the serum concentration of many drugs.

So, commonly used Xanthines such as aminophylline and theophylline require approximately 50% of dosage reduction in elderly. Similarly cimetedine and rantidine can reach toxic levels if given in standard dosage.

Altered Pharmacodynamics

Pharmacodynamics has been defined as effect of drug at receptor site. In the elderly the effects of similar drug concentration at the site of action may be larger or smaller than those in young persons. Increased sensitivity due to aging must be considered when drugs that can have serious adverse effects are used. These drugs include morphine, pentazocine, and warfarin, angiotensin converting inhibitors, diazepam and levodopa.

Although medications used by the elderly can lead to improvement in health related quality of life, negative outcomes due to drug related problems are considerable. Three important and potentially preventable negative outcomes due to drug related problems that can occur in the elderly are:
i. Adverse drug withdrawal events, which are caused by removal of a drug.
ii. Therapeutic failure (inadequate drug therapy)
iii. Adverse drug reactions.

Limited data are available about the prevalence of adverse drug withdrawal effects and related therapeutic failure in elderly. Adverse drug reactions are thought to occur more commonly among elders compared with other age groups.

Adverse Drug Reactions

Adverse drug reactions may be defined as unintended, undesirable effects of substances used in prevention, diagnosis or treatment of disease.

Many factors contribute to the problem including inadequate diagnosis, uncritical assessment of need for drug treatment initially and at medical review, excessive prescribing, tendency to initiate or repeat prescription for non pharmacological reasons, sensitivity to drugs in old age or poor compliance.

The adverse effects of drugs in the elderly are often nonspecific and may readily be confused with symptoms of disease. Therefore, adverse drug reactions should be considered as a cause of any presenting symptoms in the aging patient. The most significant non specific adverse effects of drugs are confusion, falls and incontinence.

Drug Interactions

Drug interactions are common in the elderly and risk increases with every medicine added to the patient's regimen. Drug interaction can attentuate or accentuate a medication's therapeutic or adverse effects in a patient. Scrutiny of patient's medication profile is necessary to identify and avoid serious and problematic interactions of all types. Drug interactions may be of three types.

(i) Drug - Drug interaction
(2) Drug disease interaction
(3) Drug food Interaction

A number of factors increase risk of drug related problems in the elderly including sub-optimal prescribing (e.g., overuse of medication or polypharmacy, inappropriate use and under use) medication errors in both dispensing and administration problems and patient medication non adherence, both intentional and unintentional.

Overuse (Polypharmacy)

Polypharmacy can be defined as either the concomitant use of multiple drugs or administration of more drugs than are clinically indicated. Polypharmacy practically occurs because of the multiple disease states being treated by multiple physicians. Also, most doctors have a tendency to prescribe medication for many common symptoms. Multiple medication use has been strongly associated with adverse drug reactions. The key issues are that no medication should be used without indication and no duplication of therapy should occur. Moreover if side effects develop they should be addressed through changed medication or altering the dose rather than by adding additional medication.

Under use

An important and increasingly recognized problem in elders is under use, defined as omission of drug therapy that is indicated for the treatment or prevention of disease or condition. Several studies have shown that one or more drugs were omitted in about half of elderly patients because of lack of physician prescribing. Also elderly patients with chronic disease were less likely to be treated for unrelated disorders. Under use may have an important relationship with negative health outcomes in elderly patients.

Poor Compliance /Adherence

Medication non-adherence is a common problem in the elderly. The prevalence ranges from 40-70% of patients. Overall these patients are adherent with 75% of their medication.

There are a number of factors which contribute to non-compliance in elderly.

1. Many elderly patients are unable to afford their medication.
2. Number of medication doses per day can contribute to non-compliance.
3. Some patients may not be compliant due to social and behavioural perceptions.
4. Some 50% of patients over the age of 85 have some form of cognitive impairment. This may cause them to forget whether they have taken doses of medication each day, thus putting them at the risk to over dose or under dose of essential medication.

Inappropriate Prescribing

Inappropriate prescribing can be defined as prescribing of medication outside the bounds of accepted medical standards. Alternatively inappropriate prescribing can be defined as using drugs which should avoided because their risk outweighs potential benefit.
Studies have revealed that 14-27% of persons 65 years of age and older, living in the community, take one or more such drugs. Inappropriate prescribing may pose important health risks and has been found to be associated with drug related hospital admissions and readmissions.

There is a set of medications which has been labeled problematic for elderly because they are at increased risk of adverse events from these agents.

• Obtain complete history including drug history
  
• Diagnose appropriately
  
• Choose the right medication
  
• Choose the right dose based on principle of geriatric pharmacology
  
• Monitor the drug therapy
  
• Use the lowest effective dose and least frequent dosage of medication
  
• Establish realistic treatment goals
  
• Consider non-drug alternatives
  
• Simplify drug regime
  
• Consider high prevalence of cognitive impairment
  
• Decline with aging
  
• Determine the appropriate duration of treatment
  
• Avoid drug disease interaction
  

The proportion of population that is elderly is increasing and this is the group which consumes the most medication and is at most risk of adverse reactions.

Understanding the mechanism of these reactions is helpful in minimizing their occurrence.

• The golden rule is: Start low, go slow.
  
• Another rule is: If not essential, don't prescribe.
  
• And finally remember that adverse drug reactions in the elderly tend to be non-specific and present as the geriatric triad of confusion, ataxia/falls and incontinence.