1.

0 Introduction

A drug can be any natural or synthetic substance which has the capacity to alter the
physiological state of a living organism. A drug may have either a therapeutic or a toxic
effect. However, drug response varies from one individual to another. This may be due to
various causes such as disease, environmental and genetic factors (Wilkinson, 2008).

Drug therapy consists of four major processes, namely, the pharmaceutical process, the
pharmacokinetic process, the pharmacodynamic process and the therapeutic process.

The pharmaceutical process is mainly concerned whether the drug is getting into the patient.
This process depends mainly on patient compliance and the properties of the drug
formulation which determine whether or not the drug is absorbed from the gut, skin,
subcutaneous tissues or muscle (Grahame-Smith and Aronson, 1992). The pharmacokinetic
process is concerned whether the drug is getting to its site of action. This depends on the
absorption, distribution, metabolism and excretion of drugs (Grahame- Smith and Aronson,
1992). The pharmacodynamic process is concerned with the pharmacological effect exerted
by the drug at its site of action. The pharmacological effect may lead to a therapeutic as well
as an adverse effect (Grahame- Smith and Aronson, 1992).

Inter individual variations may cause the various processes of drug therapy to vary from one
person to another, thus giving a different drug response (Galbraith et al, 2007). The figure
below shows the various factors that may affect drug response in an individual.
Figure 1: Different factors that may affect drug response in an individual (Vesell, 1991)

2.1 Diet

Differences in diet have been found to have an effect on drug response (Wilkinson, 1997).
Diet varies from one individual to another because of different ways of food preparation,
religion, culture and amount of food ingested.

Presence of food in the gut at the time of administration may affect absorption as drug
molecules compete with nutrient molecule at absorption sites. This results in lower plasma
concentration and prolonged drug action (Galbraith et al, 2007). Also some drugs such as
tetracycline antibiotics may chelate with calcium salts found in milk such that most of the
drugs are excreted in faeces (Galbraith et al, 2007). Furthermore a diet rich in protein may
accelerate the clearance of antipyrine and theophylline (Wilkinson, 1997).

Caffeine, cruciferous vegetables such as cabbage, broccoli, cawliflower etc. have been found
to increase drug metabolism (O’Mahony and Woodhouse 1994). Moreover, charcoal broiled
and smoked foods have a high content of polycyclic hydrocarbons and enhances drug
metabolism (Wilkinson 1997).

Dietary supplements are often used to supplement a normal diet and can interact with certain
drugs. For example, administration of vitamin C and ethinylestradiol leads to 50 % increase
in the level of the steroid in plasma (Wilkinson 1997). Other examples include folic acid
supplements reducing the level of anticonvulsant phenytoin in plasma and vitamin B6
lowering the bioavailability of levadopa (Wilkinson 1997). Other foods that can affect the
bioavailabity of drugs include salt, spices, garlic, and grapefruit juice and many others
(Wilkinson 1997).

2.2 Alcohol

Alcohol intake can affect absorption, distribution, metabolism, and excretion of certain drugs
such as antibiotics, anticoagulants, antihistamines, digitalis, diuretics and many others
(Seixas, 1975).

Alcohol has been found to increase blood flow in the gastrointestinal tract and also to
increase mixing of the gastric contents. As a result, the rate of drug absorption is also
increased. However, very large quantity of alcohol in the stomach can cause pyloric spasm
and thus reducing the rate of drug absorption ( Linnoila et al, 1979).

Alcohol may also have an effect on drug distribution as chronic alcoholics have low levels of
serum albumin which causes an increased distribution of certain drugs such as diazepam.
Alcohol as well as many drugs is metabolised in the liver. Alcohol has been found to inhibit
liver enzymes to metabolise some drugs and can also induce some liver enzymes to
metabolise drugs at a faster rate (Linnoila et al, 1979).

Alcohol has also been found to increase the rate of drug elimination through the kidneys and
sometimes it may reduce the rate drug elimination particularly in chronic alcoholics (Linnoila
et al, 1979).

Alcohol can also increase the adverse effects of sedatives, certain anxiolytics, sedative
antidepressants and antipsychotics and anticholinergic drugs (Linnoila et al, 1979).
 2.3 Gender

Gender differences may affect the bioavailability of certain drugs. For instance, the
bioavailability of oral drugs varies from male to female. This is because gastrointestinal
motility and concentration of enzymes responsible for drug metabolism, is different in male
and female (Franconi et al, 2006). Metabolism of certain drugs has also to been found to be
different between men and women. Furthermore, lipophilic drugs are more widely distributed
in females than males because of the higher proportion of body fat in females. Moreover,
renal excretion of drugs has been found to be more in male than in female (Franconi et al,
2006).

Pharmacodynamic processes also differ from male to female. For example, females are more
sensitive to morphine than males. On the other hand, ibuprofen is more active in men than
women (Franconi et al, 2006).

2.4 Drug disease interaction

Diseases may alter the pharmokinetic and pharmacodynamic processes of drugs. Heart
disease, renal failure, hepatic damage, gastrointestinal malabsorption, parenchymal lung
disease, hyperthyroidism and acute or chronic infection may influence binding of serum
protein to drugs, drug biotransformation or renal drug clearance (Galbraith et al, 2007).

2.4.1Hepatic function

The liver is an important site for drug metabolism in the body. Diseases of the liver can cause
accumulation of drugs to toxic levels or prolonged drug effects. The impact of liver disease
will depend on the pharmacokinetic properties of the drug (Galbraith et al, 2007).

In chronic liver diseases, blood from the portal circulation may go directly to the systemic
circulation, bypassing the hepatocytes. Also, the functional capacity of the hepatocytes and
activity of the metabolising enzymes is greatly reduced in diseases of the liver. These factors
may cause the oral bioavailability of drugs to increase by 2 to 4 times (Wilkinson, 1997).
 2.4.2 Renal Function

Kidney diseases may affect the blood concentration of many drugs. Some drugs such as
penicillins, aminoglycosides and digoxin are excreted mostly unchanged from its
administered form. Inability to excrete these drugs may lead to toxic effects in patients with
renal diseases (Galbraith et al, 2007).

2.4.3 Circulatory insufficiency

Cardiac failure or shock may reduce blood flow to the kidney and liver, thus reducing the
elimination of drugs and prolonging the drug action (Galbraith et al, 2007).

2.5 Drug- drug interaction

Drug-drug interactions may affect the pharmacokinetic and pharmacodynamic properties of

drugs. Co-administered drugs may increase or decrease absorption, may compete for binding
to tissue or serum proteins, may compete for bio transformation pathways or may affect renal
excretion (Vesell, 1991). For example non steroidal anti inflammatory drugs reduce renal
blood flow and may thus reduce excretion of drugs removed by the kidneys (Hussar, 2007).

2.6 Age

The effects of drugs may vary among people of different age groups. In young children, drug
metabolism is poor. Hepatic clearance is slow and this prolongs the half life of drugs. Also,
renal excretion of drugs is slow in neonates. Children also have different drug
pharmacodynamics as compared to adults. For example antihistamines which sedate adults
may be excitatory in children (Galbraith et al, 2007).

In the elderly, body composition and the function of excretory organs deteriorate with age.
The levels of body fluid fall with age and the amount of fatty tissues increases. Fat soluble
drugs are distributed in adipose tissues, reducing the amount of free drug at the receptors and
prolonging the duration of action. Also, there is increased sensitivity to adverse effects of
drugs for example haemorrhage from anticoagulants (O’Mahony and Woodhouse 1994).

2.7 Pregnancy

Pregnancy may have an effect on the absorption of some drugs. During pregnancy, peristalsis
and gastric emptying are slowed down. Furthermore, secretion of gastric increases during
pregnancy which may affect absorption of acidic drugs (Galbraith et al, 2007).

2.8 Compliance

Patient compliance may cause inter individual variations in drug response. Patients in most of
the cases do not adhere to the therapeutic plan. Thus, corrective measures such as patient
education are very important for a therapeutic outcome (Macleod and Soldin, 1986).

2.9Smoking

Chemicals from cigarette smoke have been found to enhance clearance of certain drugs such
as antipyrine, phenacetin and theopylline. This may be because cigarette smoke affects
biotransformation in the liver by increasing the activity of hepatic enzymes (O’Mahony and
Woodhouse 1994).

2.10 Occupation

Workers in agriculture and chemical manufacturing are continuously being exposed to

chemicals such as pesticides and insecticides which might alter drug metabolism. Thus,
response to certain drugs would be different in these individual as compared to those not
exposed to these chemicals (Galbraith et al, 2007).
 2.11 Body weight

An increase in the amount of body fat may affect the distribution of drugs. Lipophilic drugs
become highly bound in adipose tissue which acts a reservoir. This may reduce the amount of
free drug at the receptors and prolong the duration of action. For instance, the level of
theophylline is lower in obese patients (Galbraith et al, 2007).

2.12 Pharmacogenetics

Pharmacogenetics is defined as the study of genetic variations causing variable drug response
and includes the study of genetic polymorphism of drug transporters, drug metabolizing
enzymes and drug receptors (Severino and Del Zompo, 2004).

Mutations in the receptor genes can sometimes cause cells to be hyporesponsive to certain
ligands. For example, mutations in the vitamin D receptor cause them to have lower affinity
than the normal vitamin D receptor, leading to cellular resistance and decreased
responsiveness to hormone (Lu, 1998).

Genetic variations in drug transporters could also contribute to the pharmacokinetic

variations among individuals. For example, transporters for neurotransmitters exhibit genetic
variations and have been linked to variations in drug response (Evans and Johnson, 2001)

Another important determinant of drug disposition and action is the binding of drugs to
plasma proteins. Variations in protein binding have been noted among individuals because of
differences in the quality and quantity of the plasma proteins particularly serum albumin and
α1-acid glycoprotein (AAG) (Lu, 1998)

Cytochrome P450 enzymes is a family of enzymes involved in metabolism of many drugs.

Genetic variations of a number of enzymes of this family, such as CYP2D6 and CYP2C9,
have been found. CYP2D6 catalyzes the oxidation of many drugs, such as antiarrhythmics,
antidepressants, and neuroleptics. For CYP2D6, some individuals are ultra rapid
metabolisers while some are poor metabolisers. The ultra rapid metabolisers metabolise the
drug very rapidly such that there is no therapeutic effect at standard doses. On the other hand,
there is increased risk of toxicity at standard doses in poor metabolisers (Lu, 1998)
 3.0 Conclusion

Large variations have been found in the way patients respond to drugs. Thus, it is important
to consider these factors for effective clinical trials and drug prescription to produce a reliable
and therapeutic effect .
References

1. Evans, W and Johnson J. 2001. Pharmacogenomics: the inherited basis for

interindividual differences in drug response. Annual review of genomics and human
genetics. 2(9), p. 9-39

2. Franconi, F. Brunelleschi, S. Steardo, L. Cuomo, V. 2007. Gender differences in

drug responses. Pharmacological Research, 55(2), p. 81-95

3. Galbraith, A. Bullock, S. Manias, E. Hunt, B. Richards, A. 2007. Fundamentals of

Pharmacology: an applied approach for nursing and health. Second edition. England.
Pearson Education Limited.

4.

5. Hussar, D A. 2007. Drug Interactions: Factors affecting response to drugs. Available

from http://www.merck.com/mmhe/sec02/ch013/ch013c.html. [Accessed 10 February
2010]

6. Linnoila, M. Malttila MJ. Kitchell BS. 1979. Drug interactions with alcohol. Drugs.
18(4), p. 299-311

7. Lu, Y H A. 1998. V Drug-Metabolism Research Challenges in the New Millenniu:

Individual Variability in Drug Therapy and Drug Safety. Drug Metabolism and
Disposition. 26 (12). p.1217-1222

8. Macleod, S M and Soldin, S J. 1986. Determinants of drug disposition in man.

Clinical Biochemistry. 19, p.67-71

9. O’Mahony, M S and Woodhouse, K W. 1994. Age, environmental factors and drug

metabolism. Pharmacology and Therapeutics. 61, p. 279-287

10. Severino, G and Del Zompo, M. 2004. Adverse Drug reactions: role of
pharmacogenetics. Pharmacological Research. 49(4), p.363-373

11. Seixas FA. 1975. Alcohol and its drug interaction. Annals of Internal Medicine. 83(1),
p. 86-92.
12. Vesell, E S. 1991. Genetic and environmental factors causing variation in drug
response. Mutation Research. 247, p. 241-257

13. Wilkinson, GR. 2005. Drug Metabolism and Variability among Patients in Drug
Response. The New England Journal of Medicine, 352(21), p.2211-2224