TDM Clinic Guide PDF
TDM Clinic Guide PDF
TDM Clinic Guide PDF
Ndubuisi Nwobodo
Department of Pharmacology and Therapeutics, Ebonyi State University, Abakaliki, PMB 53, Nigeria
Corresponding author: Ndubuisi Nwobodo. Email: [email protected]
Genetic polymorphism evidenced by marked vari- of warfarin metabolism by cytochrome P45020, while
ations in the cytochrome P450 isoenzymes affects high dose chronic alcoholism has been shown to
serum drug concentration measurements. CYP1A2, decrease warfarin activity as evidenced by decreased
CYP3A4, CYP2C9, CYP2D6 and CYP2E1 are the international normalisation ratio (INR) due to
main cytochrome P450 isoenzymes that mediate the increased warfarin metabolism.21 Tobacco contains
oxidative metabolism of drugs. The major and most substances such as nicotine, polycyclic aromatic
predominant cytochrome P450 hepatic oxidative iso- hydrocarbons (PAHs) and N-nitrosoamines which
enzyme is CYP3A4.14 Pharmacogenetic polymorph- induce certain cytochrome P450 enzymes involved in
isms affect the biotransformation and clinical drug metabolism. There is increased metabolism of
outcome of a number of drugs. There are marked drugs in smokers leading to significant reduction in
differences in the pharmacokinetic parameters in serum concentration, hence the need to receive larger
oral antidepressant drugs metabolised via the cyto- doses of drugs than non-smokers to achieve similar
chrome P450 isoenzyme CYP2D6. CYP2C9 accounts pharmacological and clinical effects.22 Studies have
for up to 10-fold difference in pharmacokinetic par- also reported changes in warfarin disposition in smo-
ameters in oral hypoglycemic agents, oral anticoagu- kers relative to non-smokers, with demonstrable
lants and non-steroidal anti-inflammatory agents. increases in INR after cessation of smoking with con-
Hence, individualisation of therapy could be effect- sequent reduction in warfarin dose.23,24
ively predicated on pharmacogenitically based dosage A number of disease conditions affect drug dispos-
adjustments. Pharmacogenetic tests, which are now ition. Liver disease causes impairment of drug clear-
advocated prior to prescription of specific anticancer ance and depression of cytochrome P450 enzyme
and cardiovascular drugs, may likely become wide- activities and gene expression.25 Serum proteins pro-
spread as these tests become more cost effective and duced in the liver to which many drugs bind are
accessible. decreased in hepatic disease. Hence, there is elevated
Gender differences exist in response to drug treat- serum concentration of free or unbound drug with
ment. Increases in distribution of hydrophilic drugs profound effect on drug toxicity, justifying the need
in females result from greater body fat in women and for monitoring and dose adjustment in liver disease.
larger distribution volumes in males.15 Individual Cholestasis leads to increased risk of toxicity due to
variations in drug efficacy and toxicity are dependent reduced bile clearance.26 There is increased risk of
on gender differences in the pharmacokinetic param- adverse effects due to accumulation of drugs and
eters of several drugs. These gender-based differences metabolites in circulation resulting from impaired
underlie variations in the expression of hepatic micro- renal function. Impairment in drug clearance which
somal enzymes involved in the metabolism of drugs. is dependent on glomerular filtration rate occurs in
The female predominant expression of CYP3A4 renal disease. Drug therapy in elderly patients even in
accounts for sex differences in drug metabolism in drugs with a wide therapeutic window requires dose
humans. The temporal pattern of plasma growth hor- adjustment based on renal function.27 Uremia in
mone release by the pituitary regulates the sexually severe renal impairment results to diminution of
dimorphic expression of the cytochrome P450 isoen- serum binding proteins, with implication of incre-
zyme system. ment in free drug concentration of strongly bound
The main consideration in drug therapy during drugs with consequent increase in drug toxicity.
pregnancy is safety of the foetus. Monitoring is essen- Congestive heart failure results in diminished
tial to achieve individualisation of therapy, consider- tissue perfusion, reduced clearance and decrease in
ing challenges in drug disposition during volume of distribution (Vd). Higher plasma drug con-
pregnancy.16 Pharmacokinetics of drug use in preg- centrations occur in congestive heart failure due to
nancy are influenced by compartmentalisation of decrease in volume of distribution and clearance
drug in the foetus/placenta, placental transport of resulting from impaired metabolism, thereby requir-
drug and foetal/placental drug metabolism.17 ing monitoring due to increased risk of toxicity.28
Chronic alcoholism induces the microsomal alco- Thyroid function has been shown to influence the
hol oxidising system involving CYP2E1 which is metabolism of a number of drugs. Hypothyroidism
involved in the metabolism of toxic substances and inhibits the cytochrome P450 microsomal enzyme
plays a role in alcohol-induced liver damage.18 The system leading to increased serum drug levels with
activity of hepatic alcohol dehydrogenase, the major high risk of toxicity, while hyperthyroidism causes
liver metabolising enzyme, is reduced by H2-receptor its activation leading to significantly low serum
antagonists used in the treatment of peptic ulcer dis- drug levels and reduced risk of toxicity.29,30
ease.19 Low-dose alcohol consumption has been Hypothyroidism results to remarkable elongation in
shown to increase warfarin activity due to inhibition the half-life of antipyrine, which is appreciably
4 Journal of the Royal Society of Medicine Open 5(8)
shortened during hyperthyroidism. Higher doses than 2. Gross AS. Best practice in therapeutic drug monitor-
usual of digitalis are required in hyperthyroid than ing. Br J Clin Pharmacol 1998; 46: 95–99.
hypothyroid patients, due to altered disposition of 3. TriMark Publications. Therapeutic drug monitoring
digitalis in thyroid dysfunction. There is no alteration to spike $2.69 billion by 2019. See http://www.
trimarkpublications.com/therapeutic-drug-monitoring-
in disposition of propylthiouracil during thyrotoxicosis.
markets/(last checked 22 May 2014).
However, there is a reduction in plasma half-life of 4. Shenfield GM. Therapeutic drug monitoring. Br J Clin
methimazole during thyrotoxicosis, which is observed Pharmacol 2001; 52: 35–45.
to be elevated during hypothyroidism. Reduction in 5. Nicoll D. Pocket Guide to Diagnostic Tests, 3rd ed.
serum level of free thyroxine (T4), associated with New York: Lange/McGraw-Hill, 2001.
decreased cytochrome P450-mediated hydroxylation 6. Siemens. Therapeutic drug monitoring: an educational
of phenytoin, results in increased phenytoin toxicity. guide. See http://www.siemens.com/diagnostics (last
Immunosuppressant therapy in organ transplantation checked 22 May 2014).
is affected by thyroid function. Hypothyroidism results 7. Dandekar UP, Chendra RS, Dalvi SS, et al. Analysis of
to decreased metabolism of cyclosporine leading to ele- a clinically important interaction between phenytoin
vation in plasma levels and consequent toxicity. and Shankhapushpi, an ayurvedic preparation.
J Ethnopharmacol 1992; 35: 285–288.
8. Miller LG. Herbal medicinals: selected clinical consid-
Conclusion erations focusing on known or potential drug-herb
interactions. Arch Int Med 1998; 158: 2200–2211.
Therapeutic drug monitoring service in a developing 9. Hamilton JR. Health research in the developing world:
nation such as Nigeria remains poorly developed. This a gastroenterological view from Bangladesh. Can J
may be largely attributed not only to constraints posed Gastroenterol 1997; 11: 94–98.
by limited scarce resources but also ignorance among 10. Krishnaswamy K. Nutrition and drug metabolism. Ind
health practitioners. There is, therefore, urgent need J Med Res 1978; 68(suppl): 109–120.
for advocacy and proper enlightenment of the health 11. Birkett DJ. Therapeutic drug monitoring. Aust Prescr
practitioners and managers on the relevance of thera- 1997; 20: 9–10.
peutic drug monitoring in enhancing patient care and 12. Florence AT and Jani PU. Novel oral drug formula-
tions: their potential in modulating adverse effects.
overall clinical outcome. Full fledged clinical pharma-
Drug Saf 1994; 10: 233–266.
cology departments should be established across 13. Tam YK. Individual variation in first pass metabolism.
teaching hospitals in Nigeria, well equipped to offer Clin Pharmacokinet 1993; 25: 300–328.
therapeutic drug monitoring service. Deans of medical 14. Wilkinson GR. Cytochrome P450 (CYP3A4) metabol-
schools should be encouraged to incorporate teaching ism: prediction of in vivo activity in humans.
the basics of therapeutic drug monitoring in the cur- J Pharmacokinet Biopharm 1996; 24: 475–490.
riculum. The principle and practice of therapeutic 15. Schwartz JB. The influence of sex on pharmacokinet-
drug monitoring should be emphasised in the continu- ics. Clin Pharmacokinet 2003; 42: 107–121.
ing medical education lecture series periodically orga- 16. Leobstein R and Koren G. Clinical relevance of thera-
nised to update health practitioners. peutic drug monitoring during pregnancy. Ther Drug
Monit 2002; 24: 15–22.
17. Rakhmania N, Van den Anker and Soldin SJ. Safety
Declarations
and pharmacokinetics of antiretroviral therapy during
Competing interests: None declared
pregnancy. Ther Drug Monit 2004; 26: 110–115.
Funding: None declared 18. Jimenez-Lopez JM and Cederbaum AI. CYP2E1
Ethical approval: Not applicable dependent oxidative stress and toxicity: role in ethanol
induced liver injury. Expert Opin Drug Metab Toxicol
Guarantor: NN
2005; 1: 671–685.
Contributorship: NN is the sole author responsible for the con- 19. Caballeria J, Baraona E, Deulofeu R, Hernandez-
ception, drafting, editing and review of the manuscript. Munoz R, Rodes J and Lieber CS. Effects of H2-recep-
Acknowledgements: The author wishes to acknowledge Samuel tor agonists on gastric alcohol dehydrogenase activity.
Igwe for critically reviewing the draft manuscript and offering Digest Dis Sci 1991; 36: 1673–1679.
useful advice. 20. Harrda DE, Mai T and Clonlahen J. Enhanced antith-
Provenance: Not commissioned; peer-reviewed by Mubarak rombotic effect of warfarin associated with low dose
Nasser Al Amer alcohol consumption. Pharmacotherapy 2005; 25:
303–307.
21. Weathermon R and Crabb DW. Alcohol and medica-
References tion interactions. Alcohol Res Health 1999; 23: 40–54.
1. Watson I, Potter J, Yatscoff R, Fraser A, Himberg JJ 22. Kroon LA. Drug interactions and smoking: raising
and Wenk M. Therapeutic drug monitoring [Editorial]. awareness for acute and critical care provider. Crit
Drug Monit 1997; 19: 125. Care Nurs Clin North Am 2006; 18: 53–62.
Nwobodo 5
23. Evans M and Lewis GM. Increase in international nor- 28. Shammas FV and Dickstein K. Clinical pharmacokin-
malization ratio associated with smoking cessation. etics in heart failure: an updated review. Clin
Ann Pharmacother 2001; 35: 385–386. Pharmacokinet 1988; 15: 94–113.
24. Evans M and Lewis GM. Increase in international nor- 29. Croxson MS and Ibbertson HK. Serum digoxin in
malization ratio after smoking cessation in a patient patients with thyroid disease. Br Med J 1975; 3:
receiving warfarin. Pharmacotherapy 2005; 25: 566–568.
1656–1659. 30. Nishimura M, Yamada K, Matsushita K, Sakamoto
25. Cheng PY and Morgan ET. Hepatic cytochrome P450 K, Saisu T, Kashiwabara H, et al. Changes in trough
regulation in disease state. Curr Drug Metab 2001; 2: levels of whole blood cyclosporine and graft function of
165–183. a kidney transplant recipient with onset of hypothyroid-
26. Rollins DE and Klaasen CD. Biliary excretion of drugs ism after transplantation. Transplantation 1996; 62:
in man. Clin Pharmacokinet 1979; 4: 368–379. 1509–1511.
27. Terrel KM, Heard K and Miller DK. Prescribing
to older ED patients. Ann Emerg Med 2006; 24:
468–478.