pROF jAZANUL aNWAR*Liver damage Some analgesics Acetaminophen
(use of excessive doses)Kidney damage Nonsteroidal
anti-Ibuprofeninflammatory drug Ketoprofen (repeated use of
Naproxen excessive doses) Aminoglycoside Kanamycin
antibioticsGentamicin Cisplatin
Confusion and Sedatives, Diphenhydramine drowsiness many
antihistamines Antidepressants Amitriptyline (especially in older
people) Imipramine Adverse Drug Reaction Types of Drugs
Examples
************Things to say-This definition is taken from the
CSM/MCAs Guidance notes document (October 2002) which has been
written for new reporters. Details of where to find this document
on the MCA/CSM website is given later on.-Be aware that whenever a
patient takes a drug, there is a potential risk of an adverse
reaction to that drug. -The terms "adverse reaction" and "adverse
effect" are interchangeable, however an adverse effect is seen from
the point of view of the drug, whereas an adverse reaction is seen
from the point of view of the patient. The term side effect is also
used.
Useful informationMCA/CSM Suspected adverse drug reaction (ADR)
reporting and the Yellow Card Scheme, Guidance
noteshttp://www.mca.gov.uk/ourwork/monitorsafequalmed/yellowcard/ycguidancenotes.pdf
Alternative definition for an ADR:-WHO definition"a response to a
drug that is noxious and unintended and occurs at doses normally
used in man for the prophylaxis, diagnosis or therapy of disease,
or for modification of physiological function
**InformationUse these examples or examples of your own*Things
to sayAge The very old and the very young are more susceptible to
ADRs. In children, systems for handling drugs are not developed and
in the elderly these systems may be slowing with age. The elderly
are also likely to have multiple and often chronic diseases. E.g.
Elderly patients much more susceptible to the effects of
benzodiazepines leading to drowsiness the next day.
Gender Women appear to be at a higher risk of suffering ADRs.
The reason is not clear.
Multiple therapies The incidence of ADRs increases sharply with
the number of drugs taken, 50% patients on 5 drugs are likely to
experience an ADR.
Intercurrent diseases Drug handling may be altered in patients
with renal, hepatic, and cardiac disease. Allergy patients with a
history of allergic disorders are at the greatest risk of
experiencing an allergic reaction.
Useful informationSpecific diseases predispose to ADRs eg in HIV
positive patients there is an increased frequency of idiosyncratic
toxicity with anti-infective drugs such as co-trimoxazole (50% vs
3% in HIV negative patients).
**Things to sayAdverse drug reactions are a major clinical
problem1) Cause around 5% of all hospital admissions. A pilot study
of 200 acute medical admissions undertaken at the Royal Liverpool
University Hospital identified that 7.5% were due to ADRs. 2) Cause
death in 1 in 1000 medical inpatients (and 1 in 10,000 surgical
inpatients)
3) Drug therapy may affect the patients quality of life. In some
cases medicines may have a greater impact on the patient than the
symptoms of the disease itself. e.g. Drugs used to treat
hypertension often produce adverse effects while hypertension
itself often has no symptoms.
4) Non-compliance may lead to re-emergence of the original
disease and can be particularly important if the treatment is
prophylactic. E.g malaria prophylaxis, the oral contraceptive.
Useful informationRef for 1) Green CF et al. Adverse drug reactions
as a cause of admissions to an acute medical assessment unit: a
pilot study. J Clin Pharm Ther 2000; 25: 355-361Ref for 2)
Pirmohamed et al. Adverse drug reactions. BMJ 1998; 316: 1295-1298
*Things to sayYou can use these examples or examples of your
own
Obvious interactions -many drugs interact with warfarin causing
alteration of the INR which may lead to bleeding episodesUse of
contra-indicated drugs - use of a non-selective beta-blocker in an
asthmatic can lead to bronchospasmDrug use in an inappropriate
clinical indication or medically unnecessary -antibiotics for a
viral infection will not cure the infection but will expose
patients to the adverse effects of the drug.*Things to say
We now know what an ADR is and why ADRs are a problem
So
How can you identify ADRs? **Things to say
Not all ADRs will be apparent to the patient or the health care
professional as ADRs can mimic any disease process. Always be alert
to the possibility of ADRs as a cause of the patients symptoms.
Useful information
Quote taken from Edwards IR and Aronson JK. Adverse drug
reactions: definitions, diagnosis, and management. Lancet 2000;
356: 1255-1259
***Things to say1) Up to 40% patients receiving drugs in the
community are though to experience ADRs. It is difficult to study
ADRs in the community and there are very few well designed
studies2) NSAID use is associated with significant morbidity and
mortality in the UK each year. There is a strong association
between NSAID use and likelihood for upper GI emergency
admission.
Useful informationRef for 1) In a 1979 study in general practice
41% of 817 patients surveyed were thought to have certainly or
probably experienced an ADR. Martyrs C. Adverse reactions to drugs
in general practice. BMJ 1979; 2: 1194-1197)Ref for 2) The data
recorded in the trial was extrapolated to give the estimated UK
figures. The study was a retrospective survey of case notes of all
emergency upper GI admissions per annum attributable to NSAID use.
The study was undertaken at 2 District General Hospitals in the
North West of England (catchment population 550,000). Matched
controls were emergency admissions not caused by upper GI
diagnoses. (Blower et al. Emergency admissions for upper
gastrointestinal disease and their relation to NSAID use. Aliment
Pharmacol Ther 1997; 11: 283-291)
***The above list includes types of ADRs which are considered
reportable.***The next few slides will review some of the
mechanisms for drug interactions in more detail. Several examples
of drug interactions that occur prior to drug administration are
listed here. When phenytoin is added to solutions of dextrose, a
precipitate forms and the phenytoin falls to the bottom of the IV
bag as an insoluble salt. When this happens, it is no longer
available to control seizures.
Amphotericin is still used widely as a urinary bladder perfusion
to treat aggressive fungal infections. If it is administered in
saline, the drug precipitates and can erode through the bladder
wall if not removed. The clinical presentation of such cases is an
acute abdomen due to perforation of the bladder.(Personal
Communication, David Flockhart, MD, PhD., University of Indiana,
July 2001)
Lastly, aminoglycosides should not be co-mixed in IV fluids with
beta-lactam antibiotics because covalent bonds are formed between
the two drugs. This can markedly reduce antibiotic efficacy. *The
next few slides will review some of the mechanisms for drug
interactions in more detail. Several examples of drug interactions
that occur prior to drug administration are listed here. When
phenytoin is added to solutions of dextrose, a precipitate forms
and the phenytoin falls to the bottom of the IV bag as an insoluble
salt. When this happens, it is no longer available to control
seizures.
Amphotericin is still used widely as a urinary bladder perfusion
to treat aggressive fungal infections. If it is administered in
saline, the drug precipitates and can erode through the bladder
wall if not removed. The clinical presentation of such cases is an
acute abdomen due to perforation of the bladder.(Personal
Communication, David Flockhart, MD, PhD., University of Indiana,
July 2001)
Lastly, aminoglycosides should not be co-mixed in IV fluids with
beta-lactam antibiotics because covalent bonds are formed between
the two drugs. This can markedly reduce antibiotic efficacy. *A
number of interactions occur in the GI tract and reduce the entry
of drugs into the systemic circulation.
Particularly notable among these is the ability of
aluminum-containing medicines such as sucralfate (Carafate) and
antacids to reduce the absorption of expensive and potentially
life-saving antibiotics like ciprofloxacin (Cipro) and azithromycin
(Zithromax). Women taking iron supplements often do not consider
them as a medicine, and should be specifically questioned about
whether they are taking iron if they are to be prescribed a
quinolone or azithromycin. Drugs such as ketoconazole (Nizoral) and
delavirdine (Rescriptor) require an acidic environment to be in the
non-charged form that is preferentially absorbed. Solubility is
drastically reduced in neutral or basic environments that occur
when the patient takes medications such as omeprazole (Prilosec),
lansoprazole (Prevacid), or H2-antagonists that raise the stomachs
pH. *Some drugs can bump other drugs off proteins in the plasma and
result in an increased amount of free drug, but this is only
transient because the usual elimination mechanisms respond by
increasing the rate of elimination. There is no clinically relevant
protein bumping interaction that has been reported. The cited
examples have been subsequently shown to be due to inhibition of
elimination, not plasma protein displacement.
*The next few slides will focus on drug metabolism. Some
important preventable drug interactions are due to their effects on
drug metabolizing enzymes, resulting in either inhibition of the
enzyme or induction of the enzyme. There are many potential
consequences of changes in drug metabolism for a given drug. It is
made more complex by the fact that there are multiple pathways of
metabolism for many drugs.
The majority of drugs that are metabolized are converted to
inactive metabolites. This is the most common fate for most drugs.
Of the remaining drugs, some are converted to metabolites that
retain the same activity as the parent. An example of this is
fexofenadine (Allegra), the active metabolite of terfenadine that
has equal potency at the histamine receptor and now is on the
market and used clinically for allergic rhinitis. However,
fexofenadine is is more than 50 times less active in blocking
potassium channels in the heart and therefore, unlike terfenadine,
does not cause torsades de pointes.{Woosley} In some cases the
metabolites are actually more potent than the parent. For example,
a pro-drug such as enalapril must be hydrolyzed to enalaprilat to
become active. In some cases, the metabolites have entirely new
pharmacologic actions not seen with the parent drug. Metabolites
can also be toxic, such as the metabolites of acetaminophen which
can cause liver failure or the metabolite of meperidine which can
cause seizures. Inhibition of metabolism could result in
potentially toxic concentrations of the parent compound. On the
other hand, if the parent drug needs to be metabolized to the
active compound, therapeutic failure could result (as happens, for
example, if codeine is not metabolized to morphine). Induction of
drug metabolizing enzymes could similarly result in a
subtherapeutic effect by reducing drug levels below that required
for efficacy.
Woosley RL, Chen Y, Freiman JP, Gillis RA. Mechanism of the
cardiotoxic actions of terfenadine. JAMA 1993;
269(12):1532-1536.
*
The major group of enzymes in the liver that metabolize drugs
can be isolated in a subcellular fraction termed the microsomes.
The largest and most important of these enzymes are the cytochrome
P450 family of enzymes. The origin of the term cytochrome P450 will
be explained later. In addition to cytochrome P450, there are other
enzymes in microsomes such as flavin monooxygenase (termed FMO3).
These are also responsible for metabolism of some drugs, but not as
generally important as the cytochrome P450 system.*In addition to
the drug-drug interactions just reviewed, drug-disease interactions
can occur. These include interactions between certain drugs and
specific disease states. Severe liver disease can be associated
with reduced metabolic clearance and higher plasma levels of drugs
extensively metabolized by the liver.{Brouwer} Although liver
disease reduces drug clearance on average, the change is relatively
small and usually not clinically relevant except in patients with
near terminal liver disease. The effects of renal disease on
elimination of drugs that are primarily cleared renally are more
predictable, and well-established guidelines exist for dosage of
many drugs in renal disease.{Lam} Heart failure reduces liver blood
flow and causes a reduction in clearance for drugs such as
lidocaine or propranolol that are usually extensively cleared by
the liver,{Shammas} and acute myocardial infarction reduces
clearance of some drugs, such as lidocaine, as well.{Pieper} Acute
viral infection and changes in thyroid function have been
associated with altered clearance for some drugs, such as
theophylline and warfarin.{Pokrajac}{Stephens}{Yamaguchi} However,
the results are so variable between individuals that it is hard to
predict who is at risk, and these changes are usually only clinical
important in cases of extremely impaired organ function.
Brouwer KLR, Dukes GE, Powell JR. Influence of liver function on
drug disposition. In: Evans WE, Schentag JJ, Jusko WJ, editors.
Applied Pharmacokinetics: Principles of Therapeutic Drug
Monitoring. Vancouver, WA: Applied Therapeutics, Inc., 1992:
6-1-6-59.
Lam YW, Banerji S, Hatfield C, Talbert RL. Principles of drug
administration in renal insufficiency. Clin Pharmacokinet 1997;
32(1):30-57.Shammas FV, Dickstein K. Clinical pharmacokinetics in
heart failure. An updated review. Clin Pharmacokinet 1988;
15(2):94-113.Pieper JA, Johnson KE. Lidocaine. In: Evans WE,
Schentag JJ, Jusko WJ, editors. Applied Pharmacokinetics:
Principles of Therapeutic Drug Monitoring. Vancouver,WA: Applied
Therapeutics, Inc., 1992: 21-1-21-37.Pokrajac M, Simic D, Varagic
VM. Pharmacokinetics of theophylline in hyperthyroid and
hypothyroid patients with chronic obstructive pulmonary disease.
Eur J Clin Pharmacol 1987; 33(5):483-486. Stephens MA, Self TH,
Lancaster D, Nash T. Hypothyroidism: effect on warfarin
anticoagulation. South Med J 1989; 82(12):1585-1586.Yamaguchi A,
Tateishi T, Okano Y, Matuda T, Akimoto Y, Miyoshi T et al. Higher
incidence of elevated body temperature or increased C-reactive
protein level in asthmatic children showing transient reduction of
theophylline metabolism. J Clin Pharmacol 2000; 40(3):284-289.
*Several drugs are known to interact with foods,{Williams} some
of which are listed here. One of the early observations was the
reduced absorption of tetracycline when taken with milk products.
The chelation of tetracycline by calcium prevents it from being
absorbed from the intestines. Dietary sources of vitamin K, such as
spinach or broccoli, may increase the dosage requirement for
warfarin by a pharmacodynamic antagonism of its effect. Patients
should be counseled to maintain a consistent diet during warfarin
therapy.
Grapefruit juice contains a bioflavonoid that inhibits CYP3A and
blocks the metabolism of many drugs. This was first described for
felodipine (Plendil) {Bailey 1991} but has now been observed with
several drugs.{Kane} This interaction can lead to reduced clearance
and higher blood levels when the dugs are taken simultaneously with
grapefruit juice. With regular consumption, grapefruit juice also
reduces the expression of CYP3A in the GI tract.{Lown}Williams L,
Davis JA, Lowenthal DT. The influence of food on the absorption and
metabolism of drugs. Med Clin N Am 1993; 77(4):815-829.
Bailey DG, Spence JD, Munoz C, Arnold JM. Interaction of citrus
juices with felodipine and nifedipine. Lancet 1991;
337(8736):268-269.
Kane GC, Lipsky JJ. Drug-grapefruit juice interactions. Mayo
Clin Proc 2000; 75(9):933-942.
Lown KS, Bailey DG, Fontana RJ, Janardan SK, Adair CH, Fortlage
LA et al. Grapefruit juice increases felodipine oral availability
in humans by decreasing intestinal CYP3A protein expression. J Clin
Invest 1997; 99(10):2545-2553.
***
