Drug Induced FeverDrug Induced Fever

Presented By :Presented By :PharmacistPharmacist

Sufian .M.SulaimanSufian .M.SulaimanDrugs And Poisons Information CenterDrugs And Poisons Information Center

Al Khansa Teaching HospitalAl Khansa Teaching Hospital10 / 1 / 201210 / 1 / 2012

Body temperature is controlled by the hypothalamus. Body temperature is controlled by the hypothalamus.

According to studies of healthy individuals 18-40 According to studies of healthy individuals 18-40 years, the mean oral temperature is 36.8years, the mean oral temperature is 36.8± 0.4 ± 0.4 c, c, with low level at 6 A.M. and higher levels at 4-6 P.M.with low level at 6 A.M. and higher levels at 4-6 P.M.

The maximum normal oral temperature is 37.2 The maximum normal oral temperature is 37.2 c at c at 6 A.M. and 37.7 6 A.M. and 37.7 c at 4 P.M. c at 4 P.M.

Fever = temperatures greater than 37.8 Fever = temperatures greater than 37.8 cc

The mechanism of fever Body temperature is usually controlled within a narrow range by a number of physiological processes. It rises when heat absorption or production exceeds heat loss. Heat is absorbed from the environment, and endogenous production depends on metabolic rate, muscular activity, and ‘non- shivering thermogenesis’. Heat is lost from the body by convection and radiation from the surface and evaporation from the skin and lungs. The normal physiological response to a rising temperature is dilatation of skin blood vessels and increased sweating

The balance between heat production and heat loss is controlled by a combination of mechanisms including the behaviour of the whole organism (avoiding heat, shedding clothes, etc.) and homoeostatic mechanisms. Infection results in the introduction of exogenous pyrogens like bacterial lipopolysaccharide, and inflammation results in the production of endogenous pyrogens, such as the cytokine interleukin-lb. These act on the preoptic region of the hypo thalamus, where they lead to the production of prostaglandin E2 (PGE2) which is the neural mediator of fever, stimulating the endogenous pyrogen receptor (EP3).

In this short review we will outline a classification of the various mechanisms of drug-induced fever and give a number of examples. Classification of drug-induced fever , A drug can cause fever in the following ways:

1 - By acting as a direct or indirect pyrogen or by causing inflammation or tissue damage.

Interferons commonly cause a ´flu-like illness with fever. They have a broad role in regulating the immune response, possibly through induction of interleukin-6, since low doses of corticosteroids reduce the symptoms at the onset of interferon betalb therapy in multiple sclerosis.

Drugs that cause local inflammation or tissue damage A local chemical phlebitis that can lead to fever can occur with intravenous injections or infusions of antibiotics (e.g. erythromycin, vancomycin, or cephalosporins), cytotoxic drugs, and other drugs, for example amiodarone, barbiturates, unemulsified diazepam, and also with hypertonic fluids and solutions given for parenteral nutrition

2 - By causing pyrogen release as part of its pharmacological action.

An example of this is the Jarisch-Herxheimer reaction, in which endotoxin is released front bacteria. There is an abrupt onset of fever, myalgia, hyperventilation, and tachycardia about 6-8 hours after starting bactericidal therapy - classically treatment with penicillin for secondary syphilis14 but also in other infections. The Jarisch- Hetxheimer reaction is associated with raised concentrations of tumour necrosis factor (TNF) alpha, interleukin-6 and interleukin-8. Treatment with anti- TNF-alpha Fab before giving penicillin seems to suppress the reaction.

3 - By altering thermoregulation by central, peripheral, or metabolic means.

in several ways. Centrally, they can alter the ‘set point’ body temperature and alter adaptive responses to high temperature. Opioids, sedatives, and alcohol can affect the ability of a person to deal with excess heat. Peripherally, drugs can reduce the ability to lose heat by vasodilatation or sweating

Metabolism can be altered, leading to an increase in heat production. However, most drugs do not simply act at one level but have multiple effects, especially in overdosage. Anticholinergic agents, phenothiazines, tricyclic antidepressants, antihistamines and synthetic alkaloids impair hypo- thalamic function centrally and reduce sweating peripherally, leading to an anticholinergic ‘toxidrome’ of diminished sweating, coma, hyperreflexia, tachycardia, psychosis, dilated pupils, urinary retention, flushing and pyrexia.

4 - By causing hypersensitivity reactions.

Hypersensitivity reactions to drugs can include fever, as well as other features of hypersensitivity such as anaphylaxis (Type 1) or immune-complex disease (Type 3). Drug-induced fever due to Type 3 hypersensitivity typically presents as a low-grade fever that subsequently rises. It usually starts in the first 7-10 days of drug administration, particularly with anti- microbials

The fever subsides rapidly with drug withdrawal .

Antimicrobials can cause fever, and of course this can lead to diagnostic difficulty when there is the possibility of under-treated sepsis, requiring further antimicrobial treatment.

Antituberculous drugs, in particular, are associated with drug fever. Rifampicin causes a ‘flu-like syndrome of fever, rigors, bone pain, and malaise lasting about 12 hours after each dose when given intermittently- in keeping with a hyper- sensitivity reaction. Other antituberculous drugs - isoniazid, pyrazinamide and, rarely, ethambutol can also cause fever. Piperacillin has been implicated in drug fever especially in the treatment of patients with cystic fibrosis, who are often taking multiple drug regimens. Drug-induced fever is seen in up to 5 per cent of patients treated with vancomycin, and not uncommonly with sulphamethoxazole, trimethoprim, or co-trimoxazole.

5 - By inducing immunosuppression.

Patients who are immunocompromised by cancer chemotherapy, immunosuppressants (such as azathioprine), are at risk of opportunistic infections. Cytotoxic drugs, phenothiazines, many antibiotics, NSAIDs, antithyroid agents, and psychotropic drugs are among those that cause neutropenia. Fever in such patients is a common haematological emergency and management depends on rational antimicrobial use, thorough investigation, and measures to reduce exposure to infection. Idiosyncratic drug fever Some individuals are especially prone to the effects of a drug, and drug-induced fever is one manifestation of this.

Malignant hyperthermia is a dangerous hypermetabotic state after anaesthesia with suxamethonium and/or volatile halogenated anaesthetic agents. It is also seen, in susceptible individuals, after severe exercise in high ambient temperatures, in infections, in overheated infants, and during treatment with neuroleptic drugs. It is characterised by a sustained rise in body temperature (without shivering), tachycardia, cyanosis, and generalized muscle rigidity during or soon after the anaesthetic. To the non-anaesthetist, it can be mistaken for heat stroke, rhabdomyolysis, muscle pains, neuroleptic malignant syndrome, or sudden infant death syndrome. Treatment consists of supportive measures, reversal of acidosis, and dantrolene

6 - As a result of patient idiosyncrasy.

Neuroleptic malignant syndrome is an idiosyncratic reaction to antipsychotic drugs such as phenothiazines, butyrophenones, and risperidone, but has also been seen after abrupt withdrawal of antiparkinsonian agents and treatment with dopamine-depleting agents or lithium. It is characterized by fever, hypertonia, fluctuating consciousness, and autonomic disturbances such as tachycardia, sweating, and labile blood pressure.

Drug-induced fever - Generally occurs after 7 - 10 days of therapy- Resolves within 48 hours of the drug’s discontinuation

Antibiotics: penicillin is the most common antibiotic reported to cause fever

DrugsDrugsAtropineAtropine AllopurinolAllopurinol CaptoprilCaptopril

AmphotericinAmphotericin HydralazineHydralazine CimetidineCimetidine PenicillinsPenicillins Isoniazid Isoniazid Clofibrate Clofibrate

CephalosporinsCephalosporins Rifampicin Rifampicin Heparin HeparinPhenytoinPhenytoin MacrolidesMacrolides MeperidineMeperidine

ProcainamideProcainamide Clindamycin Clindamycin HCTZ HCTZ QuinidineQuinidine VancomycinVancomycin MethyldopaMethyldopa SulfonamidesSulfonamides AminoglycosidesAminoglycosides NifedipineNifedipine

Drug fever should be suspected in any febrile Drug fever should be suspected in any febrile patient receiving any medication.patient receiving any medication.

Urticaria, skin rash or eosinophilia are suggestive Urticaria, skin rash or eosinophilia are suggestive of drug feverof drug fever

Resolution of fever after withdrawal of a drug is Resolution of fever after withdrawal of a drug is strongly suggestive but the recurrence of fever on strongly suggestive but the recurrence of fever on reexposure is definitive evidence of drug fever reexposure is definitive evidence of drug fever Past history can be of use if the patient can tell of Past history can be of use if the patient can tell of previous medicationsprevious medications

Diagnosis and treatment

DDrug-inducerug-induced fever found in numerous textbooks d fever found in numerous textbooks and review articles.and review articles.

Considerable variability has been reported in the Considerable variability has been reported in the length of time between the initiation of drug length of time between the initiation of drug therapy and the onset of fever due to the drug.therapy and the onset of fever due to the drug.

Drugs can be changed to alternatives of a different Drugs can be changed to alternatives of a different class. class.

After stopping the drug, the fever will usually resolve within 3 days, although it may take as long as 2 weeks.

If the fever remits, the physician can definitively confirm the diagnosis by re-instituting the agent, which characteristically elicits fever again within a few hours.

This procedure is safe unless drug-induced organ damage e.g. interstitial nephritis or hepatitis, has occurred.

When patients are receiving several drugs and hypersensitivity fever is suspected, all nonessential drug therapy should first be discontinued.

No matter which mechanism proves responsible of drug-induced fever.

It is only required that the physician always place it in the differential diagnosis of a febrile patient