Adverse drug reaction / REF / 111 / 2014

An adverse drug reaction (abbreviated ADR) is an expression that describes harm associated with the use of given medications at a normal dosage during normal use. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs. The meaning of this expression differs from the meaning of "side effect", as this last expression might also imply that the effects can be beneficial. The study of ADRs is the concern of the field known as pharmacovigilance. An adverse drug event (abbreviated ADE) refers to any injury caused by the drug (at normal dosage and/or due to overdose) and any harm associated with the use of the drug (e.g. discontinuation of drug therapy). ADRs are a special type of ADEs.

Classification

ADRs may be classified by e.g. cause and severity.

Cause

• Type A: Augmented pharmacologic effects - dose dependent and predictable

Type A reactions, which constitute approximately 80% of adverse drug reactions, are usually a consequence of the drug’s primary pharmacological effect (e.g. bleeding from warfarin)or a low therapeutic index (e.g. nausea from digoxin), and they are therefore predictable. They are dose-related and usually mild, although they may be serious or even fatal (e.g. intracranial bleeding from warfarin). Such reactions are usually due to inappropriate dosage, especially when drug elimination is impaired. The term ‘side effects’ is often applied to minor type A reactions.

• Type B: Bizarre effects (or idiosyncratic) - dose independent and unpredictable
• Type C: Chronic effects
• Type D: Delayed effects
• Type E: End-of-treatment effects
• Type F: Failure of therapy
• Type G: Genetic reactions
• Type I: Idiosyncratic

Types A and B were proposed in the 1970s, and the other types were proposed subsequently when the first two proved insufficient to classify ADRs.

Seriousness and severity

The American Food and Drug Administration defines a serious adverse event as one when the patient outcome is one of the following:

• Death
• Life-threatening
• Hospitalization (initial or prolonged)
• Disability - significant, persistent, or permanent change, impairment, damage or disruption in the patient's body function/structure, physical activities or quality of life.
• Congenital anomaly
• Requires intervention to prevent permanent impairment or damage

Severity is a point on an arbitrary scale of intensity of the adverse event in question. The terms "severe" and "serious" when applied to adverse events are technically very different. They are easily confused but can not be used interchangeably, requiring care in usage.

A headache is severe, if it causes intense pain. There are scales like "visual analog scale" that help us assess the severity. On the other hand, a headache is not usually serious (but may be in case of subarachnoid haemorrhage, subdural bleed, even a migraine may temporally fit criteria), unless it also satisfies the criteria for seriousness listed above.

Overall Drug Risk

While no official scale exists yet to communicate overall drug risk, the iGuard Drug Risk Rating System is a five color rating scale similar to the Homeland Security Advisory System:

• Red (high risk)
• Orange (elevated risk)
• Yellow (guarded risk)
• Blue (general risk)
• Green (low risk)

Location

Adverse effects may be local, i.e. limited to a certain location, or systemic, where a medication has caused adverse effects throughout the systemic circulation.

For instance, some ocular antihypertensives cause systemic effects, although they are administered locally as eye drops, since a fraction escapes to the systemic circulation.

Mechanisms

As research better explains the biochemistry of drug use, fewer ADRs are Type B and more are Type A. Common mechanisms are:

• Abnormal pharmacokinetics due to
• genetic factors
• comorbid disease states
• Synergistic effects between either
• a drug and a disease
• two drugs

Abnormal pharmacokinetics

Comorbid disease states

Various diseases, especially those that cause renal or hepatic insufficiency, may alter drug metabolism. Resources are available that report changes in a drug's metabolism due to disease states.

Genetic factors

Abnormal drug metabolism may be due to inherited factors of either Phase I oxidation or Phase II conjugation. Pharmacogenomics is the study of the inherited basis for abnormal drug reactions.

Phase I reactions

Inheriting abnormal alleles of cytochrome P450 can alter drug metabolism. Tables are available to check for drug interactions due to P450 interactions.

Inheriting abnormal butyrylcholinesterase (pseudocholinesterase) may affect metabolism of drugs such as succinylcholine

Phase II reactions

Inheriting abnormal N-acetyltransferase which conjugated some drugs to facilitate excretion may affect the metabolism of drugs such as isoniazid, hydralazine, and procainamide.

Inheriting abnormal thiopurine S-methyltransferase may affect the metabolism of the thiopurine drugs mercaptopurine and azathioprine.

Interactions with other drugs

The risk of drug interactions is increased with polypharmacy.

Protein binding

These interactions are usually transient and mild until a new steady state is achieved. These are mainly for drugs without much first-pass liver metabolism. The principal plasma proteins for drug binding are:

1. albumin
2. α1-acid glycoprotein
3. lipoproteins

Some drug interactions with warfarin are due to changes in protein binding.

Cytochrome P450

Patients have abnormal metabolism by cytochrome P450 due to either inheriting abnormal alleles or due to drug interactions. Tables are available to check for drug interactions due to P450 interactions.

Synergistic effects

An example of synergism is two drugs that both prolong the QT interval.

Assessing causality

Causality assessment is used to determine the likelihood that a drug caused a suspected ADR. There are a number of different methods used to judge causation, including the Naranjo algorithm, the Venulet algorithm and the WHO causality term assessment criteria. Each have pros and cons associated with their use and most require some level of expert judgement to apply. An ADR should not be labeled as 'certain' unless the ADR abates with a challenge-dechallenge-rechallenge protocol (stopping and starting the agent in question). The chronology of the onset of the suspected ADR is important, as another substance or factor may be implicated as a cause; co-prescribed medications and underlying psychiatric conditions may be factors in the ADR. A simple scale is available at 

Assigning causality to a specific agent often proves difficult, unless the event is found during a clinical study or large databases are used. Both methods have difficulties and can be fraught with error. Even in clinical studies some ADRs may be missed as large numbers of test individuals are required to find that adverse drug reaction. Psychiatric ADRs are often missed as they are grouped together in the questionnaires used to assess the population.

Examples of adverse effects associated with specific medications

Condition	Substance
Abortion, miscarriage or uterine hemorrhage	misoprostol, a labor-inducing drug (this is a case where the adverse effect has been used legally and illegally for performing abortions)
Addiction	many sedatives, hypnotics and opioid analgesics (such as diazepam, morphine, etc.); clomethiazole
Birth defects	thalidomide; isotretinoin
Bleeding of the intestine	aspirin
Cardiovascular disease	COX-2 inhibitors (i.e. rofecoxib)
Deafness and kidney failure	gentamicin (an antibiotic)
Death, following sedation	propofol
Depression or hepatic injury	interferon
Depression	tetrabenazine, rimonabant and other CB1 antagonists; efavirenz
Diarrhea	orlistat
Erectile dysfunction and/or loss of libido	many drugs, such as antidepressants
Fever	vaccination (in the past, imperfectly manufactured vaccines, such as BCG and poliomyelitis, have caused the very disease they intended to fight)
Flatulence	acarbose
Glaucoma	corticosteroid-based eye drops
Hair loss and anemia	chemotherapy against cancer, leukemia, etc.
Headache	spinal anesthesia
Hyperkalemia	potassium-sparing diuretics (such as amiloride)
Hypertension	ephedrine (which prompted FDA to remove the status of dietary supplement of ephedra extracts)
Hypokalemia	some diuretics (like furosemide and hydrochlorothiazide)
Impaired glucose tolerance and diabetes mellitus	atypical antipsychotic medications (such as clozapine and olanzapine)
Insomnia	stimulants (e.g. methylphenidate, amphetamine, etc.); some antidepressants (like fluoxetine); efavirenz
Kidney stones	indinavir, carbonic anhydrase inhibitors (such as topiramate)
Lactic acidosis	stavudine (an antiretroviral drug); metformin (oral anti-diabetic medication)
Liver failure	paracetamol
Melasma and thrombosis	estrogen-containing hormonal contraception (such as the combined oral contraceptive pill)
Nausea	SSRIs, SNRIs, various chemotherapy agents
Nightmares	efavirenz
Pathological addiction, like gambling, shopping; sexual and other intense urges	dopamine agonists
Irreversible peripheral neuropathy	fluoroquinolone medications
Rhabdomyolysis	statins (a class of lipid-lowering drugs)
Seizures	withdrawal from benzodiazepines; clozapine; bupropion
Sleepwalking, “sleepdriving” and other complex behaviors	hypnotics (like zolpidem)
Stroke or heart attack	sildenafil when used with nitroglycerine; COX-2 inhibitors
Suicide, increased tendency	antidepressants
Parkinsonism	MPTP, a meperidine related drug considered highly neurotoxic
Tardive dyskinesia	long-term use of metoclopramide, cinnarizine and many antipsychotic medications
Spontaneous tendon rupture	fluoroquinolone drugs even occurring as late as 6 months after treatment had been terminated.
Weight loss	some antidepressants (like fluoxetine and bupropion)
Weight gain	some antipsychotics (e.g. olanzapine and clozapine) and antidepressants (imipramine, mirtazapine, paroxetine)

Epidemiology

A in 2011found that sedatives and hypnotics were a leading source for adverse drug events seen in the hospital setting. Approximately 2.8% of all ADEs present on admission and 4.4% of ADEs that originated during a hospital stay were caused by a sedative or hypnotic drug. A second study by AHRQ found that in 2011, the most common specifically identified causes of adverse drug events that originated during hospital stays in the U.S. were steroids, antibiotics, opiates and narcotics, and anticoagulants. Patients treated in urban teaching hospitals had higher rates of ADEs involving antibiotics and opiates/narcotics compared to those treated in urban nonteaching hospitals. Those treated in private, not-for-profit hospitals had higher rates of most ADE causes compared to patients treated in public or private, for-profit hospitals.

In the U.S., females had a higher rate of ADEs involving opiates and narcotics than males in 2011, while male patients had a higher rate of anticoagulant ADEs. Nearly 8 in 1,000 adults aged 65 years or older experienced one of the four most common ADEs (steroids, antibiotics, opiates and narcotics, and anticoagulants) during hospitalization.

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