Clinical Pharmacy I

IZZATULLAH KHAN
ASSISTANT PROFESSOR(LCPS)
PHARM D (BMU) M.Sc.(Uk)
 Drug-Induced Disease

 “A drug-induced disease is the unintended effect of a

drug, which results in mortality or morbidity with
symptoms sufficient to prompt a patient to seek medical
attention and/or require hospitalization”
 Drug-induced disease can be anticipated or
unanticipated. Disease can also be caused by the drug
impurities, as was the case with deaths attribute to the
use of contaminated heparin in 2008
 Vigilance on the part of regulatory authorities, drug
manufacturer, clinicians and patients is necessary to
minimize the potential for harm that is inherent in drug
use.
 Understanding the pharmacodynamic mechanism of
action of drugs helps to explain and predict multiple and
adverse end organ toxicities of many drugs.
 For example,
 Group of nonsteroidal anti-inflammatory drugs
(NSAIDs) through their action on the prostaglandin
system can induce adverse drug effect on circulating
platelets and gastrointestinal tract.
 Some ADEs are due to the differing sensitivity of drug on
the target site ; individuals with the same serum drug
level may experience different degree of ADE intensity.
 Drug Reactions

 These are three types of reactions

1. Predictable reactions
 Also called type A reaction, are expected extensions of
an individual drug’s know pharmacological properties
and responsible for bulk of ADEs. ( hypotension due to
antihypertensive agent)
 It may not be due to the primary pharmacological effect
of drug but may be due to secondary effect of drug (e.g.
Anticholenergic effect with the tricyclic antidepressent
drugs)
 Even though their incidence and morbidity is high but
they are rarely life-threatening.
2. Unpredictable reaction
 Also called type B reaction, are not expected extensions
of an individual drug’s know pharmacological, seeming to
be more a function of patient susceptibility than the
intrinsic toxicity of drugs.
 These include idiosyncratic reaction, immunological or
allergic reaction, e.g.
 Anaphylactic shock due to penicillin
 A person with G6PD deficiency having acute haemolytic
anaemia when expose to anti-malarials( Primiquine or
sulphonamide)
 Type B reactions, while uncommon, are often among
the most serious and potentially life-threatening of
ADEs, are the major cause of different Drug-
Induced Disease.
3. Withdrawal Reaction
After discontinuation of therapy. e.g. Acute
Addisonian crisis after stoppage of corticosteroids
therapy.
 Drug Induced Liver Diseases

 Drug-induced liver diseases are diseases of the liver

that are caused by physician-prescribed medications,
over-the-counter medications, vitamins, hormones,
herbs, illicit ("recreational") drugs, and
environmental toxins.
 Drugs can induce almost all form of acute and
chronic liver disease, with some drugs producing
more than one type of hepatic reaction.
 Liver

The liver is an organ that is located in the

upper right hand side of the abdomen,
mostly behind the rib cage. The liver of an
adult normally weighs close to three
pounds and has many functions.
 Function of Liver

 The liver removes chemicals from the blood (usually changing them into
harmless chemicals) and then either secretes them with the bile for
elimination in the stool, or secretes them back into the blood where they then
are removed by the kidneys and eliminated in the urine.

 The liver produces many important substances, especially proteins that are
necessary for good health. For example, it produces proteins like albumin (a
protein that carries other molecules through the blood stream), as well as the
proteins that cause blood to clot properly.

 The liver produces and secretes bile into the intestine where the bile assists
with the digestion of dietary fat.

 The liver helps purify the blood by changing potentially harmful chemicals into
harmless ones. The sources of these chemicals can be outside the body (for
example, medications or alcohol), or inside the body (for example, ammonia,
which is produced from the break-up of proteins; or bilirubin, which is
produced from the break-up of haemoglobin.
 Epidemiology

 The prevalence of drug induced liver disease (DILD)

has continued to rise steadily since the late 1960s,
although the incidence of idiosyncratic reactions for
the most drug remain low, approximately 1 in every
1000 patients at therapeutic doses
 DILD is not usually life-threatening; however, for the
small number of the patient who develop drug-
induced acute liver failure (ALF) the prognosis is
poor, with 60% to 80% mortality rate.
 It is estimated that 15-40% of ALF cases may be due
to the drugs
 In the early 1990s acute overdose acute overdose
with paracetamol accounted for 30,000-40,000
hospital admissions and over half the cases of ALF
referred to liver unit
 It is the definite cause of the approximately 100
deaths per year in UK
 ALF induced by paracetamol has become an
important indication for liver transplant.
 Risk factors

 Pre-existing liver disease

 Pre-existing liver disease may increase the risk of
developing drug induced hepatic injury with agent
such as methotrexate, cytotoxic agent, aspirin,
sodium valproate.
 A past medical history of DILD from any medication
has been shown to be a predictor of future DILD
from other drug.
 Age
 In generally elderly are at an increased risk of DILD. There are multiple
reasons for this, including higher exposure rate and decrease
metabolism
 Drug induced hepatic injury is more likely to occur in elderly patients
than in those under 35 years.
 Gender
 The frequency of drug induced hepatotoxicity is thought to be more
common in female than male, particularly in halothane, isoniazid,
chlorpromazine and erythromycin
 There is weak evidence of a gender difference in toxicity of sodium
valproate, being more common in boys before puberty and in female
after puberty.
 Cholestatic jaundice associated with co-amoxiclav has been reported to
be more common in male than female.
 Polypharmacy
A typical example of this is NSAIDs. The risk of liver
disease with NSAIDs is normally low but is increased
when NSAIDs are used with other hepatotoxic drugs
 Genetics
 Genetic differences that affect an individual’s ability to
metabolised the certain drugs may predispose to DILD.
 For example both fast and slow acetylators may be more
susceptible to isoniazid-induced liver damage.
 Fast acetylators are at risk of toxic reactions due to
transformation of acetylehydrazine into reactive
metabolite and slow acetylation may result in the toxicity
due to formation of hydrazin which is toxic itself.
 Enzyme induction
Alcohol, rifampacin and other drugs that induce
cytochrome P450 isoenzyme 2EI potentiate the risk
of hepatotoxicity with other drug such as
paracetamol, isoniazid and halothane.
 Concurrent disease and pregnancy
Pre-existing renal disease, diabetes, pregnancy and
poor nutrition may also affect the ability of liver to
metabolise the drug.
 Aetiology

 Drug-induced hepatotoxicity may present as acute insult

which may or may not progress to chronic disease.
 The type of lesion may be cytotoxic or cholestatic.
Cytotoxic damage can be classified as necrotic or
steatic.
 The machanism of drug-induced hepatic damage can be
divided into intrinsic(type A) and idiosyncratic(type B).
 The precise mechanism resulting in DILD are often not
completely understood but injury of hepatocytes may
result from interference with intracellular function,
membrane integrity or indirectly by immune-mediated
damage to cells.
 Necrosis
 Necrosis is characterised by hepatocellular destruction
and is general associated with poor prognosis.
 Drug associated with DILD having different tendency to
cause hepatic necrosis.
 For example hepatic necrosis has been reported in 3% of
cases with co-amoxiclave DILD compare to 89% in
individual with halothane DILD.
 Paracetamol causes hepatic necrosis when its normal
metabolic pathway become saturated. An alternative
pathway produce toxic metabolite which covalently binds
to liver cell protein and causes necrosis.
 Steatosis
 Hepatocytes become filled with small droplets of
lipid (microvescular fatty liver) or sometime with
large lipid droplets(macrovesicular fatty liver).
 Tetracyclinnes are thought to cause steatosis by
interfering with synthesis of lipoproteins that
normally remove triglyceride from the liver.
 Cholestasis
 “Some drugs injure the bile ducts and cause partial or
complete obstruction of the common bile duct, resulting
in retention of bile acids and condition known as
cholestasis”
 Cholestasis caused by the anabolic and contraceptive
steroid is due the inhibition of bilirubin excretion from
the hepatocytes into the bile.
 The penicillins, although commonly associated with
allergic drug reactions, are a very rare cause of liver
disease.
 Isoxazoyl group present in the synthetic beta
lactamase resistant oxypenicillins has been
implicated as cause of liver injury.
 Flucloxacillin and dicloxacillin are also associated
with acute cholestatic hepatitis.
 Moreover , there is likely to be underreporting due to
delay in onset of up to 42 days after stopping
treatment.
 Rifampicin causes hyperbilirubinaemia by inhibiting
uptake of bilirubin by the hepatic cells as well as
inhibiting the excretion the bilirubin into bile