SCHOOL OF PHARMACY

Subject: PRINCIPLES OF MEDICAL PHARMACOLOGYSubject code: SPH1102

Assignment #2: DRUG TOXICITYGROUP 4: C) ORGAN & TISSUE TOXICITY

Prepared by:

NAME ID

1. PAVITRA A/P KRISHNAN 012014052393

2. ESHWARI A/P GUNASEGARAN 012014052405

3. ANNISA HAYATUNNUFUS 012014052438

4. DURGA DEVI A/P RAGGU 012014110838

5. VARISHAPRIYAA A/P CHANDRA SEKARAN 012014052274

6. CHRISTINE SHALIN A/P SELVARAJ 012014052277

7.HONG TSHUN KUAN 012014110766

8. MUHAMMAD REZA ALFAATHIANSYAH 012014110827

9. MUHAMMAD HAIDIR BIN MOKHTAR 012014110769

10. YEOH CHUN SIONG 012014110822

Lecturer’s Name : MISS DEBRA DOROTEADate of submission : Wednesday, 27th June 2015

RUBRIC

I. CONTENT................................................................................................................3

1. Drug-induced Hepatotoxicity........................................................................3

A. Types of Liver Injury..............................................................................3

B. Risk Factors..........................................................................................4

C. Mechanism...........................................................................................4

D. Examples of Hepatoxicants..................................................................5

E. Metabolic Activation of Hepatoxicants..................................................5

F. Prevention.............................................................................................5

2. Drug-induced Renal Toxicity........................................................................6

A. Pathogenic Mechanisms.......................................................................6

B. Drugs That Cause Nephrotoxicity.........................................................7

C. Symptoms of Nephrotoxicity.................................................................9

D. Treatment of Nephrotoxicity................................................................10

E. Prevention of Nephrotoxicity...............................................................10

3. Drug-induced Neurotoxicity........................................................................11

A. Vinca Alkaloids-induced Neurotoxicity................................................11

B. Taxanes-induced Neurotoxicity...........................................................13

C. Platinum Compound-induced Neurotoxicity........................................14

4. Drug-induced Skeletal Muscle Toxicity......................................................16

A. Disorders.............................................................................................16

B. Physiologic Mechanisms of Rhabdomyolisis.......................................17

C. Drug-induced Rhabdomyolisis Effects on Skeletal Muscle.................18

D. Examples of Drugs That Causes Rhabdomyolisis..............................19

E. Rhabdomyolisis Clinical Presentation.................................................22

F. Rhabdomyolisis Treatment..................................................................22

II. REFERENCES.....................................................................................................23

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I. CONTENT

1. DRUG-INDUCED HEPATOTOXICITY

The basic structure of liver consists of rows of hepatic cells (hepatocytes and

parencymal cells) perforated by specialized blood capillaries called sinusoids. The liver

plays a major role in storage, metabolizing and biosynthesis drugs and other chemicals

from the body and is susceptible to toxicity from these agents. Many drugs taken in

overdose cause hepatotoxic injury and some cause damage even when used in normal

therapeutic doses. Herbal agents, illicit drugs, and environmental chemicals can cause

hepatotoxicity. Hepatotoxicity is the main reason for postmarketing drug withdrawal. The

annual incidence of drug-induced hepatotoxicity ranges between 1.27 and 40.6 cases per

100,000 persons. Worldwide, the overall frequency of drug-induced liver diseases as a

percentage of all drug reactions is 3% to 9%. (JAMES E. TISDALE, DOUGLAS A.

MILLER, 2010)

A. Types of liver injury

The types of injury to the liver depend on the type of toxic agent, severity of

intoxification, and the type of exposure, whether acute or chronic.

a) Fatty liver:

Fatty liver refers to abnormal accumulation of fat in hepatocytes. Lipid

accumulation is related to disturbances in either the synthesis or secretion of

lipoproteins. Triglycerides are secreted from the liver as a very low density

lipoprotein (VLDL). This process can be disrupted when interference with transfer

of VLDL across cell membrane, decreased synthesis of phospholipids or impaired

conjugation of triglyceride with lipoprotein.

b) Necrosis:

Cell necrosis is a degenerative process leading to cell death. Necrosis,

usually an acute injury, may be localized and affect only few hepatocytes (focal

necrosis) or maybe involve the entire lobe (massive necrosis). The biochemical

events that contribute this condition are binding of reactive metabolites to proteins

and unsaturated lipids disturbance of cellular Ca+2 homeostasis, interference with

metabolic pathways, shifts in Na+ and K+ balance, and inhibition of protein

synthesis.

c) Apoptosis:

Apoptosis is a controlled form of cell death that serves as a regulation point

for biologic processes. Although apoptosis is a normal physiological process, it

can also be induced by a number of exogenous factors, such as xenobiotic

chemicals, oxidative stress, anoxia and radiation. Toxicants, however, do not

always act in a clear-cut fashion, and some toxicants can induce both apoptosis

and necrosis either concurrently or sequentially.

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d) Cholestasis:

Cholestasis is the suppression of bile flow, and may have either intrahepatic

or extrahepatic causes. Inflammation or blockage of the bile ducts results in

retention of bile salts as well as bilirubin accumulation, an event that lead to

jaundice. Cholestasis is usually a drug induced and difficult to produce in

experimental animals.

B. Risk Factors

Genetic predisposition

Sex

Age

Alcohol consumption

Magnetic of a single dose or

cumulative dose

Chronic viral infections (HIV)

Pharmacokinetics or pharmacodynamic

interactions

Illicit drug use (cocaine) and toxic mushrooms

Food exposures or household or occupational

exposure to chemical agents

(JAMES E. TISDALE, DOUGLAS A. MILLER,

2010)

C. Mechanisms of hepatoxicity:

Cell injury can be initiated by a number of mechanisms, such as inhibition of

enzymes, depletion of cofactors or metabolites or depletion of energy (ATP) stores,

interaction with receptors and alteration of cell membranes. In recent years attention

has focused on biotransformation of chemicals to highly reactive metabolites that

initiate cellular toxicity. Many compounds, including clinically useful drugs, can cause

cellular damage through metabolic activation of the chemical to highly reactive

compounds, such as free radicals, carbenes, and nitrenes.

These reactive metabolites can bind covalently to cellular macromolecules

such as nucleic acids, proteins, cofactors, lipids, and polysaccharides, thereby

changing their biologic properties. The liver is particularly vulnerable to toxicity

produced by reactive metabolites because it is the major site of xenobiotic

metabolism. Most activation reactions are catalyzed by the cytochrome P450

enzymes, and agents that induce these enzymes, such as Phenobarbital and 3-

methylcholantherene, often increases toxicity. Conversely, inhibitors of cytochrome

P450, such as SKF25A and piperonylbutoxide, frequently decrease toxicity.

Mechanisms such as conjugation of reactive chemical with glutathione are

protective mechanisms that exist within the cell for the rapid removal and inactivation

of many potentially toxic compounds. Because of these interactions, cellular toxicity is

a function of the balance between the rate of formation of reactive metabolites and

the rate of their removal.

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D. Examples of hepatotixicants

Carbon tetrachloride

Ethanol

Bromobenzene

Acetaminophen

E. Metabolic activation of hepatotixicants

Liver toxicity caused by Bromobenzene, acetaminophen, and other

compounds have led to some important observations concerning tissue damage.

Toxicity may be correlated with the formation of a minor but highly reactive

intermediate.

A threshold tissue concentration of the reactive metabolite must be attained

before tissue injury occurs.

Endogenous substances, such as glutathione, play an essential role in protecting

the cell from injury by removing chemically reactive intermediates and by keeping

the sulfhydrl groups of proteins in the reduced state.

Pathways such as those catalyzed by glutathione transferase and epoxide

hydrolases play an important role in protecting the cell.

Agents that selectively induce or inhibits the xenobiotic metabolizing enzymes

may alter the toxicity of xenobiotic chemicals. (HODGSON, 2004)

F. Prevention:

Recognition and rapid discontinuation of the agent is the best preventive

measure. Patient with risk factors should not receive hepatotoxic agents if and when

alternative agents are available. Many manufactures of drugs known to cause hepatic

injury provide guidelines for monitoring liver enzymes while patients are receiving the

potential hepatotoxin (isoniazide, etretinate, synthetic retinoids, ketoconazole,

methotrexate, pemoline, tacrine). Monthly monitoring liver associated biochemistry

may be cost-effective for drugs that produces serious liver dysfunction in 1% to 2% of

exposures, but not for drugs that are less frequently associated with this drug-induced

hepatotoxicity. (JAMES E. TISDALE, DOUGLAS A. MILLER, 2010).

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2. DRUG-INDUCED RENAL TOXICITY

Drugs are a common source of acute kidney injury. Drugs shown to cause

renal toxicity exert their toxic effects by one or more common pathogenic

mechanisms. Drug-induced renal toxicity tends to be more common among certain

patients and in specific clinical situation. Some patient-related risk factors for drug-

induced renal toxicity are age older than 60 years, underlying renal insufficiency (e.g.,

glomerular filtration rate of less than 60 mL per minute per 1.73 m2), volume

depletion, diabetes and heart failure.

A. Pathogenic mechanisms

Most drugs found to cause renal toxicity exert toxic effects by one or more

common pathogenic mechanisms. These include tubular cell toxicity, inflammation

and thrombotic microangiopathy.

I. Tubular cell toxicity

Renal tubular cells, in particular proximal tubule cells, are vulnerable to

the toxic effects of drugs because their role in concentrating and reabsorbing

glomerular filtrate exposes them to high levels of circulating toxins. Drugs that

cause tubular cell toxicity do so by impairing mitochondrial function, interfering

with tubular transport, increasing oxidative stress, or forming free radicals.

Drugs associated with this pathogenic mechanism of injury include

aminoglycosides, antiretrovirals (adefovir [Hepsera], cidofovir [Vistide], tenofovir

[Viread]), cisplatin (Platinol), contrast dye, foscarnet (Foscavir), and zoledronate

(Zometa).

II. Inflammation

Drugs can cause inflammatory changes in the glomerulus, renal tubular

cells, and the surrounding interstitium, leading to fibrosis and renal scarring.

Glomerulonephritis is an inflammatory condition caused primarily by immune

mechanisms and is often associated with proteinuria in the nephrotic range.

Medications such as gold therapy, hydralazine (Apresoline; brand not available

in the United States), interferon-alfa (Intron A), lithium, NSAIDs, propylthiouracil,

and pamidronate (Aredia; in high doses or prolonged courses) have been

reported as causative agents.

III. Thrombotic microangiopathy

Organ damage is caused by platelet thrombi in the microcirculation, as in

thrombotic thrombocytopenic purpura. Mechanisms of renal injury secondary to

drug-induced thrombotic microangiopathy include an immune-mediated reaction

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or direct endothelial toxicity. Drugs most often associated with this pathogenic

mechanism of nephrotoxicity include antiplatelet agents (e.g., clopidogrel[Plavix],

ticlopidine [Ticlid]), cyclosporine, mitomycin-C (Mutamycin), and quinine

(Qualaquin).

B. Drugs that cause nephrotoxicity

Aminoglycoside

antibiotics cover

Gram-negative

infections. They

are prototype

drugs having

nephrotoxicity as

major side effects. It remains relatively common cause of acute deterioration in renal

function. Renal toxicity is caused by proximal tubular injury that leads that cause cell

necrosis. Nephrotoxic risk increases with Na+ and K+ depleted state, renal ischemia,

increasing age, liver disease, diuretics, concomitant use of nephrotoxic agents and

with duration of therapy reaching, 50% when given for 14 days or more.

Relative toxicity: neomycin > gentamycin > tobramycin

>netilmycin>amikacin> streptomycin

Acute lithium-induced renal injury may present as early as 8 weeks after

treatment initiation and cause a reduced urinary concentrating capacity. When serum

concentrations are high, for example, 1.2 mmol/L), urine output increases and

glomerular filtration rate decreases mildly. Acute renal failure has been reported with

lithium intoxication, but the mechanism is uncertain and it may be due to factors such

as volume depletion, direct nephrotoxicity or a combination of both. Nephrogenic

diabetes insipidus is the most common adverse effect of lithium therapy and may

occur up to 40% of patients.

Over-the-counter availability of these Non-steroidal anti-inflammatory drugs

(NSAIDs) puts a large population at risk. Higher than usual dose, volume depletion,

congestive heart failure, nephrotic syndrome, cirrhosis particularly with ascites, pre-

existing renal disease and age >65 years are the factors which increase its toxicity.

All the Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin

synthesis, leading to unopposed, intrarenal vasoconstriction. This decreases the

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Commonly-used drugs which can affect renal functionDiuretics

Beta blockersVasodilators

Non-steroidal anti-inflammatory drugsACE inhibitors

AminoglycosidesRadio contrast mediaCompound analgesics

Antiviral agentsLithium

glomerular filtration rate. This results in fluid retention, with the risk of increasing

cardiac failure in patients with pre-existing cardiac dysfunction, and resistance to

antihypertensive therapy in patients with normal cardiac function.

Diuretics, particularly the more potent loop diuretics, for example, frusemide,

ethacrynic acid, bumetanide, may cause volume depletion. This decreases cardiac

output, particularly in patients who already have decreased ‘effective’ blood volume,

such as those suffering cardiac failure, liver failure or nephrotic syndrome. These

cause reduction in GFR by extracellular fluid volume contraction.

Analgesics are widely prescribed and can cause renal toxicity when used

acutely or chronically NSAIDs may impair glomerular filtration by inhibiting renal

vasodilator prostaglandins and cause acute renal failure. NSAID-induced

tubulointerstitial nephritis tends not to present with systemic findings of

hypersensitivity and is associated with proteinuria in the nephrotic range in most

cases. Paracetamol lacks peripheral prostaglandin inhibition, but may cause acute

tubular necrosis in overdose. Chronic interstitial nephritis and papillary necrosis can

develop as a consequence of long-term abuse of combination analgesics, particularly

those containing phenacetin.

By interfering with the production of angiotensin II, the ACE inhibitors

decrease efferent arteriolar regulation. Clinically significant alterations in renal

function may result, particularly in low perfusion states, such as renal artery stenosis

to a solitary kidney, or if there is bilateral renal artery disease. If the ACE inhibitor

adversely affects renal function you should consider the presence of functionally

significant renovascular disease, however the absence of such effect does not rule

out the presence of renal artery lesion. Furthermore, a small deterioration in renal

function may occur in patients who have no renovascular disease, but have a pre-

existing mild elevation of serum creatinine when they start an ACE inhibitor. This

deterioration will often reverse in time if the ACE inhibitor continued.

Drugs with negative inotropic effects, such as beta blockers and some

calcium channel antagonists, have the potential to impair renal function, especially if

cardiac output is already compromised. In clinical practice, the adverse effects on the

heart usually predominate so the drug is often stopped before the renal dysfunction

becomes clinically relevant.

Vasodilator drugs, such as minoxidil and prazosin, rarely cause deterioration

of renal function themselves. However, they may be associated with marked salt and

water retention, requiring the addition of loop diuretics. Calcium channel blockers,

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while causing oedema of the eyes and ankles, are actually natriuretic and do not

cause salt and water retention.

The kidney is exposed to many medications. Patients with comorbidities,

particularly the aged and those with pre-existing renal disease, diabetes and cardiac

failure, are especially at risk of renal impairment. With the increasing availability of

computer access to the relevant medical literature, it is wise to check the list of

precautions and adverse effects before prescribing for these patients.

C. Symptoms of drug-induced renal disease

Symptoms of nephrotoxic injury have a wide range and—in some cases—depend

uponthe type of toxin involved. In general, symptoms are

similartothoseofrenalfailureandinclude:

i) Urinary Signs

The kidneys help to flush out toxins through the urine, so when they are not

working properly, such as due to toxic kidney, certain urinary symptoms can be

present. According to Wrong Diagnosis, these include proteinuria and enzymuria.

Enzymuria is a condition in which there are enzymes present in the urine.

Proteinuria is a condition in which excessive amounts of protein are excreted in

the urine.

ii) Blood Signs

There are several different blood signs of toxic kidney. These include

increased blood-urea levels, increased levels of electrolytes in the blood,

increased blood-hydrogen ion level, increased blood pressure and anemia, says

Wrong Diagnosis. Anemia occurs when the number of red blood cells present in

the blood is reduced.

iii) Kidney Signs

Toxic kidney affects the kidney, so there are certain signs and symptoms

exclusive to the kidneys. According to Wrong Diagnosis, these include kidney

damage, tubular necrosis and kidney dysfunction. Kidney damage is simply

damage affecting the kidneys. Kidney dysfunction occurs when the kidneys are

not working at their optimal level. Tubular necrosis is a condition in which the

kidney's tubule cells become damaged due to the kidney tissues receiving less

oxygen than they need to function normally. Tubular necrosis ultimately leads to

acute kidney failure, according to Medline Plus, which can lead to decreased

urine output, fluid retention, nausea, drowsiness and confusion.

iv) Imbalances and Fatigue

Water imbalance, electrolyte imbalance, and fatigue are also signs of toxic

kidney. These three signs occur as a result of the kidneys not functioning

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properly. A water imbalance occurs when the body's sodium concentration is

either too low or too high, according to Discovery Health. When the amount of

water within the body either increases or decreases, an electrolyte imbalance can

occur. These imbalances can lead to muscle cramps, thirst, irritability, changes in

heart rate and blood pressure and seizures. Toxic kidney can also cause fatigue.

If the toxin's effect on the kidneys remains unchecked,more serious symptoms of 

kidney failure may occur, including seizures and coma. You may have no

symptoms or warnings at all when the kidneys first begin to function improperly.

However, in some patients there may be earlier onset of symptoms.

D. Treatment

Treatment of nephrotoxic injury takes place in the hospital and focuses on

removing the toxin from the patient’s system, while maintaining kidney fuction.

Removal methods are targeted to specific toxins and may include the use of diuretics

or chelates to enhance excretion of the toxin in urine, or, in extreme cases, the direct

removal of toxins from the blood via hemodialysis or passing the blood over

unabsorbent substance such as charcoal. Support of kidney function depends on the

extent of damage to the organs and ranges from monitoring fluid levels to dialysis.

Most patients with ARF recover with conservative management which

includes fluid monitoring, protein restriction, drug adjustments, dietary or potassium

control, and dialysis (usually temporary).

E. Prevention

In brief, the best clinical approach to drug-induced nephrotoxicity is

prevention, which starts with the recognition that drug-induced renal injury occurs and

is seen predominantly in patients at risk. The following steps are necessary:

Be aware of specific drugs.

Identify patients at risk (those with renal insufficiency, dehydration, salt-

retaining states, diabetes, and multiplemyeloma).

Be aware of increased risk in elderly patients.

Whenever possible, select diagnostic procedures or therapeutic measures

without nephrotoxic potential.

Avoid dehydration mandatorily in high-risk patients. Pretreatment hydration is

very important.

Limit total daily dosage and duration of treatment with certain drugs.

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F. DRUG-INDUCED NEUROTOXICITY

Drug induced neurotoxicity is most often associated with the use of cancer

chemotherapeutic agents. In most cases, neurotoxicity manifests in the peripheral nerves,

but the central nervous system may be affected as well. Peripheral neuropathy has been

associated with vinca alkaloids (eg:vinchristine, vinblastine), taxanes (eg: paclitaxel) and

platinum compounds (eg: cisplatin). The neuropathy cause by vinca alkaloids and

taxanesis directly related to their primary mechanism of action, microtubule disruption. In

peripheral nerves, microtubule disruption is thought to result in altered axonal trafficking

and both sensory and motor neuropathy. Platinum-containing compounds may have

direct toxic effects on peripheral nerves.

VINCA ALKALOIDS

Example of drugs areVinchristine& Vinblastine. Vincristine itself is a vinca alkaloid

used to treat many cancers such as leukemia, lymphomas, sarcomas, and brain tumors.

Its main toxicityis an axonal neuropathy, resulting from disruption of the microtubules

within axons and interference with axonal transport. The neuropathy involves both

sensory and motor fibers, although small sensory fibers are especially affected. Virtually

all patients have some degree of neuropathy, which is the dose-limiting toxicity. The

clinical features resemble those of other axonal neuropathies such as diabetic

neuropathies. The followings are the symptoms to vinca-alkaloids-induced neurotoxicity:

Paresthesias in the fingertips and feet and muscle cramps. These symptoms may

occur after several weeks of treatment, or even after the drug has been discontinued,

and progress for several months before improving. Children tend to recover more

quickly than adults.

Loss of ankle jerks . Initially, objective sensory findings tend to be relatively minor

compared to the symptoms, but is common.

Profound weakness , with bilateral foot and wrist drop and loss of all sensory

modalities.

Severe neuropathies. This is likely to develop in older patients who are cachectic,

patients who have received prior radiation to the peripheral nerves or concomitant

hematopoietic colony-stimulating factors, and those who have preexisting neurologic

conditions such as Charcot-Marie-Tooth.

Mild neuropathies can receive full doses of vincristine, but when the neuropathies

increase in severity and interfere with neurologic function. Reduction in dose or

discontinuation of the drug may be necessary.

Focal neuropathies. Although anecdotal reports indicate that glutamine may help

some patients with vincristine neuropathy, generally no effective treatment. Rarely,

vincristine can cause a fulminant neuropathy with severe quadriparesis that mimics

Guillain-Barré syndrome.

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Autonomic neuropathy

Abdominal pain and constipation.A paralytic ileus may occur because of the known

adverse gastrointestinal effects, patients receiving vincristine should take prophylactic

stool softeners and laxatives

Impotence

Postural hypotension

Atonic bladders

Cranial neuropathies

The most common nerve to be involved is the oculomotor nerve, resulting in ptosis

and ophthalmoplegia. Other nerves that may be involved include the recurrent

laryngeal nerve, optic nerve, facial nerve, and the auditory vestibular system.

Retinal damage and night blindness

Jaw and parotid pain.

Central Nervous System (CNS) complications are rare, as vincristine poorly

penetrates the blood-brain barrier. Rarely, vincristine may cause the syndrome of

inappropriate secretion of antidiuretic hormone, resulting in hyponatremia, confusion, and

seizures. CNS complications unrelated to the syndrome of inappropriate secretion of

antidiuretic hormone may also occur. These include seizures, encephalopathy, reversible

posterior leukoencephalopathy, transient cortical blindness, ataxia, athetosis, and a

Parkinson syndrome.

The related vinca alkaloids vindesine and vinblastine tend to have less

neurotoxicity. This may be related to differences in lipid solubility, plasma clearance,

terminal half life, and sensitivities of axoplasmic transport. Vinblastine is now also used in

the treatment of non-Hodgkin lymphomas, mycosis fungoides, testicular carcinoma,

Kaposi sarcoma, and histiocytosis X.

ManagementThe only effective management of vinca-induced neuropathy is reduction of the

dose, which usually reverses most major signs and symptoms without necessarily

requiring a discontinuation of the drug. Venlafaxine inhibits hyperalgesia in a rat model of

painful vincristine neuropathy. There is at least 1 case report of the successful utilization

of plasma exchange for vinblastine overdose with severe neuropathy as a feature;

however, this is an unusual circumstance.

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TAXANES

Taxanesare used to treat a variety of cancers including ovary, breast, and

nonsmall cell lung cancers. They contain a plant alkaloid that inhibits microtubule

function, leading to mitotic arrest. One of the examples of the drug is Paclitaxel.

Paclitaxel produces a dose-limiting peripheral neuropathy, which occurs in 60%

of patients receiving 250 mg/m2. Toxicity is predominantly characterized by a symmetric,

sensory axonal neuropathy affecting both large and small fibers. Symptoms usually begin

after 1 to 3 weeks of treatment. Patients develop:

1. Burning paresthesias of the hands and feet

2. Loss of reflexes

3. Neuropathy (often does not progress despite continued treatment, and there have

even been reports of patients improving with continuing therapy)

4. Arthralgias and myalgias(begins 2 to 3 days after a course of paclitaxel lasting 2 to 4

days)

5. Motor neuropathies that predominantly affect proximal muscles, perioral numbness,

and autonomic neuropathies.

6. Rarely causes visual scotomas, optic neuropathies, seizures, vocal cord palsies,

transient encephalopathies, or phantom limb pain in patients with prior amputation.

7. Acute encephalopathy and death.High-dose paclitaxel (greater than 600 mg/m2) can

cause this to patients between 7 and 23 days after treatment.

The neurotoxic effects of paclitaxel are increased when combined with cisplatin.

Liposomal encapsulation of paclitaxel may reduce the incidence of neurotoxicity. The

2014 American Society for Clinical Oncology Clinical Practice guideline on

chemotherapy-induced peripheral neuropathy does not recommend any agents for the

prevention of taxane-induced neuropathy but does provide moderate recommendation for

treatment of established neuropathy with paclitaxel.

Management/Prevention/Treatment of Paclitaxel-induced neurotoxicity  may be found in

new formulations of paclitaxel to improve solubility and delivery, including nanoparticle

albumin-bound (Nab) paclitaxel and liposomal-encapsulated paclitaxel, may also assist in

enabling lower doses and reduced toxicity.

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PLATINUM COMPOUNDS

Example of platinum compounds drug is Cisplatin. It is an alkylating agent used

to treat ovarian, testicular, cervical, bladder, lung, gastrointestinal, and head and neck

cancers. It frequently causes neurotoxicity, especially peripheral neuropathies and

ototoxicity.

1) Neuropathy .

The main neurologic complication of cisplatin is an axonal neuropathy

affecting predominantly large myelinated sensory fibers.

Symptoms primarily result from injury to the dorsal root ganglion. The

peripheral nerve may also be affected. The neuropathy is characterized by subacute

development of numbness, paresthesias, and occasionally pain in the extremities.

Symptoms usually begin in the toes and then spread to the fingers and then, in

ascending fashion, affect the proximal legs and arms. Proprioception is impaired and

reflexes are lost, but pinprick sensation, temperature sensation, and power are often

spared. Nerve conduction studies show decreased amplitude of sensory action

potentials and prolonged sensory latencies consistent with a sensory axonopathy.

Sural nerve biopsy may show both demyelination and axonal loss.

The main differential diagnoses include paraneoplastic neuropathies and

neuropathies associated with autoimmune disorders such as Sjögren syndrome.

Paraneoplastic neuropathies tend to involve all sensory fibers and progress despite

discontinuation of cisplatin. Some patients test positive for antineuronal antibodies

(anti-Hu) in serum. Patients with autoimmune neuropathies often have clinical

features of the underlying connective tissue disease, and autoimmune antibodies are

usually present in the serum.

There is marked individual susceptibility to the development of cisplatin-

induced neuropathies. Typically, neuropathies develop in patients following

cumulative doses of cisplatin greater than 400 mg/m2. Increased dose intensity of

cisplatin administration does not appear to enhance the severity of the neuropathy.

Patients with mild neuropathies can continue to receive full doses of cisplatin. Once

the neuropathy becomes more severe and begins to interfere with neurologic

function, the clinician must decide whether to continue with therapy and risk

potentially disabling neurotoxicity, reduce the dose of drug, or discontinue the drug

and replace it with less neurotoxic agents. The most appropriate course of action

varies with each patient and must take into account factors such as the severity of the

neuropathy and the availability of less neurotoxic alternatives. After cessation of

chemotherapy, the neuropathy usually continues to deteriorate for several months in

30% of patients. Most patients eventually improve, although recovery is often

incomplete. Many agents have been tested for the prevention or treatment of

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chemotherapy-induced peripheral neuropathy, including neuropathy caused by

cisplatin.

2) Cranial neuropathies

Cisplatin may cause ototoxicity, leading to high-frequency sensorineural hearing

loss and tinnitus. The toxicity is due to peripheral receptor (hair) loss in the organ of

Corti and is related to dose. Audiometric hearing loss is present in 74% to 88% of

patients receiving cisplatin, and symptomatic hearing loss occurs in 16% to 20% of

patients. Cranial irradiation probably increases the likelihood of significant hearing

loss. The hearing loss tends to be worse in children, although they have a slightly

greater ability to improve after the drug has been stopped. Neurotrophin-4/5

enhances the survival of cultured spiral ganglion cells in vitro and may have

therapeutic value in preventing cisplatin-induced ototoxicity.

Cisplatin may also cause a vestibulopathy, resulting in ataxia and vertigo. It may

or may not be associated with hearing loss. Previous use of aminoglycosides may

exacerbate the vestibulopathy. Intraarterial infusion of cisplatin for head and neck

cancer produces cranial palsies in approximately 6% of patients. Intracarotid infusion

of cisplatin may also cause ocular toxicity, although these complications may also

rarely occur after intravenous administration of the drug. They include retinopathy,

papilledema, optic neuritis and disturbed color perception due to dysfunction of retinal

cones. Other complications of intraarterial cisplatin include headaches, confusion,

and seizures.

3) Myelotoxicity (Lhermitte sign) .

This symptom, characterized by paresthesias in the upper back and extremities

with neck flexion, is seen in 20% to 40% of patients receiving cisplatin. Patients tend

to develop this symptom after several weeks or months of treatment. Neurologic

exam and MRI scans are usually normal and the Lhermitte sign usually resolves

spontaneously several months after the drug has been discontinued. It is thought to

result from transient demyelination of the posterior columns. Very rarely, a true

myelopathy has been reported.

G. DRUG-INDUCED SKELETAL MUSCLE

Drug induced musculoskeletal disorders can potentially affect the spectrum of

anatomical structures including bone, connective tissue and the musculature. Skeletal

muscles represent a significant proportion of the body’s mass, receive a large fraction of

blood supply, and are metabolically highly active. This tissue therefore has significant

exposure to circulating drugs, which has the potential to cause drug induced disorders

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ranging from trivial myalgias and asymptomatic elevations in creatine kinase through to

life threatening rhabdomyolysis with myoglobin induced renal failure.

A. Disorders

Myalgia (muscle pain) is characterised by diffuse muscle pain, tenderness and

cramps with the presence or absence of muscle weakness. Myalgia is not accompanied

by elevations in creatine kinase. While the presentation may be mild, symptoms such as

muscle cramps and aches or non-specific muscle pain may be a precursor to more

serious musculoskeletal conditions such as rhabdomyolysis.

Myositis is the inflammation of voluntary muscle fibres and has muscle symptoms

similar to myalgia but is accompanied by an elevation in serum creatine kinase (CK). The

two main sources of creatine kinase are myocardium (relatively small contributor) and

skeletal muscle which accounts for around 94% of creatine kinase. The presence of this

marker for muscle damage may result from exercise, physical muscle trauma, inherited or

acquired diseases or extrinsic drug causes.

Myopathy is a general term referring to any disease of muscles and is sometimes

used interchangeably with myositis. Myopathies can be acquired or inherited and can

occur at birth or in later life. There is a strong correlation between many drugs and

myopathy.

Features of drug induced myopathy are polymorphous and include

:FatigueGeneralised muscle

painMuscle tendernessMuscle

weaknessSignificantly elevated

serum creatine kinase (CK) > 10 x

upper limit of normal (ULN)Nocturnal

crampingTendon pai

nThe symptoms of myopathy tend to be worse at night and are aggravated by

exercise. Myopathy should be considered when serum CK levels are more than 10 x

ULN, or in patients with increases in serum CK (less than 10 x ULN) accompanied by

symptoms of myalgia. Muscle biopsy is non-specific but may reveal muscle fibre

inflammation, atrophy and in some cases necrosis and regeneration. Muscle biopsy may

be useful where CK remains elevated post drug withdrawal.

Rhabdomyolysis is a syndrome in which skeletal muscle disintegration results in

the release of large quantities of toxic muscle cell components into the plasma. The

etiology of skeletal muscle injury is quite diverse, including excessive muscular stress and

ischemia, genetic defects, and direct toxic or physical damage. In the past, the more

common causes of acute rhabdomyolysis were from crush injuries during wartime and

natural disasters.

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More recently, as noted in one published series, drugs and alcohol have become

frequent causative agents in up to 81% of cases of rhabdomyolysis. Drug-induced

rhabdomyolysis can be divided into a primary or a secondary myotoxic effect. Primary

toxic-induced rhabdomyolysis is caused by a direct insult on the skeletal myocyte function

and integrity. Secondary effects of toxins are due to predisposing risk factors such as

local muscle compression in coma, prolonged seizures, trauma, and metabolic

abnormalities. The clinical features of rhabdomyolysis range from muscle weakness to

fulminant life-threatening acute renal failure. The classic triad of presenting symptoms is

skeletal muscle injury, pigmented urine, and some aspect of renal dysfunction. However,

in drug-induced rhabdomyolysis, a subclinical presentation without these common

features may be overlooked, due to other presenting symptoms that may predominate the

clinical findings.

B. Physiologic mechanisms of Rhabdomyolysis

Rhabdomyolysis is defined as a clinical and biochemical syndrome in which

leakage of intracellular myocyte contents are released into the extracellular fluid and

circulation. Myoglobin is a protein that functions as an important oxygen carrier that

maintains the ability of red muscles to consume oxygen.

The normal level of myoglobin in serum is 3 to 80 μg/L. The serum level of

myoglobin is dependent upon the glomerular filtration rate. When 100 g of muscle tissue

has been injured, the serum proteins reach the saturation level. All myoglobin above 230

mg/L is filtered through the glomerulus. The presence of myoglobin in the urine will

produce a dark red-brown pigmentation if the level exceeds 1g/L. At or below a pH of 5.6,

myoglobin dissociates into ferrihemate and globulin. Ferrihemate causes a direct

deterioration of renal function, impairment of renal tubular transport mechanisms, and cell

death.

Myoglobinuric renal failure may be explained by a direct nephrotoxicity due to

ferrihemate, tubular obstruction by precipitation of myoglobin casts, and alterations in

glomerular filtration rate. Myoglobin can be detected in the urine in levels as low as 5 to

10 mg/L with a dipstick method that uses the orthotolidine reaction. Hemoglobinuria may

also cause a positive orthotolidine reaction; however, the plasma will be pink, and red

blood cells will be present on the microscopic evaluation. Myoglobinuria may precede and

resolve prior to an increase in creatine kinase (CK) due to a short half-life of 1to 3 hours.

Therefore, a negative orthotolidine reaction does not rule out rhabdomyolysis.

Human tissues are composed of three different CK isoenzymes. The predominant

isoenzyme is skeletal muscle and cardiac tissue is CK-MM. The function of CK is to

convert myocyte creatine phosphate into high energy phosphate groups (adenosine

triphosphate) used in energy requiring reactions. The release of CK into the serum may

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reach levels up into the hundreds of thousands. Degradation of approximately 200 g of

muscle can cause an increase in serum CK. Therefore, total serum CK is the most

sensitive biochemical indicator of rhabdomyolysis. Serum concentration begins to

increase 2 to 12 hours after the initial muscle injury and will peak at 3 to 5 days. Thus it is

possible for myoglobinuria to be resolved prior to an elevated serum CK. Therefore, it is

important to remember that in the initial acute rhabdomyolysis syndrome, serum CK may

be normal.

When massive myocyte breakdown of cell membranes occurs, other intracellular

constituents are released besides myoglobin and CK. A substantial amount of fluid can

accumulate within the affected muscles causing elevated pressures in the fascial

compartments. Intracellular potassium is released that can cause a significant

hyperkalemia. Approximately 150 g of muscle necrosis will release more than 15 mmol of

potassium. The resulting hyperkalemia may increase the risk for cardiac arrhythmias and

complicate an existing acute renal failure. In the beginning phases of rhabdomyolysis,

calcium accumulates within the muscle with a resulting hypocalcemia. During the later

stages, calcium is mobilized from the necrotic muscle tissue and results in hypercalcemia.

Release of phosphate further contributes to the hypocalcemia by forming a calcium

phosphate product that is deposited in the muscle tissue. Other metabolic abnormalities

include metabolic acidosis, hyperuricemia, elevated lactate dehydrogenase, aldolase,

creatinine, uric acid, urea, and amino transferases.

C. Drug-induced toxic effects towards skeletal muscle

Drug-induced rhabdomyolysis can occur by a primary direct toxic effect on the

myocyte function or by an indirect secondary effect that predisposes the myocyte to

develop injury. There are more than 150 medications and toxins that have been

implicated as the etiology of skeletal muscle injury. Some of the proposed direct

mechanisms by which these medications alter myocyte function are inhibition of calcium

metabolism by the sarcoplasmic reticulum, impairment of the production of adenosine

triphosphate causing disruption of cell membranes, and alterations in carbohydrate

metabolism. The secondary mechanisms include drug-induced coma causing prolonged

immobilization and muscle compression, seizures, and myoclonus causing increased

oxygen demands on skeletal muscle tissue. Trauma from drug-induced altered mental

status, agitation, and delirium can cause tissue ischemia and crush injury.

D. Drugs that cause rhabdomyolysis

Acetaminophen

Caffeine

Hydrocarbons

Methamphetamine

Strychnine

Amoxapine

Carbone Monoxide

Hydrocortisone

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Methanol

Succinylcholine

Amphetamines

Chloral hydrate

Hydroxyzine

Mineralocorticoids

Sympathomimetics

Amphotericin B

Chlorpromazine

Inhalation anesthetics

Morphine

Theophylline

Anticholinergics

Cocaine

Isoniazid

Narcotics

Trimethoprim-

sulfamethoxazole

Antidepressants

Dexamethasone

Isopropyl Alcohol

Neuroleptics

Vasopressin

Antihistamines

Diazepam

Ketamine Hydrochloride

Phencyclidine

Antipsychotics

Diuretics

Licorice

Phenobarbital

Baclofen

Ecstasy

Lithium

Phenothiazines

Barbiturates

Ethanol

Lorazepam

Phenytoin

Benzodiazepines

Fluoroacetate

Lysergic acid diethylamide

Prednisone

Betamethasone

Glutethimide

Loxapine

Salicylate

Butyrophenones

Heroin

Marijuana

Serotonin antagonists

Many of the common drugs of abuse have been reported to cause

rhabdomyolysis. One report estimated that approximately 20% of all cases of

myoglobinuria due to rhabdomyolysis were the result of alcohol ingestion. Ethanol-

induced rhabdomyolysis may develop from direct toxic effects on the sarcoplasmic

reticulum by increasing sodium permeability and disrupting calcium homeostasis,

disintegration of the cell membrane, and alterations in intracellular energy sources.

The secondary effects of alcohol pertain to the altered mental status, loss of

consciousness, and coma that can lead to prolonged immobilization and muscle

compression. Ethanol ingestions can present with a history of poor nutrition,

hypokalemia, and hypophosphatemia, which can predispose the patient to

rhabdomyolysis.

20

Cocaine, another common drug of abuse, can cause a direct effect on the

muscle tissue, inducing vasoconstriction and tissue ischemia. Cocaine has also been

shown to cause leakage of CK from skeletal muscle myocytes. Cocaine-associated

rhabdomyolysis may also be contributed to the state of hyperthermia and

hyperactivity, which increases energy requirements and depletes the energy

resources. When the body’s thermoregulatory mechanisms of heat production and

dissipation fail, the myocyte cannot maintain its function and is destroyed. There are

several other drugs that induce injury by this hypermetabolic mechanism, including

inhalation anesthetics, sympathomimetics, serotonin antagonists, antipsychotics, and

anticholinergics.

Ketamine hydrochloride is an analogue of phencyclidine and is used as a

dissociative anesthetic for procedural sedation. It can also be ingested, inhaled, or

injected as a drug of abuse. Ketamine hydrochloride, as well as phencyclidine, can

produce agitation and prolonged muscular activity that may contribute to muscle

damage. However, phencyclidine may be more likely to cause rhabdomyolysis due to

seizures, hyperthermia, and delirium requiring restraints that can predispose to

muscle tissue injury.

Methamphetamine, a drug of abuse and another stimulant, was implicated as

the most common cause of rhabdomyolysis. Ecstasy was also reported to cause

fulminant rhabdomyolysis. Ecstasy is 3,4-methylenedeoxymethamphetamine

(MDMA), which is an analog of amphetamine. One the most life-threatening

complications of Ecstasy overdose is hyperthermia. Ecstasy releases serotonin into

the brain, which stimulates sympathetic mechanisms to increase catecholamines.

Muscular hyperactivity and severe hyperthermia result from release of calcium from

the sarcoplasmic reticulum and increased metabolic demands. Other medications

that can cause prolonged muscular contractions such as choreoathetosis or dystonic

reactions are phenothiazines and butyrophenones. Prolonged seizure activity, which

can cause rhabdomyolysis, can be induced by isoniazid, strychnine, amoxapine,

loxapine, theophylline, lithium, and withdrawal from sedative hypnotics or ethanol.

Caffeine is a common drug that is usually not implicated in acute ingestions

from overdose. Caffeine interferes with calcium transport by the sarcoplasmic

reticulum resulting in accumulation of calcium within the cell. This can potentiate

muscle contraction and increase the energy demands that may cause cell

destruction. Therefore, this patient’s rhabdomyolysis was most likely due to direct

toxic effects that caused increased muscular activity and myocyte injury.

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Acetaminophen is a common agent used in pediatrics as an antipyretic and

an analgesic. It is well known that acetaminophen overdoses cause severe hepatic

injury, rhabdomyolysis, hypothermia, hyperglycemia, and acute renal failure.

Therefore, acetaminophen should be added to the list of drugs that cause direct toxic

effects on myocytes as well as hepatocytes.

Drugs that induce central nervous system depression can cause prolonged

immobilization, muscle compression, and tissue ischemia that results in myocyte

injury. Compounds such as narcotics, benzodiazepines, cyclic antidepressants,

antihistamines, ethanol, glutethimide, and barbiturates all cause an altered level of

consciousness and may predispose to the development of rhabdomyolysis. Carbon

monoxide poisoning may enable a patient unconscious for a prolonged period of time,

predisposing to the development of rhabdomyolysis. Carbon monoxide can cause a

functional anaemia that impedes oxygen delivery to tissues. Carbon monoxide also

impairs adenosine triphosphate production, causing a direct effect on myocyte energy

production. Other agents such as cyanide and hydrogen sulfide can inhibit electron

transport and disrupt adenosine triphosphate production.

There are many other drugs that induce rhabdomyolysis through other

mechanisms. Hypokalemia caused be diuretics, mineralocorticoids, licorice, and

amphotericin B can predispose to rhabdomyolysis. Corticosteroids appear to have a

direct toxic effect on skeletal muscle, as seen in severe asthmatics who develop

rhabdomyolysis. Acute hypersensitivity reactions producing rhabdomyolysis have

been reported with phenytoin and trimethoprim-sulfamethoxazole. Cholesterol-

lowering agents like HMG CoA reductase inhibitors have a direct effect on the

skeletal muscle tissue. Succinylcholine can cause myoglobinuria in the absence of

the hereditary disorder of malignant hyperthermia, especially in children.

Neuroleptic malignant syndrome is characterized by the gradual development

of hyperthermia, muscle rigidity, autonomic instability, altered mental status,

myoglobin, and elevated serum CK. Drugs that cause neuroleptic malignant

syndrome include phenothiazines, butyrophenones, antipsychotics, narcotics, and

antidepressants.

Intrathecal baclofen infusion is used for children with cerebral palsy to treat

spasticity and dystonia. Multisystem organ failure and rhabdomyolysis developed

when the catheter became disconnected from the pump. The muscle injury that

caused the rhabdomyolysis may have been due to hypertonicity, prolonged seizures,

and hyperthermia.

E. Clinical presentations

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Rhabdomyolysis may present with a wide variety of clinical symptoms from

mild myalgias to severe acute renal failure. Muscles may be tender, stiff, or weak.

However, most patients with drug-induced rhabdomyolysis do not complain of

swelling or tenderness over the involved muscle at the time of admission. They may

develop a “second wave phenomenon” in which a delayed increase in fascial

compartment pressure causes compression neuropathies, swelling, and tenderness.

Compartment syndromes in drug-induced rhabdomyolysis usually occur secondary to

prolonged immobilization or coma, which can result in contractures and amputations.

Treatment includes immediate surgical fasciotomy to release the increased

compartmental pressures. Acute renal failure is complicated by hypovolemia, cast

formation, renal vasoconstriction, and ferrihemate toxicity. Replacing circulating blood

volume and maintaining urine output is essential for prevention of acute tubular

necrosis. Disseminated intravascular coagulation can be significant in patients with

rhabdomyolysis. Thromboplastin and plasminogen activator are released from the

injured myocyte and cause fibrinolysis. Acute cardiomyopathy can present from direct

toxic effects of drugs on the cardiac muscle. Respiratory failure can result from

involvement of respiratory muscles during rhabdomyolysis.

F. Treatments

In any acute life-threatening ingestion or illness, the airway, ventilation, and

perfusion should be the initial priority. Thereafter, the goal of treatment of

rhabdomyolysis is to cease muscle destruction. The prevention of increased agitation,

seizures, and abnormal movements must be attempted with pharmacologic agents.

Treatment of hyperthermia is essential using external cooling measures and

controlling for muscular hyperactivity with benzodiazepines.

Electrolyte abnormalities that must be corrected are hyponatremia,

hypernatremia, hyperglycemia, hypocalcemia, and decreased phosphorous. If

compartment syndrome is present, the compartment pressures should be measured.

If compartmental pressures are over 30 to 50 mmHg, a fasciotomymust be

considered. Alkalinization of urine and mannitol has shown to be effective in some

patients with acute renal failure. In the case of drug-induced rhabdomyolysis,

eliminating the exposure of the toxic agent may be the only treatment.

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