Pharmacists Council of Nigeria 1 FPGOP Lecture Note on Applied Pharmacology and Toxicology APPLIED PHARMACOLOGY AND TOXICOLOGY A. GENETIC AND NUTRITIONAL FACTORS IN DRUG ACTION Course outline (1). Nutritional factors in drug action (i). Malnutrition (ii). Some features of protein-energy malnutrition and drug action (iii). Miscellaneous dietary factors and drug action (iv). Food-derived intoxicants (2). Pharmacogenetics Learning Objectives At the end of the course participants should (a). Explain how malnutrition, particularly protein-energy malnutrition, can influence drug absorption, distribution, metabolism, excretion, and therapeutic effect. (b). Mention poisons/intoxicants from food. (c). State some constituents of our diet that may affect drug action, and how? (d). Mention genetic factors involved in drug action, and the mechanisms involved. (e). Understand the roles of pharmacogenetics, including its possible applications. (f). Mention some drugs whose actions are affected by genetic polymorphisms, and the mechanism(s) involved. (g). Mention drugs and other substances to be avoided by G6PD deficient individuals. A1. NUTRITIONAL FACTORS IN DRUG ACTION Human nutrition deals with the provision of essential nutrients in food, that are necessary to support life and health. Nutrition as a science, involves the interaction of nutrients and other substances in food relative to maintenance, growth, reproduction, health and disease of humans. It encompasses food intake, absorption, catabolism and excretion. Nutrition is dependent on the diet. A good nutrition provides essential nutrients needed for good health and sustenance, while poor nutrition or malnutrition results in morbidity and mortality. (i). Malnutrition
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Pharmacists Council of Nigeria
1 FPGOP Lecture Note on Applied Pharmacology and Toxicology
APPLIED PHARMACOLOGY AND TOXICOLOGY
A. GENETIC AND NUTRITIONAL FACTORS IN DRUG ACTION
Course outline
(1). Nutritional factors in drug action
(i). Malnutrition
(ii). Some features of protein-energy malnutrition and drug action
(iii). Miscellaneous dietary factors and drug action
(iv). Food-derived intoxicants
(2). Pharmacogenetics
Learning Objectives
At the end of the course participants should
(a). Explain how malnutrition, particularly protein-energy malnutrition, can influence drug
absorption, distribution, metabolism, excretion, and therapeutic effect.
(b). Mention poisons/intoxicants from food.
(c). State some constituents of our diet that may affect drug action, and how?
(d). Mention genetic factors involved in drug action, and the mechanisms involved.
(e). Understand the roles of pharmacogenetics, including its possible applications.
(f). Mention some drugs whose actions are affected by genetic polymorphisms, and the
mechanism(s) involved.
(g). Mention drugs and other substances to be avoided by G6PD deficient individuals.
A1. NUTRITIONAL FACTORS IN DRUG ACTION
Human nutrition deals with the provision of essential nutrients in food, that are necessary to
support life and health. Nutrition as a science, involves the interaction of nutrients and other
substances in food relative to maintenance, growth, reproduction, health and disease of
humans. It encompasses food intake, absorption, catabolism and excretion. Nutrition is
dependent on the diet. A good nutrition provides essential nutrients needed for good health and
sustenance, while poor nutrition or malnutrition results in morbidity and mortality.
(i). Malnutrition
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Malnutrition is one of the major public health problems of the Third World and several million
people are underfed and suffer from deficiencies of essential nutrients.
Definition of Malnutrition
Malnutrition is a condition due to consumption of diet in which one or more nutrients are either
inadequate or in excess, resulting in ill health. Lack of adequate nutrients is called
undernutrition or undernourishment while too much is called overnutrition. Overnutrition may
result in being overweight, obesity and other disorders. Undernutrition may lead to starvation,
physical and mental underdevelopment, infections, and other diseases.
Generally, malnutrition is often used to specifically refer to undernutrition where an individual is
not getting enough calories, protein, or micronutrients. There are two main types of
undernutrition; protein-energy malnutrition and dietary deficiencies.
Protein-energy malnutrition (PEM) results when the body is lacking the calories it needs from
protein, carbohydrates and fats. In addition to macronutrient deficiency, there is clinical and/or
subclinical deficiency of micronutrients. Three forms of PEM are marasmus, kwashiorkor and
marasmic-kwashiorkor.
Kwashiokor
Kwashiorkor, also called protein malnutrition, is due to severe protein deficiency. Kwashiokor
was first described in children in 1932. The term kwashiorkor is derived from the Ga language
of coastal Ghana, translated as ‘the sickness the baby gets when the new baby comes’ or ‘the
disease of the deposed child’; this refers to the development of the disorder in an older child
who has been weaned from the breast when a younger sibling comes. In another dialect, it
connotes ‘red boy’, referring to the reddish orange discoloration of the hair that is characteristic
of the disease.
Kwashiorkor occurs in areas of famine or poor food supply, e.g. during the Nigerian civil war. It
is most often encountered in areas where the diet is high in starch and low in proteins, cases
are rare in the developed countries. In at-risk populations, kwashiorkor may develop after a
mother weans her child from breast milk (contains proteins and amino acids vital to a child's
growth), replacing it with a diet high in carbohydrates and low in proteins. It is common in
young children weaned to a diet consisting mainly of cereal grains, cassava, yam, sweet potato
or other foods high in carbohydrates. Ignorance of nutrition could also be a cause of
PM Increased toxicity of fluoropyrimidines in DPD deficient individuals Capecitabine
Morphine UGT2B7 - Morphine plasma levels affected by increased or decreased enzyme activity
Levodopa COMT (COMT) PM Lower enzyme activity results in enhanced drug effect
Irinotecan UGT1A1 PM Reduced clearance in poor metabolizers, leading to toxicity such as immunosuppression, GIT dysfunction; dose adjustment may be required.
Enhanced response (e.g. bronchodilation) to inhaled corticosteroids in asthmatics, osteopenia
Estrogen hormone replacement therapy
Estrogen receptors α and β
- Altered responses, e.g., changes in high density liopoprotein. E.g., some postmenopausal women with ERα IVSI-401 C/C genotype, with coronary disease show augmented response of HDL to hormone replacement therapy
This co-enzyme (NADPH) is required as hydrogen donor for numerous reductive processes of
various biochemical pathways as well as for the stability of catalase and the preservation and
regeneration of reduced glutathione. Catalase and glutathione are both essential for the
detoxification of hydrogen peroxide and free radicals generated during the normal cellular
metabolic processes. The defence of cells against hydrogen peroxide, free radicals and other
forms of oxidative stress, therefore, depends on G6PD for the generation of NADPH.
Since red blood cells (RBCs) do not contain mitochondria, the PPP is their only source of
NADPH; therefore, defence against oxidative damage in RBCs is essentially dependent on G6PD.
The red cells are particularly sensitive to oxidative damage in the absence or reduced activity of
G6PD as they lack other NADPH-producing enzymes.
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In individuals with deficiency of G6PD there is low level of reduced glutathione; on exposure to
specific triggers (oxidative stress), when all the remaining reduced glutathione is consumed,
enzymes and other proteins (including hemoglobin) are subsequently damaged by the oxidants,
leading to cross-bonding and protein deposition in the RBC membrane. Damaged RBCs are
phagocytosed and sequestered in the spleen. The hemoglobin is metabolized to bilirubin,
accumulation of which causes hyperbilirubinemia and jaundice.
Triggers: Triggers include moth balls (naphthalene, camphor), stress from a bacterial or viral
infection; foods such as fava beans; certain drugs including aspirin, dapsone, quinine and other
antimalarials derived from quinine (e.g. primaquine, pamaquine, and chloroquine.),
sulfonamides (such as sulfanilamide, sulfamethoxazole, and mafenide). Thiazolesulfone,
methylene blue, certain analgesics (such as phenazopyridine and acetanilide), and some non-
sulfa antibiotics (e.g.nalidixic acid, nitrofurantoin, isoniazid, and furazolidone) should also be
avoided by people with G6PD deficiency as they antagonize folate synthesis. There is evidence
that other antimalarials may also exacerbate G6PD deficiency, but only at higher doses.
Clinical Manifestations
The public health burden of G6PDD is significant. G6PD deficiency causes a clinical spectrum of
illness which includes a purely asymptomatic state, acute hemolytic episodes (elicited by drugs,
infections, ingestion of fava beans, etc.), chronic hemolysis (hereditary non-spherocytic
hemolytic anaemia), and neonatal jaundice. However, many individuals with this disorder
remain asymptomatic throughout their lives and may not be aware of it.
Hemolysis: In G6PD deficient children, exposure to triggers and pro-oxidants could lead to a
rapid imbalance in the redox status in RBCs leading to hemolysis and resultant severe anemia,
heart failure, and death if not recognized early. One of the most curious features of the acute
hemolytic reaction is that it is erratic; the same agent may cause hemolysis in one G6PD
deficient person but not in another, and in the same person at one time but not another.
Neonatal hyperbilirubinemia: G6PD deficiency causes neonatal jaundice which is
accompanied by hyperbilirubinemia and puts infants at risk for kernicterus within the first few
days of life. Kernicterus can lead to hearing deficits, behavior problems, permanent neurologic
damage, spastic cerebral palsy or death.
(d). Glucose-6-phosphate dehydrogenase deficiency and malaria
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There is a close association between malaria and G6PD deficiency. Several epidemiological
studies have shown the high frequency of G6PD deficiency in nearly all parts of the world where
malaria is or has been endemic, and that distribution of malaria was nearly the same with
distribution of G6PD deficiency. These infer that (i) G6PD deficiency confers protection against
malaria, particularly Plasmodium falciparum malaria (a similar relationship exists between
malaria and sickle-cell disease); (ii) use of some antimalarial drugs can cause life threatening
hemolytic anaemia in patients with G6PD deficiency; hence, screening for G6PD status is
recommended before treatment with antimalarial drugs.
The protection offered by G6PD deficiency against malaria could be explained by
(i). Cells infected with the Plasmodium parasite are cleared more rapidly by the spleen. This
phenomenon might give G6PD deficiency carriers an evolutionary advantage by increasing their
fitness in malaria endemic environments. In P. falciparum infection, it has been demonstrated
that shorter half-life and rapid clearance of RBCs of G6PD deficient individuals make them less
susceptible to attacks from malaria parasites.
(ii).The G6PD-deficient host has a higher level of oxidative agents, which though generally
tolerated by the host are deadly to the parasite. In vitro studies have demonstrated that P.
falciparum is very sensitive to oxidative damage; hence, there may be impaired growth and
reduced rates of replication of P. falciparum parasites in G6PD deficient RBCs.
(iii). Red cells that are G6PD deficient are resistant to P. falciparum invasion since the parasite
require the enzyme for its normal survival in the host cell.
(e). Management of G6PD deficiency
The main mode of management of G6PD deficiency is avoidance of oxidative stressors. Rarely,
anemia may be severe enough to warrant a blood transfusion, though exchange blood
transfusion may be necessary in some neonates. Phototherapy with bili lights in neonates is
beneficial.
The WHO recommends G6PD status screening in regions where prevalence of G6PD deficiency
is 3–5% or more, but this has yet to become routine practice in Nigeria. Barriers to screening
include cost, underestimation of the public health impact of G6PD deficiency by the medical
community, lack of awareness of G6PD deficiency among lay people, and a paucity of guidelines
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regarding which high risk groups should be preferentially screened when general population
screening is not possible.
Bibliography and Further Reading
Ademowo OG, Falushi AG (2002). Molecular epidemiology and activity of erythrocyte G6PD variants in a homogenous Nigerian population. East African Medical Journal, 79(1): 42-44. Bailey DG (2013). Grapefruit-medication interactions: Forbidden fruit or avoidable consequences? Canadian Medical Association Journal, 185(4): 309-316. Buchanan N (1984). Effect of protein-energy malnutrition on drug metabolism in man. World Review of Nutrition and Dietetics, 43: 129-139. Dolan LC, Matulka RA, Burdock GA (2010). Naturally occurring food toxins. Toxins (Basel), 2(9):2289-2332. Egesie OJ, Joseph DE, Isiguzoro I, Egesie UG (2008). Glucose-6-phosphate dehydrogenase (G6PD) activity and deficiency in a population of Nigerian males resident in Jos. Nigerian Journal of Physiological Sciences, 23(1-2): 9-11. Frank JE, Maj MC (2005). Diagnosis and management of G6PD deficiency. American Family Physician, 72: 1277-1282. Howes RE, Dewi M, Piel FB, Monteiro WM, Battle KE, Messina JP, Sakuntabhai A, Satyagraha AW, Williams TN, Baird JK, Hay SI (2013). Spatial distribution of G6PD deficiency variants across malaria-endemic regions. Malaria Journal 12:418. Ibrahim B, Sani AM, Timothy B (2016). Prevalence of glucose-6-phosphate dehydrogenase deficiency among children aged 0-5 years infected with Plasmodium falciparum in Katsina State, Nigeria. Advances in Biochemistry, 4(6): 66-73. Johnson JA, Lima JJ (2003). Drug receptor/effector polymorphisms and pharmacogenetics: Current status and challenges. Pharmacogenetics, 13: 525–534. Luzzatto L, Gordon-Smith EC (2001). Inherited haemolytic anaemia. In: Postgraduate Haemaology. Hoffbrand AV, Lewis SM, Tuddenham EGD (eds.) 4th edition, Arnold, London, pp 120 – 143. Meyer UA, Zanger UM (1997). Molecular mechanisms of genetic polymorphisms of drug metabolism. Annu Rev Pharmacol Toxicol, 37:269–296. Meyer UA (2000). Pharmacogenetics and adverse drug reactions. Lancet, 356:1667–1671.
Pharmacists Council of Nigeria
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Muller O, Krawinkel M (2005). Malnutrition and health in developing countries. Canadian Medical Association Journal, 173: 279-286. Nnakwe N (1995). The effect and causes of protein-energy malnutrition in Nigerian children. Nutrition Research 15: 785-794. Obasa TO, Mokuolu OA, Ojuawo A (2011). Glucose-6-phosphate dehydrogenase levels in babies delivered at the University of Ilorin Teaching Hospital. Nigerian Journal of Paediatrics, 38(4):165-169. Oshikoya KA, Senbanjo IO (2009). Pathophysiological changes that affect drug disposition in protein-energy malnourished children. Nutrition & Metabolism, 6: 50. Phillips KA, Veenstra DL, Oren E, Lee JK, Sadee W (2001). Potential role of pharmacogenomics in reducing adverse drug reactions: A systematic review. Journal of American Medical Association, 286:2270–2279. Turkay S, Kus S, Gokalp A, Baskin E, Onal A (1995). Effects of protein energy malnutrition on circulating thyroid hormones. Indian Pediatrics, 32: 193-197. Vesell ES (1991). Genetic and environmental factors causing variation in drug response. Mutation Research, 247:241–257. Weinshilboum R (2003). Inheritance and drug response. New England Journal of Medicine, 348:529–537. Williams O, Gbadero D, Edowhorhu G, Brearley A, Slusher T (2013). Glucose-6-phosphate dehydrogenase deficiency in Nigerian children. PLOS ONE 8(7): 1-8, e68800. World Health Organization Working Group (1989). Glucose-6-phosphate dehydrogenase deficiency. Bull World Health Organ. 67: 601-611. World Health Organization (2000). Management of the child with serious infection or severe malnutrition: Guidelines for care at the first-referral level in developing countries. Yoshida A, Beutler E, Motulsky AG (1971). Human glucose-6-phosphate dehydrogenase variants. Bulletin of the World Health Organization, 45: 243-253.
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B. CHEMOTHERAPY
Course Outline
(1). Antimicrobial drugs: Drugs used in tuberculosis and leprosy
(2). Antiprotozoal Drugs: Drugs used in the treatment of malaria, amebiasis,
trypanosomiasis, leishmaniasis
(3). Anthelmintics: Drugs used in ascariasis ancylostomiasis, onchocerciasis,
dracunculiasis, schistosomiasis and tapeworms infestations
Learning Objectives
At the end of the course participants should
(a). State the drugs used in the treatment of tuberculosis, their mechanism of action and
adverse effects, including how some of the adverse effects could be ameliorated.
(b). Mention the drugs used in the treatment of leprosy.
(c). State the drugs used to treat malaria, amebiasis, trypanosomiasis and leishmaniasis.
(d). Mention anthelmintics in clinical use. Delineate drugs for infestations by nematodes, filarial
worms, cestodes and trematodes.
(e). For each infection/infestation, particular attention should be paid to first-line and alternative
drugs.
B1. ANTIMICROBIAL DRUGS: DRUGS USED IN TUBERCULOSIS AND LEPROSY
(i). Drugs used in Tuberculosis
Drugs used in the treatment of tuberculosis are grouped into first-line and second-line agents.
First-line drugs combine the greatest efficacy with an acceptable degree of toxicity, and are the
preferred agents. Second-line drugs are usually considered in case of (1) resistance to first-line
agents; (2) failure of clinical response to conventional therapy; and (3) serious treatment-
limiting adverse drug reactions. Majority of patients with tuberculosis are treated successfully
with first-line drugs; however, occasionally it may be necessary to resort to second-line drugs.
Table 1: Antimicrobial drugs used in the treatment of tuberculosis
First-line Agents Second-line Agents
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(in approximate order of preference)
Isoniazid Ethionamide
Rifampicin* Aminosalicylic acid
Pyrazinamide Cycloserine
Ethambutol Capreomycin
Streptomycin Amikacin
*Rifabutin is indicated in place of rifampin for treatment of tuberculosis in HIV-infected
individuals receiving antiretroviral protease or non-nucleoside reverse transcriptase
inhibitors.
(a). First-line Drugs
Isoniazid
Isoniazid is the most active drug for the treatment of tuberculosis caused by susceptible strains.
Isoniazid penetrates into macrophages and is active against both extracellular and intracellular
organisms.
Mechanism of Action
Isoniazid inhibits synthesis of mycolic acids, which are essential components of mycobacterial
cell wall. Isoniazid is a prodrug that is activated by KatG, the mycobacterial catalase-peroxidase.
The activated form of isoniazid forms a covalent complex with an acyl carrier protein (AcpM)
and KasA, a beta-ketoacyl carrier protein synthetase, which blocks mycolic acid synthesis and
kills the cell.
Pharmacokinetics
Isoniazid is readily absorbed from the gastrointestinal tract. A 300 mg oral dose (5 mg/kg in
children) achieves peak plasma concentrations of 3–5 µg/ml within 1–2 hours. Isoniazid diffuses
readily into all body fluids and tissues, it penetrates well into caseous material. The
concentration in the central nervous system and cerebrospinal fluid is about 20 - 100% of
serum concentration. Isoniazid is metabolized by mainly acetylation by liver N-
acetyltransferase to acetylisoniazid, and enzymatic hydrolysis to isonicotinic acid. Acetylation by
liver N- acetyltransferase, is genetically determined. Human populations show genetic
heterogeneity in the rate of acetylation of isoniazid; there is a bimodal distribution of slow and
fast acetylators. Isoniazid metabolites and a small amount of unchanged drug are excreted,
mainly in the urine. The dose need not be adjusted in renal failure.
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Clinical Uses
For the treatment of all types of tuberculosis.
Pyridoxine should be administered with isoniazid to minimize adverse reactions in malnourished
patients and those predisposed to neuropathy (e.g. the elderly, pregnant women, HIV-infected
individuals, diabetics, alcoholics, etc.)
Adverse Effects
Adverse effects include:
(i). Immunologic reactions with fever and skin rashes.
(ii). Hepatotoxicity - Elevated serum aspartate and alanine transaminases are encountered
commonly; however enzyme levels often normalize even with continued therapy. Hepatitis with
loss of appetite, nausea, vomiting, jaundice, and right upper quadrant pain occurs in about 1%
of isoniazid recipients and can be fatal, particularly if the drug is not discontinued promptly.
Development of isoniazid hepatitis contraindicates further use of the drug.
(iii). Peripheral neuropathy - Most commonly paraesthesia of feet and hands. Peripheral
neuropathy is more likely to occur in slow acetylators and patients with predisposing conditions
such as malnutrition, alcoholism, diabetes, AIDS, and uremia. Neuropathy is due to a relative
pyridoxine deficiency. Isoniazid promotes excretion of pyridoxine, and this toxicity is readily
reversed by administration of pyridoxine (15 – 50 mg/day).
(iv). Central nervous system toxicity is less common, and includes memory loss, psychosis, and
seizures. These effects may also respond to pyridoxine.
(v). Other adverse effects include hematologic abnormalities, provocation of pyridoxine
deficiency anemia, tinnitus and gastrointestinal discomfort.
Drug Interactions
Isoniazid is a potent inhibitor of CYP2C19, CYP3A, and a weak inhibitor of CYP2D6. However,
isoniazid induces CYP2E1. Drugs that are metabolized by these enzymes will potentially be
affected; for example, isoniazid can reduce the metabolism of phenytoin, diazepam,
carbamazepine, increasing their blood level and toxicity. It can induce the metabolism of
acetaminophen, and potentially increase the level of its toxic metabolites.
Rifampicin (Rifampin)
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32 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Rifampicin, also known as rifampin, is a semisynthetic derivative of rifamycin, an antibiotic
produced by Streptomyces mediterranei
Rifampicin is bactericidal for mycobacteria. It readily penetrates most tissues, and also
phagocytic cells. It can kill organisms that are poorly accessible to many other drugs, such as
intracellular organisms and those sequestered in abscesses and lung cavities.
Mechanism of Action
Rifampin binds to the β subunit of bacterial DNA-dependent RNA polymerase, thereby inhibiting
RNA synthesis. Human RNA polymerase does not bind rifampicin and is not inhibited by it.
Pharmacokinetics
Rifampin is well absorbed after oral administration, relatively highly protein bound, and excreted
mainly through the liver into bile. It then undergoes enterohepatic recirculation, with the bulk
excreted as a deacylated metabolite in feces and a small amount excreted in the urine. Dosage
adjustment for renal or hepatic insufficiency is not necessary. It is distributed widely in body
fluids and tissues; however adequate cerebrospinal fluid concentrations are achieved only in the
presence of meningeal inflammation.
Clinical Uses
In combination with other mycobacterial agents to treat tuberculosis and leprosy.
In bacterial infections such as meningococcal disease, staphylococcal infection, and as
prophylaxis in H. influenza type b.
Adverse Effects
Rifampicin imparts an orange-red colour to urine, feces, saliva, sputum, sweat and tears. Other
adverse effects include rashes, nausea, vomiting, thrombocytopenia, nephritis, cholestatic
jaundice, flu-like syndrome (characterized by fever, chills, myalgias and anemia), and rarely
hepatitis.
Drug Interactions
Rifampin strongly induces most cytochrome P450 isoforms (1A2, 2C9, 2C19, 2D6, and 3A4),
thereby increasing the elimination of many drugs including HIV protease and non-nucleoside
reverse transcriptase inhibitors, coumarin anticoagulants e.g. warfarin, digoxin, ketoconazole,
propranolol, quinidine, methadone, cyclosporine, some anticonvulsants, oral contraceptives, and
others. Co-administration of rifampin results in significantly lower serum levels of these drugs.
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33 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Ethambutol
Mechanism of Action
Ethambutol inhibits mycobacterial arabinosyl transferases, which are encoded by the embCAB
operon, thereby disrupting arabinogalactan synthesis. Arabinosyl transferases are involved in
the polymerization of arabinogalactan, an essential component of the mycobacterial cell wall.
Disruption of arabinogalactan synthesis results in increased permeability of the mycobacterial
cell wall.
Pharmacokinetics
Ethambutol is well absorbed from the gastrointestinal tract, and well distributed in body tissues
and fluids. After ingestion of 25 mg/kg, a peak blood level of 2–5 µ/ml is reached in 2–4 hours.
About 20% of the unchanged drug is excreted in feces and 50% in urine. Ethambutol
accumulates in renal failure, and the dose should be reduced by half if creatinine clearance is
less than 10 ml/min. Ethambutol crosses the blood-brain barrier only when the meninges are
inflamed. Concentrations in cerebrospinal fluid are highly variable, ranging from 4 - 64% of
serum levels in meningeal inflammation.
Clinical Uses
In the treatment of tuberculosis. As with all antituberculosis drugs, resistance to ethambutol
emerges rapidly when the drug is used alone. Therefore, ethambutol is always given in
combination with other antituberculosis drugs.
Adverse Effects
The most common serious adverse reaction is retrobulbar (optic) neuritis, resulting in loss of
visual acuity and red-green color blindness (i.e. loss of ability to differentiate red from green).
This dose-related adverse effect is more likely to occur at 25 mg/kg/day continued for several
months. At 15 mg/kg/day or less, visual disturbances are rare. Periodic visual acuity testing is
desirable if the 25 mg/kg/day is used. Ethambutol is relatively contraindicated in children too
young to assess visual acuity and red-green color discrimination. Another common adverse
effect is increased concentration of urate in the blood (due to decreased renal excretion of uric
acid). Other adverse effects include rash, fever, pruritus, joint pain, gastrointestinal upset,
mental confusion, disorientation, hallucination, and rarely hypersensitivity reactions.
Pyrazinamide
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Pyrazinamide is the synthetic pyrazine analog of nicotinamide. It is stable and slightly soluble in
water. It is inactive at neutral pH, but at pH 5.5 it inhibits tubercle bacilli at concentrations of
approximately 20 µg/ml. Pyrazinamide is taken up by macrophages and exerts its activity
against mycobacteria residing within the acidic environment of lysosomes.
Mechanism of Action
Pyrazinamide is converted to its active metabolite, pyrazinoic acid, by mycobacterial
pyrazinamidase. Pyrazinoic acid disrupts mycobacterial cell membrane metabolism and transport
functions.
Pharmacokinetics
Pyrazinamide is well absorbed from the gastrointestinal tract and widely distributed in body
tissues, including inflamed meninges. On oral administration of 25 mg/kg/day, serum
concentrations of 30–50 µg/ml are achieved after 1–2 hours. The plasma t1/2 is 8–11 hours. The
parent compound is metabolized by the liver, but metabolites are renally cleared; therefore,
pyrazinamide should be administered at 25–35 mg/kg three times weekly (not daily) in
hemodialysis patients and those in whom the creatinine clearance is less than 30 ml/min. In
patients with normal renal function, a dose of 40–50 mg/kg is administered two to three times
weekly.
Clinical Uses
In tuberculosis, in combination with isoniazid and rifampin.
Adverse Effects
Adverse effects include hepatotoxicity, and hyperuricemia due to inhibition of urate excretion
(may provoke acute gouty arthritis). Other untoward effects include arthralgias, anorexia,
nausea and vomiting, dysuria, malaise, and fever.
Streptomycin
Streptomycin, an aminoglycoside, penetrates into cells poorly and is active mainly against
extracellular tubercle bacilli. Streptomycin crosses the blood-brain barrier and achieves
therapeutic concentrations with inflamed meninges.
Clinical Uses
In tuberculosis, especially when parenteral administration is desirable and in cases resistant to
other antituberculosis drugs.
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Adverse Reactions
Adverse effects include ototoxicity and nephrotoxicity. Vertigo and hearing loss are the most
common adverse effects and may be permanent. Toxicity is dose-related, and the risk is
increased in the elderly. As with all aminoglycosides, the dose must be adjusted according to
renal function. Toxicity can be reduced by limiting therapy to no more than 6 months when
possible.
(b). Second-line Drugs
Ethionamide
It is poorly water soluble and available only in oral form.
Mechanism of Action
Ethionamide is chemically related to isoniazid and also blocks the synthesis of mycolic acids,
with consequent impairment of mycobacterial cell wall synthesis.
Pharmacokinetics
The oral bioavailability of ethionamide approaches 100%, with peak concentrations achieved
about 3 hours after oral administration. It is rapidly and widely distributed in the body, the
concentrations in the blood and various organs including the cerebrospinal fluid are
approximately equal. The t1/2 is about 2 hours. It is metabolized in the liver. Metabolites are
eliminated in the urine, with <1% of ethionamide excreted in an active form.
Clinical Uses
Ethionamide is administered only orally, as a second-line antituberculosis drug.
Adverse Effects
Gastrointestinal distress manifesting as anorexia, nausea, vomiting may occur; this may reduce
compliance and could be ameliorated by taking the drug with food. Other adverse effects
include hepatotoxicity (regular monitoring of liver function is required), metallic taste, central
effects (mental depression, drowsiness, asthenia, psychiatric disturbances, and encephalopathy)
and peripheral neuropathy. The concomitant use of pyridoxine is recommended in patients on
ethionamide, as it may reduce these effects.
Drug Interactions
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Ethionamide may worsen the adverse effects of other antituberculosis drugs administered
concurrently, e.g. it increases levels of isoniazid when taken together and can lead to increased
39 FPGOP Lecture Note on Applied Pharmacology and Toxicology
atypical mycobacteria. Fluoroquinolones are used in combination with two or more active
antituberculosis agents in disease resistant to first-line agents.
Rifabutin
Rifabutin is derived from rifamycin and is related to rifampicin. It has significant activity against
M. tuberculosis, Mycobacterium avium complex (MAC), and M. fortuitum. Its activity is similar to
that of rifampicin, and cross-resistance with rifampin is virtually complete.
Rifabutin is both substrate and inducer of cytochrome P450 enzymes; however, it is a less
potent inducer, and also affects fewer types of CYP enzymes compared to rifampicin. Therefore
it is used in place of rifampicin for treatment of tuberculosis in patients with HIV infection who
are receiving antiretroviral therapy with a protease inhibitor or with a non-nucleoside reverse
transcriptase inhibitor (e.g., efavirenz), drugs that also are cytochrome P450 substrates. The
typical dosage of rifabutin is 300 mg/day, however in patients receiving a protease inhibitor the
dosage should be reduced to 150 mg/day. If efavirenz (also a cytochrome P450 inducer) is
used, the recommended dosage of rifabutin is 450 mg/day. Rifabutin is effective in prevention
and treatment of disseminated atypical mycobacterial infection in AIDS patients with CD4
counts below 50/μL. It is also effective for preventive therapy of tuberculosis, either alone in a
3–4 month regimen or with pyrazinamide in a 2 month regimen.
Rifapentine
Rifapentine, an analog of rifampicin, is active against both M. tuberculosis and MAC. As with all
rifamycins, it is a bacterial RNA polymerase inhibitor, and cross-resistance between rifampicin
and rifapentine is complete. Like rifampicin, rifapentine is a potent inducer of cytochrome P450
enzymes, and it has the same drug interaction profile. Compared to rifabutin and rifampin, the
CYP-inducing effects of rifapentine are intermediate. Toxicity is similar to that of rifampicin.
Clinical Uses
Rifapentine is indicated for treatment of tuberculosis caused by rifampicin-susceptible strains
during the continuation phase only (i.e. after the first 2 months of therapy and ideally after
conversion of sputum cultures to negative). Rifapentine should not be used to treat patients
with HIV infection because of high relapse rate with rifampicin resistant organisms.
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(ii). Drugs used in Leprosy
Four major clinical types of leprosy are:
(a). Tuberculoid leprosy, also termed paucibacillary leprosy because the bacterial burden is low
and M. leprae is rarely found in smears.
(b). Lepromatous leprosy, characterized by a disseminated infection and high bacillary burden.
(c). Borderline (dimorphous) tuberculoid disease, which has features of both tuberculoid and
lepromatous leprosy.
(d). Indeterminate disease, which has early hypopigmented lesions without features of the
lepromatous and tuberculoid leprosy.
The last two are the major intermediate forms of leprosy.
Multi-drug regimens consisting of rifampicin, clofazimine, and dapsone are used in the
treatment of leprosy. Multidrug therapy is used in leprosy to (i) reduce the development of
resistance, (ii) provide adequate therapy when primary resistance already exists, and (iii)
reduce the duration of therapy.
Dapsone
Mechanism of Action
Dapsone (diaminodiphenylsulfone) is a structural analog of para aminobenzoic acid (PABA) and
a competitive inhibitor of dihydropteroate synthase (folP1/P2) in the folate pathway, ultimately
inhibiting folate synthesis.
Pharmacokinetics
After oral administration, the absorption of dapsone is complete, with elimination half-life of 20-
30 hours. Dapsone is retained in the skin, muscle, liver and kidney. Skin heavily infected with
M. leprae may contain several times more drug than normal skin. Dapsone undergoes N-
acetylation by NAT2, and N-oxidation to dapsone hydroxylamine via CYP2E1 and to a lesser
extent by CYP2C. Dapsone hydroxylamine enters red blood cells, leading to methemoglobin
formation. Intestinal reabsorption of dapsone excreted in the bile contributes to long-term
retention in the bloodstream; consequently, periodic interruption of treatment is recommended.
Approximately 70-80% of a dose of dapsone is excreted in the urine as an acid-labile mono-N-
glucuronide and mono-N-sulphamate.
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Clinical Uses
Dapsone is used in combination with rifampin and clofazimine for initial therapy of leprosy as
resistance can emerge, e.g. in lepromatous leprosy, if very low doses are given. Dapsone is
used to prevent and treat Pneumocystis jiroveci pneumonia. It is combined with chlorproguanil
for the treatment of malaria.
Adverse Effects
Dapsone is usually well tolerated. Many patients develop hemolysis, particularly if they have
G6PD deficiency. It is recommended that G6PD deficiency testing should be performed prior to
use of dapsone if possible. Other adverse effects are methemoglobinemia, gastrointestinal
intolerance, fever, pruritus, and rashes. During dapsone therapy of lepromatous leprosy,
erythema nodosum leprosum often develops. It is sometimes difficult to distinguish reactions to
dapsone from manifestations of the underlying illness. Erythema nodosum leprosum may be
suppressed by corticosteroids or by thalidomide.
Rifampicin/Rifampin
Rifampicin is highly effective in lepromatous leprosy. It is given in combination with dapsone or
clofazimine because of the probable risk of emergence of rifampicin-resistant M. leprae.
Clofazimine
The mechanism of action of clofazimine has not been clearly elucidated. Absorption of
clofazimine from the gut is variable, and a major portion of the drug is excreted in feces.
Clofazimine is stored widely in reticuloendothelial tissues and skin, and its crystals can be seen
inside phagocytic reticuloendothelial cells. It is slowly released from these deposits, therefore
the serum t1/2 may be 2 months. Clofazimine is used in dapsone-resistant leprosy or in patients
intolerant to dapsone.
Discoloration of body secretions, eye and skin occur in most patients and can lead to depression
in some patients. Gastrointestinal problems are encountered in 40-50% of patients and include
abdominal pain, diarrhea, nausea, and vomiting.
Treatment of Reactions in Leprosy
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During the course of leprosy, immunologically mediated episodes of acute or subacute
inflammation known as reactions may occur in patients. Leprosy reactions include reversal
reaction and erythema nodosum leprosum.
Patients with tuberculoid leprosy may develop reversal reactions, which are manifestations of
delayed hypersensitivity to antigens of M. leprae. Cutaneous ulcerations and deficits of
peripheral nerve function may occur. Early therapy with corticosteroids or clofazimine is
effective.
Erythema nodosum leprosum is an immune-mediated complication of leprosy, characterized by
the presence of multiple, tender inflammatory cutaneous nodules; and systemic symptoms such
as fever, malaise, arthritis, iritis, neuritis and lymphadenitis. It is thought to be initiated by the
release of mycobacterial antigens, which trigger the formation of immune complexes. Antigen-
antibody complexes deposited in the circulation and tissues, activate the complement.
Treatment with clofazimine or thalidomide is effective.
Rifampin is a highly effective anti-leprosy drug, however, due to high kill rates and massive
release of bacterial antigens, it is not often given during a reversal reaction or in patients with
erythema nodosum leprosum. Clofazimine is only bacteriostatic against M. leprae; however, it
also has anti-inflammatory effects and is used to treat reversal reactions and erythema
nodosum leprosum.
B2. ANTIPROTOZOAL DRUGS: DRUGS USED IN THE TREATMENT OF MALARIA, AMOEBIASIS, TRYPANOSOMIASIS, LEISHMANIASIS (i). Drugs Used in the Treatment of Malaria Classification of anitmalarial drugs
Antimalarials can be classified by the stage of parasite that they affect and their clinical uses.
Some drugs have more than one type of antimalarial activity.
(1). Drugs used for casual prophylaxis
These act on primary tissue forms of Plasmodia, which will, in less than one month initiate the
erythrocytic stage of infection. Invasion of erythrocytes and further transmission of infection are
thereby prevented e.g. proguanil (the prototype). Primaquine also has such activity against P.
falciparum, but it is reserved for other clinical applications because of its toxicity.
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(2). Drugs used to prevent relapse
These drugs act on latent tissue forms of P. vivax and P. ovale remaining after the primary
hepatic forms have been released into the circulation. Such latent tissue forms eventually
mature, invade the circulation and produce malarial attacks i.e. relapse, months or years after
the initial infection.
Drugs active against latent tissue forms are used for terminal prophylaxis and for radical cure of
relapsing malarial infections. Primaquine is the prototype drug used to prevent relapse. For
terminal prophylaxis, regimens with such a drug are initiated shortly before or after a person
leaves an endemic area. To achieve radical cure, this type of drug is taken either during the
long-term latent period of infection or during an acute attack. In the latter case, the agent is
given together with an appropriate drug, e.g. artemisinins, quinine, chloroquine, etc. to
eradicate erythrocytic stages of P. vivax and P. ovale.
(3). Drugs (blood schizontocides) used for clinical and suppressive cure
These agents act on asexual erythrocytic stages of malarial parasites to interrupt erythrocytic
schizogony and thereby terminate clinical disease i.e. effect clinical cure.
Such drugs also may produce suppressive cure, which refers to complete elimination of
parasites from the body by continued therapy. Inadequate therapy with blood schizontocides
may result in recrudescence of infection due to erythrocytic schizogony.
These agents can be divided into 2 groups:
(a). Rapidly acting blood schizontocides e.g. artemisinins; classical antimalarial alkaloids e.g.
chloroquine, quinine and the related derivatives quinidine and mefloquine; atovaquone and
others.
(b). Slower-acting blood schizontocides e.g. antifolate (e.g. pyrimethamine), and antibacterial
antimalarials (e.g. sulfadoxine, sulfadiazine). These drugs are mostly used in conjunction with
the rapidly acting ones.
(4). Gametocytocides
These agents act against sexual erythrocytic forms of plasmodia, thereby preventing
transmission of malaria to mosquitoes. Chloroquine and quinine have gametocytocidal activity
against P. vivax, P. ovale and P. malariae, whereas primaquine displays especially potent
activity against gametocytes of P. falciparum. However, antimalarials are not used clinically just
for gamecytocidal action.
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(5). Sporontocides
They ablate transmission of malaria by preventing or inhibiting formation of malarial oocysts
and sporozoites in infected mosquitoes. They render gametocytes non-infective in the mosquito
e.g. pyrimethamine, proguanil. Although chloroquine prevents normal plasmodia development
within the mosquito, neither it nor other antimalarial agents are used clinically for this purpose.
Antimalarial agents are also classified into:
1. Class I: Are effective against the asexual erythrocytic forms of Plasmodium. They may be
used to prevent or treat clinically symptomatic malaria. They include artemisinins, chloroquine,
(iv). Drugs used in the treatment of Leishmaniasis
Various forms of leishmaniasis affect people in tropical and subtropical regions of the world, and
southern Europe.
Leishmaniasis is a complex vector-borne zoonosis caused by about 20 different species of
obligate intramacrophage protozoa of the genus Leishmania. Small mammals and canines
generally serve as reservoirs for these pathogens, which can be transmitted to humans by the
bite of about 30 different species of female Phlebotomine sand fly (disease vector).
Flagellated extracellular free promastigotes, regurgitated by feeding flies, enter the host, where
they attach to and become phagocytized by tissue macrophages. These transform into
amastigotes, which reside and multiply within phagolysosomes until the cell bursts. Released
amastigotes then propagate the infection by invading more macrophages. Amastigotes taken up
by feeding sandflies transform back into promastigotes, thereby completing the transformation
cycle.
The particular localized or systemic disease syndrome caused by Leishmania depends on the
species or subspecies of infecting parasite, the distribution of infected macrophages, and
particularly the host’s immune response. In increasing order of systemic involvement and
potential clinical severity, major syndromes of human leishmaniasis is classified into cutaneous,
mucocutaneous, diffuse cutaneous, and visceral (kala azar) forms. Cutaneous forms of
leishmaniasis generally are self-limiting, with cures occurring in 3-18 months after infection.
However, this form of the disease can leave disfiguring scars. The mucocutaneous, diffuse
cutaneous, and visceral forms of the disease do not resolve without therapy. Visceral
leishmaniasis caused by L. donovani is fatal unless treated.
Leishmaniasis is increasingly becoming recognized as an AIDS-associated opportunistic
infection.
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Pharmacotherapy of leishmaniasis
Pentavalent antimonials: Sodium stibogluconate and meglumine antimoniate
The mechanism of action of the antimonials is unknown.
Pharmacokinetics
They are rapidly absorbed and distributed after intravenous (preferred) or intramuscular
administration and eliminated in two phases, with short initial half-life (about 2 hours) and
much longer terminal half-life (33 - 76 hours).
Clinical Uses
Sodium stibogluconate (sodium antimony gluconate) and meglumine antimoniate, are generally
considered first-line agents for cutaneous, mucocutaneous and visceral leishmaniasis.
Their efficacy against different species may vary, possibly based on local drug resistance
patterns (e.g. their efficacy has diminished in parts of India).
Adverse Effects
Few adverse effects occur initially, but toxicity of stibogluconate increases over the course of
therapy. Most common are gastrointestinal symptoms, fever, headache, myalgias, arthralgias,
and rash. Intramuscular injections can be very painful and lead to sterile abscesses.
Electrocardiographic changes may occur, most commonly T-wave changes and QT prolongation.
These changes are generally reversible, but continued therapy may lead to dangerous
arrhythmias. Thus, the electrocardiogram should be monitored during therapy. Hemolytic
anemia and serious liver, renal, and cardiac effects are rare.
Miltefosine
Miltefosine is an alkylphosphocholine analog that is the first effective oral drug for visceral
leishmaniasis. Miltefosine is used for the treatment of visceral leishmaniasis.
Adverse effects include vomiting, diarrhea transient elevations in liver enzymes and
nephrotoxicity. Miltefosine is contraindicated in pregnancy or in women who may become
pregnant within 2 months of treatment, because of its teratogenic effects.
Liposomal amphotericin B and Paromomycin are also used to treat leishmaniasis in some
countries.
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B3. ANTHELMINTICS: DRUGS USED IN ASCARIASIS, ANCYLOSTOMIASIS, ONCHOCERCIASIS, DRACUNCULIASIS, SCHISTOSOMIASIS AND TAPEWORMS INFESTATIONS Helminths (parasitic worms) pathogenic in humans are nematodes (roundworms), cestodes
(tapeworms), and trematodes (flukes). Cestodes and trematodes are flatworms
(platyhelminthes). In regions of rural poverty in the tropics including Nigeria, with high
prevalence of helminthiasis, simultaneous infection with more than one type of helminth is
common. Soil-transmited helminth (STH) infections such as ascariasis, trichuriasis and
hookworm infestation are among the most prevalent in developing countries.
Anthelmintics are drugs that act either locally within the gut lumen to cause expulsion of worms
from the gastrointestinal tract, or systemically against helminths residing outside the
gastrointestinal tract.
Nematodes (Roundworms)
The major nematode parasites of humans include the soil-transmitted helminths (STHs;
sometimes referred to as geohelminths) and the filarial nematodes.
Soil-transmited helminths include Ascaris lumbricoides (roundworm), Trichuris trichuira
(whipworm), and hookworm (Necator americanus and Ancylostoma duodenale). Other
nematodes are Strongyloides stercoralis (threadworm), Enterobius vermicularis (pinworm),
Trichinella spiralis, etc.
Filarial nematodes include lymphatic filarial and tissue-migrating filarial parasites. Lymphatic
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Niclosamide is a second-line drug for the treatment of most tapeworm infestations.
Mechanism of Action
Niclosamide inhibits glucose uptake, oxidative phosphorylation, and anaerobic metabolism in
the tapeworm.
Pharmacokinetics
It appears to be minimally absorbed from the gastrointestinal tract; neither the drug nor its
metabolites have been recovered from the blood or urine.
Clinical Uses
1. In the treatment of Taenia saginata (Beef Tapeworm), T. solium (Pork Tapeworm),
Diphyllobothrium latum (Fish Tapeworm), and some other tapeworm infestations.
Adverse Effects
Infrequent, mild, and transitory adverse effects include nausea, vomiting, diarrhea, and
abdominal discomfort.
Cautions and Contraindications
The consumption of alcohol should be avoided on the day of treatment and for one day
afterward. The safety of the drug has not been established in pregnancy or for children younger
than 2 years of age.
Therapy with niclosamide poses a risk to people infected with T. solium because ova released
from drug-damaged gravid worms develop into larvae that can cause cysticercosis, a dangerous
infection that responds poorly to chemotherapy.
(iii). Anthelmintics used to treat infections by filarial nematodes Ivermectin Ivermectin, a semisynthetic macrocyclic lactone, is a mixture of avermectin B 1a and B 1b. It is
derived from the soil actinomycete, Streptomyces avermitilis. Ivermectin is the drug of choice in
strongyloidiasis and onchocerciasis. It is also an alternative drug for a number of other
helminthic infections.
In humans infected with O. volvulus, ivermectin causes a rapid, marked decrease in microfilarial
counts in the skin and ocular tissues that lasts for 6-12 months. It has little discernible effect on
adult parasites, even at doses as high as 800 μg/kg, but affects developing larvae and blocks
egress of microfilariae from the uterus of adult female worms. By reducing microfilariae in the
*Niclosamide is effective in T. solium infections, however its use may cause cysticercosis in people infected with T. solium. It is not used in some countries.
Bibliography and Further Reading
Alvar J, Croft S, Olliaro P (2006). Chemotherapy in the treatment and control of leishmaniasis. Adv Parasitol, 61:223–274. Balasegaram M, Harris S, Checchi F, Ghorashian S, Hamel C, Karunakara U (2006). Melarsoprol versus eflornithine for treating late-stage Gambian trypanosomiasis in the Republic of the Congo. Bull World Health Organ, 84:783–791. Balasegaram M, Young H, Chappuis F, Priotto G, Raguenaud M, Checchi F (2009). Effectiveness of melarsoprol and eflornithine as first-line regimens for gambiense sleeping sickness in nine Médecins Sans Frontières programmes. Trans R Soc Trop Med Hyg, 103:280–290. Bethony J, Brooker S, Albonico M, Geiger SM, Loukas A, Diement D, Hotez PJ (2006). Soil-transmitted helminth infections: ascariasis, trichuriasis, and hookworm. Lancet, 367:1521–1532. Blumberg HM, Burman WJ, Chaisson RE, et al (2003). American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America. Treatment of tuberculosis. Am J Respir Crit Care Med, 167:603–662. Brun R, Blum J, Chappuis F, Burri C (2010). Human African trypanosomiasis. Lancet, 375:148 - 159. Chappuis F, Udayraj N, Stietenroth K, Meussen A, Bovier PA (2005). Eflornithine is safer than melarsoprol for the treatment of second-stage Trypanosoma brucei gambiense human African trypanosomiasis. Clinical Infectious Diseases, 41:748–751. Croft SL, Barrett MP, Urbina JA (2005). Chemotherapy of trypanosomiases and leishmaniasis. Trends in Parasitology, 21:508 - 512. Cupp EW, Ochoa AO, Collins RC, Ramberg FR, Zea G (1989). The effect of multiple ivermectin treatments on infection of Simulium ochraceum with Onchocerca volvulus. American Journal of Tropical Medicine and Hygiene, 40: 501–506.
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AIDS Info (2018). Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents. Available at: http://aidsinfo.nih.gov/guidelines Drugs for parasitic infections (2007). Med Lett Drugs Ther, Suppl 1. Drugs for parasitic infections. (2010). Med Lett Drugs Ther, Supplement. Efferth T, Kaina B (2010). Toxicity of the antimalarial artemisinin and its derivatives. Critical Reviews in Toxicology, 40:405 - 421. Fox LM (2006). Ivermectin: Uses and impact 20 years on. Current Opinion in Infectious Diseases, 19:588 - 593. Greenwood BM, Bojang K, Whitty CJM, Targett GAT (2005). Malaria. Lancet, 365:1487 – 1498. Haque R, Huston CD, Hughes M, Houpt E, Petri WA (2003). Amebiasis. New England Journal of Medicine, 348:1565 - 1573. Horton J (2002). Albendazole: A broad spectrum anthelminthic for treatment of individuals and populations. Current Opinion in Infectious Diseases, 15:599 - 608. Keiser J, Utzinger J (2008). Efficacy of current drugs against soil-transmitted helminth infections: Systematic review and meta-analysis. Journal of American Medical Association, 299:1937 - 1948. Levis WR, Ernst JD (2005). Mycobacterium leprae (Leprosy, Hansen’s disease). In: Mandell, Douglas, and Bennett’s Principles and Practices of Infectious Diseases (Mandell GL, Bennett JE, Dolin R, eds.), Elsevier Churchill Livingstone, Philadelphia, pp. 2886–2896. Molyneux DH, Bradley M, Hoerauf A, Kyelem D, Taylor MJ (2003). Mass drug treatment for lymphatic filariasis and onchocerciasis. Trends in Parasitology, 19:516–522. Murray HW, Berman J, Davies CR, Saravia NG (2005). Advances in leishmaniasis. Lancet, 366:1561 - 1577. Nosten F, White NJ (2007). Artemisinin-based combination treatment of falciparum malaria. American Journal of Tropical Mediicne and Hygeine, 77(Suppl 6):181 -192. Petri WA (2003). Therapy of intestinal protozoa. Trends in Parasitology, 19:523 - 526. Pierce KK, Kirkpatrick BD (2009). Update on human infections caused by intestinal protozoa. Current Opinion in Gastroenterology, 25:12 - 17. Priotto G, Kasparian S, Mutombo W, Ngouama D et al (2009). Nifurtimox-eflornithine combination therapy for second-stage African Trypanosoma brucei gambiense trypanosomiasis: A multicentre, randomised, phase III, non-inferiority trial. Lancet, 374:56 - 64.
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Pritt BS, Clark CG (2008). Amebiasis. Mayo Clinic Proceedings, 83:1154 - 1160. Rassi A, Rassi A, Marin-Neto JA (2010). Chagas disease. Lancet, 375:1388 - 1402. Reithinger R, Dujardin J, Louzir H, Primez C, Alexander B, Brooker S (2007). Cutaneous leishmaniasis. Lancet Infectious Diseases, 7:581 - 596. Tisch DJ, Michael E, Kazura JW (2005). Mass chemotherapy options to control lymphatic filariasis: A systematic review. Lancet Infectious Diseases, 5:514 - 523. Udall DN (2007). Recent updates on onchocerciasis: Diagnosis and treatment. Clinical Infectious Diseases, 44:53 - 60. World Health Organization (1998). WHO Model Prescribing Information: Drugs used in leprosy. World Health Organization, Geneva. World Health Organization (2010). Guidelines for the treatment of malaria. Geneva. http://www.who.int/malaria/publications/atoz/9789241547925/en/ index.html
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C. TOXICOLOGY
Course Outline
1. Management of poisoning
2. Drug toxicity: Definition and mechanisms
3. Animal poisons: snakebite, scorpion stings, bee stings and their management
4. Local food poisoning
5. Pesticides
6. Solvents, vapours and gases
7. Heavy metals and their antagonists
Learning Objectives
At the end of the course participants should
(a). Outline measures for emergency management of poisoning due to drugs and other
substances.
(b). Mention known specific antidotes for poisons.
(c). Mention the chelators used in the treatment of poisoning by specific heavy metals.
(d). State sources of poisons in the home, workplace and environment.
(e). State the measures and steps involved in the management of snakebite, scorpion and bee
stings.
(f). Outline the dos and don’ts in the management of snake bite.
(g). Name some pesticides that have been banned globally.
(h). Outline the steps involved in the management of poisoning due to commonly used
insecticides (pyrethrins, etc.) and solvents.
(i). State the steps involved in the treatment of carbon monoxide poisoning
(j). Outline the steps involved in the management of cyanide, kerosene and petrol poisoning.
(k). Identify the classes of insecticides commonly used in Nigeria; and management of poisoning due to same. Definition of Toxicology
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Toxicology is a discipline concerned with the study of the harmful effects of chemical, biological
and physical agents on biological systems. Toxicology comprises the detection of the toxic
agent, mechanism by which the harmful effect is induced, the condition(s) under which it
occurs, and the treatment of the toxicity.
Divisions of toxicology include environmental toxicology, occupational toxicology, forensic
toxicology, food toxicology, and clinical toxicology.
C1. Management of Poisoning
It is pertinent to discuss the management of poisoning in general, before discussing the
poisons. Management of specific poisons shall be discussed, as appropriate under the individual
poisons.
(i). Poisoning
Poisoning is a condition or process in which an organism, e.g. humans, becomes harmed
(poisoned) by a toxic substance (poison). Poisoning could be acute or chronic.
Poisons are substances which on entering the body by whatever route (ingestion, inhalation,
absorption through the skin, etc) produce harmful effects. The effects may be damage to the
tissues or a disruption of body function. Poisonous substances may be drugs, air pollutants,
water contaminants, food residues or contaminants, soil contaminants, animal venoms, plant
toxins, etc.
Poisoning could be from drugs; industrial exposure of workers and others to toxic substances
(e.g. workers exposed to mercury, arsenic, paraquat, dibromochloropropane, etc); ingestion of
contaminated foo;, snake bites, bee sting and other animal venom or plant toxins; accidental
eating of poisonous food, like poisonous mushrooms or improperly processed food (like
cassava, with cases of cyanide poisoning); and ingestion, inhalation or contact with chemicals
and other poisonous substances.
Some of these potential toxic substances or poisons are normally found in the home as drugs;
household materials for cooking and other purposes like kerosene, fuel, diesel, detergents, etc.;
cosmetics like shampoo, hair dyes; and pesticides. These cause accidental poisoning,
particularly among children. Poisoning in adults may be accidental or suicidal.
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Generally, substances involved mostly in acute poisoning include drugs, cleaning substances,
cosmetics and personal care products, animal bites and envenomations, fumes/vapors,
pesticides, plants, food products, food poisoning, alcohols, hydrocarbons, chemical and
solvents.
(ii). Management of acute poisoning
Some general principles are applicable in the management of poisoning, whether due to drugs,
chemicals, gases, pesticides, bacteria, plant and animal toxins etc. These general principles
would be disccussed here, specific and other measures shall be discussed under the individual
poison, as appropriate.
(a). Preventive measures at home and work place
Most of the acute poisoning in the home can be prevented by:
(a). Keeping drugs in tamper-proof containers, out of the reach of children.
(b). Keeping household chemicals, e.g. detergents, bleaches, cosmetics, polish, pesticides
(insecticides, rodenticides, and others), petroleum products, etc. away from foodstuffs, under
lock and key, and out of easy reach. They should also be kept in properly labelled containers.
(c). Ensuring that all medicines are taken as directed; unused medicines should be properly
disposed.
At the workplace, there should be necessary and adequate precautions to avoid exposure to
hazardous substances including:
(a). Provision of personal protective equipment (PPE) such as coveralls, nose masks, etc.
(b). Provision of SoPs for handling and disposal of hazardous substances.
(c). Routine drills and training of staff on health and safety measures, and potential challenges
in the workplace.
(b). Treatment of acute poisoning
Emergency measures at home and work place
The essence of these measures is to remove the poison from the point of contact with the body
and prevent further damage.
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(1). If the poison was ingested, vomiting may be induced if the poison is not a corrosive
material (e.g. acid, alkali, etc), a petroleum product (e.g. kerosene, petrol, paint thinner, etc) or
a central nervous system stimulant. Vomiting can also be induced mechanically by stroking the
posterior pharynx.
NOTE: Don’t induce vomiting if the patient is drowsy or if the poison is a central nervous
system stimulant (vomiting may induce convulsion), corrosive material or a petroleum product.
(2). If the poison was inhaled, move the person immediately to area of fresh air, and give
artificial respiration if necessary.
(3). In cases of contamination of the skin, drench the skin with copious amount of water, after
removal of clothing. Then clean the skin with soap and water, if applicable.
(4). In cases of contamination of the eye, wash the affected eye with running water for about
15 minutes.
After the emergency intervention at home or in the work place, the patient should be taken to
the hospital for treatment. The poison in its container should be taken along for identification
and better treatment.
Emergency treatment of acute poisoning
Treatment of acute poisoning must be prompt, and is carried out in the hospital by well trained
personnel. The treatment goals are (i) supportive care and symptomatic treatment to maintain
vital functions; (ii) to keep the concentration of poison in the vital tissues as low as possible by
preventing absorption, and enhancing removal and elimination of the poison; (iii) to combat the
pharmacological and toxicological effects at the effector sites by neutralising the effect of the
poisons by administration of an antidote where available.
It is important to note that specific antidotes are available for only a few toxic agents. Even
these are not always effective, particularly if the poisoning is severe. The best treatment begins
with supportive care and maintenance of vital functions; this includes resuscitation (if
necessary), maintenance of respiratory and cardiovascular functions, correction of fluid and
electrolytes imbalance, etc.
I. General Supportive care and symptomatic treatment of poisoned patients in the
hospital
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Supportive care and symptomatic treatment is the mainstay of management of the poisoned
patient. The adage, ‘treat the patient, not the poison,’ remains the most basic and important
principle of management of poisoning. Maintenance of respiration, blood pressure and other
vital functions are crucial. Serial measurement and charting of vital signs and important reflexes
help to judge the progress of intoxication, response to therapy, and need for additional
treatment. This monitoring usually requires hospitalization. Supportive measures and
symptomatic treatment include:
(1). Improvement of respiration: Assisted ventilation and oxygen should be provided if
necessary.
Note: Respiratory stimulants are not beneficial, and are potentially dangerous.
(2). Normalisation of blood pressure: For example hypotension is common in severe poisoning
with central nervous system depressants (barbiturates, benzodiazepine, etc), β-blockers, etc,
and may lead to irreversible brain damage or renal tubular damage, among others. Therefore,
timely normalisation of the blood pressure is important.
(3). Cardiac arrhythmias, and other conduction defects are corrected. Arrhythmias often
respond to corrections of underlying hypoxia or acidosis.
(4). Normalisation of body temperature as there may be hypo- or hyperthermia.
(5). Treatment of convulsions with e.g. diazepam.
(6). Correction of fluid and electrolyte imbalance.
II. Removal and elimination of poisons
(a). Removal of the poison from the skin, eye and gastrointestinal tract
The poison should be removed from the skin, eyes and the gastrointestinal tract (GIT), as
applicable.
(i). Initial treatment of all types of chemical injuries to the eye must be rapid. Thorough
irrigation of the contaminated eye with water for 15 minutes should be performed immediately.
(ii). The contaminated skin should be washed thoroughly with water. Contaminated clothing
should be removed.
(iii). If the poison was inhaled, the patient should be removed immediately from the source of
exposure to area of fresh, uncontaminated air, and artificial respiration administered if
necessary.
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(iv). Gastrointestinal tract - Ingestion is the most common route of poisoning. Poison can be
removed from the GIT by the following means:
Emesis
The routine induction of emesis in emergency rooms is declining. Although emesis still may be
indicated for immediate intervention after poisoning by oral ingestion of chemicals, it is
contraindicated if the patient (i) has ingested a corrosive poison, such as a strong acid or alkali
(e.g., drain cleaners) - emesis increases the likelihood of gastric perforation and further necrosis
of the esophagus; (ii) is comatose or in a state of stupor or delirium - emesis may cause
aspiration of the gastric contents; (iii) has ingested a central nervous system stimulant - further
stimulation associated with vomiting may precipitate convulsions; and (iv) has ingested a
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pricks/punctures at the site of the bite or in the bitten limb, attempts to suck the venom out of
the wound, use of (black) snake stones, tying tight bands (tourniquets) around the limb,
electric shock, topical instillation or application of chemicals, or ice packs.
It is dangerous to delay medical treatment
The goals of first aid is to (i) attempt to retard systemic absorption of venom; (ii) preserve life
and prevent complications before the victim can receive medical care; (iii) control distressing or
dangerous early symptoms of envenomation; (iv) arrange transport of the victim to a place
where they can receive medical care; (v) do no harm!
Do not attempt to kill the snake as this may be dangerous. However, if the snake has already
been killed, it should be taken to the dispensary or hospital with the victim in case it can be
identified. However, the snake should not be handled with bare hands as even a severed head
can bite (envenomate).
Snakebite first aid recommendations vary, partly because different snakes have different types
of venom. Some have little local effect, but life-threatening systemic effects (e.g Elapids), in
which case containing the venom in the region of the bite by pressure immobilization is
desirable. Other venoms elicit localized tissue damage around the bitten area, and
immobilization may increase the severity of the damage in this area, but also reduce the total
area affected (the benefit of this measure in this case is equivocal).
Recommended first aid measures include:
(i). Reassure the victim who may be very anxious
(ii). Immobilize the whole of the patient’s body by laying him/her down in a comfortable and
safe position and, especially, immobilize the bitten limb with a splint or sling. The patient must
not be allowed to walk, run, and take alcohol or stimulants. Any movement or muscular
contraction increases absorption of venom into the bloodstream and lymphatics.
If the necessary equipment and skills are available, pressure-immobilization or pressure pad (to
contain the venom in the region of the bite) are recommended for bites by neurotoxic elapid
snakes.
Pressure Immobilization: Pressure immobilization serves to contain venom within a bitten
limb and prevent it from moving through the lymphatic system to the vital organs. This therapy
has two components: pressure to prevent lymphatic drainage, and immobilization of the bitten
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limb. It is recommended for snakebites due to elapids which are neurotoxic. Generally, it is not
recommended for bites from non-neurotoxic snakes; however, in some regions, pressure
immobilization is recommended in all cases where the type of snake is unknown.
(iii). Avoid any interference with the bite wound (e.g. incisions, rubbing, vigorous cleaning,
massage, application of herbs or chemicals) as this may introduce infection, increase absorption
of the venom and increase local bleeding.
(iv). Tight bands, bandages and ligatures used, should not be released until the patient is under
medical care in hospital, resuscitation facilities are available and antivenom treatment has been
started.
Traditional first aid methods should be discouraged, as they do more harm than good.
List of DO NOTs in management of snake bite
Do not pick up the snake or try to wrap it up or kill it, as this will increase the chance of getting another bite. Even a dead snake is able to bite (envenomate).
Do not apply a tourniquet. Do not cut across the site of the bite marks. Do not try to suck out the venom. Do not apply ice, electric shock, etc. Do not immerse the wounded area in water. Do not take alcohol, beverages with caffeine, other stimulants
(2). Transport to hospital - The greatest fear is that a snakebite victim might develop fatal
respiratory paralysis or shock before reaching a place where they may be resuscitated. This risk
may be reduced by speeding up transport to hospital. The patient must be transported to a
place where he can receive adequate medical care as quickly, but as safely and comfortably, as
possible. Any movement especially movement of the bitten limb, must be reduced to an
absolute minimum to avoid increasing the systemic absorption of venom. Any muscular
contraction will increase the spread of venom from the site of the bite. A stretcher, bicycle,
motorbike, cart, horse, motor vehicle, train or boat, etc. may be used, or the patient can be
carried (e.g. using the Fireman’s Lift technique). If possible, patients should be placed in the
and renal toxicities that can progress to kidney failure and death.
Treatment of arsenic poisoning
Following acute exposure to arsenic,
(1). The patient should be stabilized and further absorption of the poison prevented.
(2). Close monitoring of fluid levels is important because arsenic can cause fatal hypovolemic
shock. Hypotension may necessitate fluid replacement and use of pressor agents (e.g.
dopamine).
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(3). Chelation therapy is effective following short-term exposure to arsenic but has very little or
no benefit in chronically exposed individuals. Chelators used in arsenic poisoning include
dimercaprol, penicillamine, and succimer
(4).Exchange transfusion to restore blood cells and remove arsenic often is necessary following
arsine gas exposure.
(ii). Heavy Metal Antagonists
Treatment of acute heavy metal intoxications often involves the use of heavy metal antagonists
or chelators. A chelator is a compound that forms stable complexes with metals, typically as
five- or six-membered rings. Formation of complexes between chelators and metals should
prevent or reverse metal binding to biological ligands.
(a).Properties of an ideal chelating agent
The ideal chelator should have the following properties:
(i). High solubility in water.
(ii). Resistance to biotransformation.
(iii). Ability to reach sites of metal storage.
(iv). Ability to form stable and non-toxic complexes with toxic metals.
(v). Ready excretion of the metal-chelator complex.
(vi). A low affinity for the essential metals – such as calcium and zinc – is also desirable,
because toxic metals often act through competition with these metals for protein binding.
(b). Chelating agents
Dimercaprol
Dimercaprol (British anti-lewisite; BAL) was developed during World War II as a therapeutic
antidote against poisoning by the arsenic-containing warfare agent lewisite.
Dimercaprol is an oily, colourless liquid with pungent, disagreeable odour. Because aqueous
solutions of dimercaprol are unstable and oxidize readily, it is dispensed in 10% solution in
peanut oil and must be administered by intramuscular injection, which is often painful.
Mechanism of Action
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Dimercaprol acts through the formation of chelation complexes between its sulfhydryl groups (-
SH) and metals. Dimercaprol is more effective when given soon after exposure to the metal,
because it more effectively prevents inhibition of sulfhydryl enzyme than in reactivating them.
Pharmacokinetics
Dimercaprol cannot be administered orally; it is given by deep intramuscular injection as a 100
mg/ml solution in peanut oil and should not be used in patients who are allergic to peanuts or
peanut products. Peak concentrations in blood are attained in 30-60 minutes. The t1/2 is short,
and metabolic degradation and excretion are complete within 4 hours. Dimercaprol and its
chelates are excreted in both urine and bile.
Adverse Effects
Adverse effects of dimercaprol include hypertension; tachycardia; nausea and vomiting;
headache; a burning sensation in the lips, mouth and throat, and a feeling of constriction,
sometimes pain in the throat, chest or hands; conjunctivitis; lacrimation; salivation; fever
(particularly in children); pain at the injection site; thrombocytopenia and increased
prothrombin time (these may limit intramuscular injection because of the risk of hematoma
formation at the injection site).
Ethylenediaminetetracetic acid (EDTA) and its derivatives
Ethylenediaminetetracetic acid and its various salts are effective chelators of divalent and
trivalent metals. However, not all salts are used therapeutically, for example rapid intravenous
administration of Na2EDTA causes hypocalcemic tetany. In contrast, CaNa2EDTA can be
administered intravenously with negligible change in the concentration of Ca2+ in plasma and
total body. Therefore, to prevent potentially life-threatening depletion of calcium, the calcium
disodium salt is used.
Calcium disodium EDTA (CaNa2EDTA) is the preferred EDTA salt for metal poisoning, provided
that the metal has a higher affinity for EDTA than calcium. CaNa2EDTA is effective for the
treatment of acute lead poisoning, particularly in combination with dimercaprol, but is not an
effective chelator of mercury or arsenic in vivo.
Mechanism of Action
The pharmacological effects of CaNa2EDTA result from chelation of divalent and trivalent metals
in the body. Accessible metal ions (both exogenous and endogenous) with a higher affinity for
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CaNa2EDTA than Ca2+ are chelated, mobilized, and usually excreted. CaNa2EDTA mobilizes
several endogenous metallic cations, including those of zinc, manganese, and iron. Additional
supplementation with zinc following chelation therapy may be beneficial. Since it is charged at
physiological pH, EDTA does not significantly penetrate cell membranes and therefore chelates
extracellular metal ions much more effectively than intracellular ions.
Pharmacokinetics
Less than 5% of CaNa2EDTA is absorbed from the GIT, hence it is not used orally. After
intravenous administration, CaNa2EDTA has a t1/2 of 20-60 minutes. In blood, CaNa2EDTA is
found only in the plasma. It is distributed mainly in the extracellular fluids; very little enters the
spinal fluid (5% of the plasma concentration). There is very little metabolic degradation of
EDTA. CaNa2EDTA is excreted in the urine by glomerular filtration, so adequate renal function is
necessary for successful therapy. Altering either the pH or the rate of urine flow has no effect
on the rate of excretion.
Adverse Effects
The principal toxic effect of CaNa2EDTA is renal toxicity. Other adverse effects include malaise,
fatigue and excessive thirst, followed by the sudden appearance of chills and fever and
subsequent myalgia; frontal headache; anorexia; occasional nausea and vomiting; and rarely,
increased urinary frequency and urgency. Sneezing, nasal congestion and lacrimation;
glycosuria; anemia; dermatitis with lesions strikingly similar to those of vitamin B6 deficiency;
transient lowering of systolic and diastolic blood pressures; prolonged prothrombin time; and T-
wave inversion on the electrocardiogram, may also occur.
Penicillamine
Penicillamine is a white crystalline, water-soluble derivative of penicillin. D-Penicillamine is less
toxic than the L-isomer, and consequently is the preferred therapeutic form. Penicillamine is an
effective chelator of copper, mercury, zinc and lead, and promotes the excretion of these
metals in the urine.
Penicillamine is more toxic and is less potent and selective for chelation of heavy metals relative
to other available chelators. It is therefore not a first-line treatment for acute intoxication with
lead, mercury, or arsenic. However, because it is inexpensive and orally bioavailable, it is often
given at fairly low doses following treatment with CaNa2EDTA and/or dimercaprol to ensure that
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the concentration of metal in the blood stays low following the patient’s release from the
hospital.
Mechanism of Action
Penicillamine binds to some heavy metals; the penicillamine-metal complex is then eliminated
from the body.
Pharmacokinetics
Penicillamine is available for oral administration. It should be given on an empty stomach to
avoid interference by metals in food. Penicillamine is well absorbed (40-70%) from the GIT.
Food, antacids, and iron reduce its absorption. Peak concentrations in blood are obtained
between 1 and 3 hours after administration. Penicillamine is primarily degraded by hepatic
biotransformation, and very little drug is excreted unchanged. Metabolites are found in both
urine and feces.
Adverse Effects
Most common adverse effect of penicillamine is hypersensitivity reactions including rash,
pruritus, and drug fever. Penicillamine should be used with extreme caution, if at all, in patients
with a history of penicillin allergy. Other adverse effects include renal toxicity with proteinuria
and haematuria; haematological reactions with leukopenia, aplastic anaemia, pancytopenia and
agranulocytosis. Toxicity to the pulmonary system is uncommon, but severe dyspnea has been
reported from penicillamine-induced bronchoalveolitis. Less serious side effects include nausea,
vomiting, diarrhea, dyspepsia, anorexia, and a transient loss of taste for sweet and salt, which
is relieved by supplementation of the diet with copper.
With long-term use, penicillamine induces several cutaneous lesions, including urticaria, macular
or papular reactions, pemphigoid lesions, lupus erythematosus, dermatomyositis, adverse
effects on collagen; and other less serious reactions, such as dryness and scaling. Cross-
reactivity with penicillin may be responsible for some episodes of urticarial or maculopapular
reactions with generalized edema, pruritus, and fever that occur in as many as one-third of
patients taking penicillamine.
Contraindications to penicillamine therapy include pregnancy, renal insufficiency, or a previous
history of penicillamine-induced agranulocytosis or aplastic anemia.
Succimer
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Succimer (2,3-dimercaptosuccinic acid; DMSA) is an orally effective chelator that is chemically
similar to dimercaprol but contains two carboxylic acids that modify the spectrum of absorption,
distribution, and chelation of the drug. It has an improved toxicity profile over dimercaprol.
Succimer has several desirable features over other chelators. It is orally bioavailable, and
because of its hydrophilic nature, does not mobilize metals to the brain or enter cells. It also
does not significantly chelate essential metals such as zinc, copper, or iron. As a result of these
properties, succimer exhibits a much better toxicity profile relative to other chelators. Succimer
is a chelator of lead, arsenic, cadmium, mercury, and other toxic metals.
Mechanisms of Action
Succimer binds to some heavy metals, leading to the elimination of the metal from the body.
Adverse Effects
Succimer is much less toxic than dimercaprol. Adverse effects include nausea, vomiting,
diarrhea, loss of appetite, rashes and transient elevations in hepatic transaminases.
Deferoxamine mesylate
Deferoxamine is isolated as the iron chelate from Streptomyces pilosus; and it undergoes
chemical modification to obtain the metal-free ligand.
Deferoxamine has some desirable properties such as, a remarkably high affinity for ferric iron, a
very low affinity for calcium, and it does not remove iron from hemoglobin or cytochromes.
Mechanism of Action
Deferoxamine binds with high affinity to iron, thereby enhancing its elimination from the body.
Pharmacokinetics
Deferoxamine is poorly absorbed after oral administration, and may increase iron absorption
when given by this route. Hence, parenteral administration is preferred. In severe iron toxicity
(serum iron levels >500 μg/dL), the intravenous route is preferred. Deferoxamine is
metabolized, but the pathways are unknown. The iron- chelator complex is excreted in the
urine, often turning the urine an orange-red color.
Adverse Effects
Deferoxamine causes a number of allergic reactions, including pruritus, wheals, rash, and
anaphylaxis. Other adverse effects include dysuria, abdominal discomfort, diarrhea, fever, leg
cramps, tachycardia, and cataract formation. Pulmonary complications (e.g., acute respiratory
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distress syndrome; tachypnea, hypoxemia, fever, and eosinophilia are prominent symptoms)
have been reported in some patients undergoing deferoxamine infusions lasting longer than 24
hours; and neurotoxicity and increased susceptibility to certain infections (e.g., with Yersinia
enterocolitica) have been reported after long-term therapy of iron overload conditions (e.g.,
thalassemia major).
Deferoxamine is contraindicated in renal insufficiency and anuria. It should be used during
pregnancy only if clearly indicated.
Deferasirox
Deferasirox is an orally administered chelator of iron, with a high affinity for iron and low
affinity for other metals, e.g., zinc and copper. It is well absorbed on oral administration. It
binds iron in the circulation, and the complex is excreted in bile.
Adverse Effects
Long-term daily use of deferasirox is generally well tolerated, most common adverse effects
include mild to moderate gastrointestinal disturbances and skin rash.
Trientine
Trientine (triethylenetetramine dihydrochloride) is an orally effective acceptable alternative to
penicillamine in Wilson’s disease. Although it may be less potent than penicillamine, it could be
used in patients that may not tolerate the undesirable effects/toxicities of penicillamine.
Trientine may cause iron deficiency; this can be overcome with short courses of iron therapy,
but iron and trientine should not be ingested within 2 hours of each other.
Unithiol
Unithiol (Sodium 2,3-Dimercaptopropane Sulfonate; DMPS), a dimercapto chelating agent, is a
water-soluble analog of dimercaprol. Unithiol is a clinically effective chelator of lead, arsenic,
and especially mercury. It is negatively charged and exhibits distribution properties similar to
those of succimer. It is less toxic than dimercaprol, but mobilizes zinc and copper and thus is
more toxic than succimer.
Unithiol can be administered orally and intravenously. Bioavailability by the oral route is
approximately 50%, with peak blood levels occurring in approximately 3.7 hours. It is rapidly
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excreted, primarily through the kidneys. Over 80% of an intravenous dose is excreted in the
urine, mainly as cyclic DMPS sulfides. Unithiol increases the excretion of mercury, arsenic, and
lead in humans.
Bibliography and Further Reading
Agency for Toxic Substances and Disease Registry (ATSDR) (1999). Toxicological Profile for
Mercury. ATSDR, Atlanta.
Agency for Toxic Substances and Disease Registry (ATSDR) (2007a). Toxicological Profile for
Arsenic. ATSDR, Atlanta.
Agency for Toxic Substances and Disease Registry (ATSDR) (2007b). Toxicological Profile for
Lead. ATSDR, Atlanta.
American Academy of Clinical Toxicology, and the European Association of Poisons Centres and
Clinical Toxicologists (1999). Position statement and practice guidelines on the use of multidose
activated charcoal in the treatment of acute poisoning. Clinical Toxicolology, 37:731–751.
American Academy of Clinical Toxicology, and the European Association of Poisons Centres and
Clinical Toxicologists (2004). Position paper: Gastric lavage. Journal of Toxicology CLINICAL
TOXICOLOGY, 42:933–943.
American Academy of Clinical Toxicology, and the European Association of Poisons Centres and
Clinical Toxicologists (2005). Position paper: Single-dose activated charcoal. Clinical Toxicology,
43:61–87.
American Academy of Pediatrics Committee on Injury, Violence, and Poison Prevention (2003). Poison treatment in the home. Pediatrics, 112:1182–1185. Andersen O, Aaseth J (2002). Molecular mechanisms of in vivo metal chelation: Implications for clinical treatment of metal intoxications. Environmental Health Perspectives, 110 (suppl): 887–890. Clarkson TW, Magos L (2006). The toxicology of mercury and its chemical compounds. Critical Reviews in Toxicology, 36:609-662. Kao JW, Nanagas KA (2004). Carbon monoxide poisoning. Emergency Medicine Clinics of North
America, 22:985-1018.
Klaassen CD (2007). Casarett and Doull’s Toxicology, 7th ed. McGraw-Hill.
Kosnett MJ, Wedeen RP, Rothenberg SJ, Hipkins KL, Materna BL, Schwartz BS, Hu H, Woolf A
(2007). Recommendations for medical management of adult lead exposure. Environmental
Health Perspectives, 115:463-471.
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Kosnett MJ (2010). Chelation for heavy metals (arsenic, lead, and mercury): Protective or