Dose related toxicity

Not recommended due to excessive dose-related toxicity Maintenance dose ... 

Many of these reactions are related to the quantity of excipient found in a dosage form. Benzyl alcohol benzalkonium chloride, propylene glycol, lactose, and polysorbates are all associated with dose-related toxic reactions [52-54], Large-volume parenterals containing 1.5% benzyl alcohol as a preservative have caused metabolic acidosis, cardiovascular collapse, and death in low birth weight premature neonates and infants. The cumulative dose of benzyl alcohol ranged from 99 to 234 mg/kg per day in these patients [55,56], Dose-related adverse effects to excipients are of particular concern in the preterm, low birth weight infant because... 

The duration of treatment for skin diseases is often longer than it is for malaria, and therefore, dose-related toxicities are important. The most serious toxicities are ophthalmological. Reversible alterations include ciliary body dysfunction and corneal changes with edema and deposits. Irreversible retinopathy also occurs however, it is less common with quinacrine than with the other two drugs. Toxicity may be asymptomatic, but the earliest symptoms are night blindness, scotoma, or tunnel vision. 

In previously treated epileptic patients, the administration of a large loading dose of phenytoin may cause some dose-related toxicity such as ataxia. This is usually a relatively minor problem during the acute status episode and is easily alleviated by later adjustment of plasma levels. 

To decrease dose-related toxicity by using reduced doses of one or more components of the drug regimen. The use of flucytosine in combination with amphotericin for the treatment of cryptococcal meningitis in non-HIV-infected patients allows for a reduction in amphotericin dosage with decreased amphotericin -induced nephrotoxicity. 

Adverse effect Lactic acidosis due to biguanides Dose-relation toxic effect Time-course time-independent Susceptibility factors genetic (slow phenformin metabolizers) age disease (impaired liver, kidney, or cardiac function, alcoholism)... 

More in-depth behavioral tests are required if dose-related toxicant effects are noted in screening tests. These tests may also be required as part of more selective toxicological screening, such as for developmental neurotoxicity. Focused tests of neuromotor function and activity, sensory functions, memory, attention, and motivation help to identify sites of toxicant-mediated lesioning, aid in the classification of neurotoxicants, and may suggest mechanisms of action. Some of these tests, like the schedule-controlled operant behavior tests for cognitive function, require animal training and extensive operator interaction with the animals. 

Dose-related toxicities of azathioprine or 6-mercaptopurine include nausea, vomiting, bone marrow depression (leading to leukopenia, macrocytosis, anemia, or thrombocytopenia), and hepatic toxicity. Routine laboratory monitoring with complete blood count and liver function tests is required. Leukopenia or elevations in liver chemistries usually respond to medication dose reduction. Severe leukopenia may predispose to opportunistic infections leukopenia may respond to therapy with granulocyte stimulating factor. Hypersensitivity reactions to azathioprine or 6-mercaptopurine occur in 5% of patients. These include fever, rash, pancreatitis, diarrhea, and hepatitis. 

For a drug that has never been used in humans previously, the initial step that a pharmaceutical company must take is to perform preclinical toxicity studies involving appropriate in vitro systems or whole animals. The FDA usually requires that dose-related toxicity be determined in at least two mammalian species (routinely rodents). The toxicity information obtained from these studies can then be used to make risk/benefit assessments and help determine the acceptability of the drug for testing in humans, and to estimate a safe starting dose. 

It is important to monitor peak and trough plasma levels (see p. 20) of gentamicin, tobramycin, netilmicin, and amikacin to avoid concentrations that cause dose-related toxicities (Figure 31.7). [Note Peak levels are defined as those obtained 1/2 to 1 hour after infusion. Trough levels are obtained immediately before the next dose.] Patient factors, such as old age, previous exposure to aminoglycosides, gender, and liver disease, tend to predispose patients to adverse reactions. The elderly are particularly susceptible to nephrotoxicity and ototoxicity. 

Adverse effects Fever with chills occurs during the first few days of treatment. Dose-related toxicity includes leukopenia and possibly thrombocytopenia. Fatigue, malaise, anorexia, weight loss, alopecia, and transient elevation of liver enzymes have also been reported. Transient and reversible nephrotoxicity with proteinuria have been seen at high doses. 

Potentiation The situation in which a chemical becomes more toxic when applied together with another chemical that by itself is nontoxic. Potentiation is a special case of synergism in case of synergism, both chemicals in the mixture show a dose-related toxicity when applied individually. 

Dose-relation toxic effect Time-course intermediate or delayed Susceptibility factors high doses or intravenous administration psychiatric disorders dehydration postpartum... 

DoTS classification (BMJ 2003 327 1222-5) Dose-relation Toxic Time-course Time independent Susceptibility factors Not known... 

The treatment of thalassemia, as in other metal overload disorder, is chelation therapy. The chelating agent most widely nsed is deferoxamine administered subcutaneously. The search for an orally administered iron chelator has intensified in recent years, leading to cUnical trials of many potential new iron chelators snch as deferiprone(Ll). However, many issues regarding the nse of these drugs, such as dose-related toxicity and recommended age of initiation, remain unresolved. " ... 

Chloramphenicol causes two types of hematopoietic abnormality. The first is a dose-related toxic effect causing a bone marrow depression associated with inhibition of mitochondrial protein synthesis. Usually, discontinuing the antibiotic reverses this toxicity. 

Dose-Related Toxicity Often Occurs When Impaired Renal Function is Unrecognized... 

Despite these technical advances, adverse reactions still occur frequently with digoxin, phenytoin, and many other drugs for which drug concentration measurements are routinely available. The persistence in contemporary practice of dose-related toxicity with these drugs most likely reflects inadequate understanding of basic pharmacokinetic principles. This is illustrated by the following case history (5) ... 

Adverse effects are in general uncommon, apart from allergy (above). It is salutary to reflect that the first clinically useful true antibiotic (1942) is still in use and is also amongst the least toxic. Only in patients with bacterial endocarditis, where the requirement for high doses can co-exist with reduced clearance due to immune complex glomerulonephritis, does a risk of dose related toxicity (convulsions) arise. 

Alcohol has a dose-related toxic effect on erythropoiesis. In this context, vacuolization of the nuclei and plasma of the proerythroblasts (so-called McCurdy cells) can mostly be observed. The mean corpuscular volume of erythrocytes (MCV) increases with rising alcohol consumption in 50—60% of patients, particularly when consuming high-proof alcoholic drinks. Megaloblastic anaemia... 

Dose-relation toxic effect Time-course time-independent... 

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