Muscle adverse drug effects

Cautious use of pre-clinical data, involving the insertion of safety (uncertainty) factors, provides the basis for selecting doses for the early clinical trials, but the predictive value of animal data is far from perfect, so that in most cases some adverse side effects will be observed in the human trials. Most often those effects are subjective in nature -headache, nausea, muscle pain - and could not have been suspected from animal studies. More serious side effects sometimes occur, and may put a halt to further development of the drug. 

Rhabdomyolysis is a problem with several lipid-lowering drugs (SEDA-13, 1325 SEDA-13, 1328 SEDA-13, 1330 SEDA-19, 409), especially when they are used in combination (37). In individuals with pre-existing renal insufficiency this can lead to an earlier need for chronic dialysis (38). All statins can cause myopathy and rhabdomyolysis, but not all statins are alike. For example, the evidence to date, based on almost 2 decades of experience, points to an extremely low risk of myopathy and rhabdomyolysis with lovastatin, and lovastatin 20 mg tablets are being considered for non-prescription availability in several countries (39). Furthermore, muscle adverse effects do not necessarily occur after a change from one statin to another (40). Interactions between various hypolipidemic drugs and other drugs also sometimes cause rhabdomyolysis (SEDA-18, 426). For instance, itraconazole markedly increases plasma concentrations of lovastatin, and in one subject plasma creatine kinase was increased 10-fold within 24 hours of administration of this combination (41). 

In a placebo-controlled study of 1142 hypercholestero-lemic patients treated with pravastatin for 8-16 weeks, the numbers of adverse drug experiences were similar in the treated and untreated individuals (1). Rash was the only adverse clinical event that was different (4.0 versus 1.1%). However, in the same patients withdrawal of therapy during follow-up was thought to be necessary in 3.2% of those given pravastatin alone. Myopathy was observed in one instance only, and increases in creatine kinase activity in those taking pravastatin did not differ significantly from controls. There were marked persistent increases in transaminases in 1.1%, with no cases of symptomatic hepatitis. Pravastatin is believed to have a particularly low potential for nervous system-related adverse effects, as it has not been shown to enter the cerebrospinal fluid, and clinical experience suggests that muscle toxicity occurs less often with pravastatin than with lovastatin (2). 

Prazosin, oxazosin and terazosin (see p. 73) produce a competitive block of oci adrenoceptors. They decrease peripheral vascular resistance and lower arterial blood pressure by causing the relaxation of both arterial and venous smooth muscle. These drugs cause only minimal changes in cardiac output, renal blood flow, and glomerular filtration rate. Therefore, long-term tachycardia and increased renin release do not occur. Postural hypotension may occur in some individuals. Prazosin is used to treat mild to moderate hypertension and is prescribed in combination with propranolol or a diuretic for additive effects. Reflex tachycardia and first dose syncope are almost universal adverse effects. Concomitant use of a p-blocker may be necessary to blunt the short-term effect of reflex tachycardia. 

All the statins have been variously implicated in muscle-related adverse drug reactions such as myalgia, myopathy and rhabdomyolysis, which are thought to occur as a direct effect of HMG GoA-reductase inhibition in a dose-dependent marmer [30]. There have been fatalities. If patients have increased exposure to a drug due to a reduction in first-pass or subsequent metabolism by hepatocytes, these adverse effects are more likely to occur. 

Adverse CNS effects occur when the procaine portion of the procaine benzylpenicillin (procaine penicillin) formulation is given intravascularly. The signs of toxicity include hyperexcitability, muscle tremors, ataxia, apnea and cardiac arrest. There is no specific treatment for procaine toxicity one can only attempt to prevent the horse from injuring itself and others imtil the effects of the procaine wear off. The CNS reaction can be prevented by pretreatment with diazepam. The solubility of the procaine fraction of procaine benzylpenicillin (procaine penicillin) formulations increases with increasing ambient temperature, so these products should be stored in a cool place to reduce the risk of reactions. Procaine is a common cause of positive drug tests in racehorses and other performance horses. Procaine benzylpenicillin (procaine penicillin) should be avoided in these animals. 

Cardiac function can be impaired by the action of drugs on specific receptors. To deal with every adverse reaction that is mediated via the effects of drugs acting on specific cardiac receptors is beyond the scope of this chapter. Among the most dominant membrane-bound receptors in the cardiac muscle that can contribute to adverse drug reactions are the p-adrenergic and cholinergic (muscarinic) receptors. 

Neuroleptic-like malignant syndrome is a serious but very rare adverse effect of some drugs, of e.g., neuroleptics, some anaesthetics and apparently tolca-pone. Symptoms include hyperthermia, muscle deterioration, even dissolution. 

MDMA overdose as well as the concomitant consumption of selective serotonin reuptake inhibitors (SSRI) with other dmgs that exert serotoninergic effects (such as inhibitors of monoamine oxidase) can rapidly lead to the serotonin syndrome. Its symptoms, which are reversible upon cessation, of the drug include confusion, muscle rigidity in the lower limbs, and hyperthermia suggesting an acute reaction to serotonin overflow in the CNS. Blocking the function of SERT outside the brain causes side effects (e.g., nausea), which may be due to elevated 5HT however , impairment of transporter function is not equivalent to direct activation of 5HT recqrtors in causing adverse effects such as fibrosis and pulmonary hypertension. 

Theophylline is a non-specific phosphodiesterase inhibitor that increases intracellular cAMP within airway smooth muscle resulting in bronchodilation. It has a modest bronchodila-tor effect in patients with COPD, and its use is limited due to a narrow therapeutic index, multiple drug interactions, and adverse effects. Theophylline should be reserved for patients who cannot use inhaled medications or who remain symptomatic despite appropriate use of inhaled bronchodilators. 

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