1. Critical illnesses are often associated with circulatory, respiratory, hepatic and/or renal dys­function that may alter the pharmacokinetics and/or pharmacodynamics of drugs.
2. Decisions about routes of administration and doses of drugs used during medical emergen­cies must consider the physiological status of the patient, the pharmacokinetic and pharmacodynamic characteristics of the particular drug, and how the two interact.
3. Adverse drug reactions and interactions are more likely in critically ill patients due to the effect of the disease on drug kinetics, the decreased toxic-therapeutic ratio due to severe under­lying illness, and the large number of medications that such patients receive. Adverse reactions to drugs should be considered when unexplained deterioration or failure to respond to therapy are encountered.
4. Preservation of function of vital organs is a fundamental concept of critical care therapeutics. Preservation of cardiovascular functions requires attention to fluid and electrolyte status, prompt correction of arrhythmias and shock, and measures to preserve the myocardium against ischaemic injury.
5. Preservation of respiratory function requires protection of the airway, cautious use of fluids and oxygen, and prompt recognition and management of infection.
6. Preservation of cerebral function requires maintaining cerebral blood flow with adequate oxygen and glucose sufficient to meet the metabolic demands of the brain. This entails main­taining adequate systemic circulation, control of intracranial hypertension, and prompt control of seizures and hyperthermia.



7. Critically ill patients are particularly susceptible to infections, gastric stress erosions and ulcers, adult respiratory distress syndrome, pulmonary emboli, and haemostatic disorders. The risks of such complications may be reduced by meticulous care of catheters, pulmonary toilet, cautious use of fluids, prompt treatment of infection when it occurs, and selective prophylactic drug therapies.
8. Shock can be produced by many different processes including myocardial infarction, hypovolaemia, sepsis, drug overdose, burns, hypothermia, spinal cord transsection and anaphylaxis. Optimum treatment of shock depends on knowledge of the pathophysiology of the shock state and the pharmacology of the drugs.
9. Features of acute drug intoxication include coma, agitated delirium, seizures, hypo- and hyperthermia, shock, arrhythmias, aspiration and pulmonary oedema. Successful therapy of acute drug intoxication depends on the integration and application of knowledge of the pharmacology of both the intoxicating drug and the drugs used in therapy, as well as the principles of supportive critical care.

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Never­theless, poisoned patients are often unnecessar­ily subjected to these potentially harmful meas­ures, and the literature is full of anecdotal accounts of miraculous recovery attributed to such treatment (Winchester et al. 1977). Prop­erly controlled clinical trials are difficult to carry out, and very few have been published. With the possible exception of forced alkaline di­uresis for poisoning with salicylate and long act­ing barbiturates such as phenobarbitone, none of these methods for enhancement of drug re­moval has ever been shown to reduce morbidity or mortality in poisoned patients (Todd 1984).

Indeed, some studies suggest the opposite result. This is not to say that such measures are never necessary, or indeed sometimes life saving, but a more critical appraisal of their role is required.

In some cases, the drug presumed to have been taken has never been chemically identi­fied, while, in others, haemodialysis has been carried out in patients with less than therapeutic plasma concentrations of the drug in question. Other studies have shown removal of only a very small and insignificant fraction of the ingested dose, sometimes amounting to the equivalent of less than 1 tablet or capsule (see, for example, Comstock et al. 1983; Heath et al. 1983). A mis­leading impression of efficacy may be gained by the use of nonspecific analytical methods for drug assay (Prescott 1974).

Other Binding Agents

Other agents have been used in attempts to bind unabsorbed drug in the gastrointestinal tract. Paraquat, a lethal weedkiller for which there is no known antidote, binds very strongly to Fuller’s earth and bentonite, and these ad­sorbents are used routinely in the treatment of paraquat poisoning.

Although bentonite may re­duce the normally slow absorption of paraquat in pure aqueous solution in rats (Smith et al. 1974), ail the evidence points to extremely rapid absorption of paraquat from commercial weed­killers in man. Our experience of paraquat poi poi­soning has been disastrous, with no apparent benefit from the early use of bentonite.

Cholestyramine binds acidic drugs and can reduce the absorption of paracetamol (aceta­minophen) taken at the same time. Like acti­vated charcoal, however, it is virtually useless when the delay between ingestion and admin­istration exceeds 1 hour (Dordoni et al. 1973).

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• Anxiety,
• tension,
• symptoms of acute alcohol withdrawal,
• partial seizures,
• fatigue,
• agitation,
• irritable bowel syndrome,
• and panic attacks.

General Information of the drug

• Clorazepate dipotassium is a benzodiazepine, which directly affect the brain. This drug is a central-nervous-system depressant, and can relax you and make you more tranquil or sleepier, or they can slow nervous system transmissions in such a way as to act as an anticonvulsant.
• Many doctors prefer benzodiazepines to other drugs that can be used to similar effect because they tend to be safer, have fewer side effects.
• Clorazepate may increase blood levels of digoxin and the chances of digoxin toxicity.
• Don’t mix it with alcohol, other sedatives, narcotics, barbiturates, monoamine oxidase inhibitor and other antidepressants, and antihistamines.
• Taking clorazepate with other similar effects drugs may result in excessive depression, tiredness, sleepiness, breathing difficulties, or related symptoms.
• Combining clorazepate with phenytoin may increase phenytoin blood concentrations and the chances of phenytoin toxicity.
• Smoking may reduce clorazepate’s effectiveness by increasing the rate at which it is broken down by the body.
• Clorazepate’s effects may be prolonged when it is mixed with cimetidine, contraceptive drugs, disulfiram, fluoxetine, isoniazid, ketoconazole, metoprolol, probenecid, propoxyphene, propranolol, rifampin, or valproic acid.
• If you have to take Tranxene for a prolong period of time, your doctor will need to monitor your blood counts and liver function to be sure of your health state.
• Theophylline may reduce clorazepate’s sedative effects.
• If you take antacids, separate them from your clorazepate dose by at least 1 hour to prevent them from interfering with the absorption of clorazepate into the bloodstream.
• The effect of levodopa + carbidopa may be decreased if it is taken together with clorazepate.

Cautions ( This drug may be addictive ! )

• Clorazepate may be addictive. It should be used with caution in people with a history of drug dependence.
• Do not take clorazepate if you are allergic or sensitive to any of its ingredients or to another benzodiazepine drug, including clonazepam.
• Clorazepate can aggravate narrow-angle glaucoma, but you may take it if you have open-angle glaucoma and are receiving therapy for it.
• Clorazepate should not be taken by psychotic patients because it is not effective for them and can trigger unusual excitement, stimulation, and rage.
• Clorazepate is not intended to be used for more than 3-4 months at a time. Your doctor should reassess your condition before continuing your prescription beyond that time.
• Your dosage should always be reduced gradually to prevent drug withdrawal symptoms, which may develop if you stop taking it after as few as 4 weeks of regular use but is more likely after longer use.
• Drug withdrawal symptoms may start with anxiety and progress to tingling in the hands or feet, sensitivity to bright light, sleep disturbances, cramps, tremors, muscle tension or twitching, poor concentration, flu-like symptoms, fatigue, appetite loss, sweating. and changes in mental state.
• Other conditions in which clorazepate should be avoided are: severe depression, severe lung disease, sleep apnea (intermittent cessation of breathing during sleep), liver disease, drunkenness, and kidney disease. In each of these conditions, the depressive effects of clorazepate may be enhanced or could be detrimental to your overall condition.

Note

• This drug is for Adult Only ! It is not recommended for child.
• Clorazepate is best taken on an empty stomach, but if it upsets your stomach then it may be taken with food. Consult your doctor on this.
• Clorazepate can cause tiredness, drowsiness, inability to concentrate, or similar symptoms. Be careful if you are driving, operating machinery, or performing other activities that require concentration.
• People taking clorazepate for more than 3 or 4 months at a time may develop drug withdrawal reactions if the medication is stopped suddenly (see “Cautions” section above). Do not stop taking clorazepate or increase or decrease your dosage without first consulting your doctor.
• Do not take a double dose. If you forget a dose of clorazepate, take it as soon as you remember. If it is almost time for your next dose, skip the dose you forgot and continue with your regular schedule.

Pregnancy/Breast-feeding period :

• Clorazepate may cause birth defects if taken during the first 3 months of pregnancy.
• Avoid this drug if you are or might be pregnant, as Clorazepate may pass into breast milk. Nursing mothers who must take clorazepate should switch to use infant formula.

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1. Specific antidotal therapy is available for very few poisons. The mainstay of treatment of severe poisoning is intensive supportive therapy and good nursing care.

2. The great majority of poisoned patients recover with intensive supportive therapy alone, and enthusiastic claims for the success of other treatment often cannot be justified.

3. With some important exceptions, the management of poisoning is not altered by knowledge of plasma drug concentrations. There are many pitfalls in the interpretation of drug concen­trations in poisoned patients, especially when nonspecific analytical methods are used.

4. Gastric lavage and induction of nemesis soon after ingestion may be effective in removing unabsorbed drug, but are unreliable. Adsorbents such as activated charcoal are usually ineffec­tive in limiting absorption when given more than 1 hour after ingestion.

5. Poisoned patients are often subjected to unnecessary and potentially harmful haemodialysis, haemoperfusion and diuresis. The efficacy of these measures has been established for relatively few substances in terms of reduction in morbidity and mortality or removal of toxicologically significant amounts of active drug or poison.

6. The efficacy of methods for extracorporeal removal can be predicted from pharmacokinetic principles. It depends primarily on the volume of drug distribution, plasma protein binding, rate of transfer from peripheral to central compartments, and dialysis clearance relative to the endogenous total body clearance.

7. Haemoperfusion with activated charcoal or exchange resins is more effective than haemo­dialysis in removing drugs from the blood. Peritoneal dialysis is less effective than haemodi­alysis. Drugs with large volumes of distribution cannot be removed rapidly by any of these techniques, and indications for their use are limited.

8. Forced diuresis can only increase the renal clearance of reabsorbed compounds, and clearance may be dramatically increased by appropriate manipulation of urine pH. However, the renal excretion of most drugs is insignificant in relation to the metabolic clearance. Forced alkaline diuresis is largely restricted to salicylate and phenobarbitone poisoning.

9. Repeated oral activated charcoal effectively increases the body clearance of a number of drugs. It probably acts by irreversibly binding drug diffusing from the circulation to the gut lumen and may also interrupt the enterohepatic circulation.

10. The toxicity of a few drugs and poisons can be reversed by specific antidotal therapy. Mechanisms include pharmacological antagonism, inhibition of conversion to toxic metabolites, inactivation of highly reactive alkylating intermediates, chelation and binding with drug-specific antibodies.

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Although unabsorbed drug in the stomach may be removed by gastric aspiration and lav­age its usefulness in practice has been seriously questioned (Proudfoot 1984). Most drugs and poisons seem to be absorbed rapidly and this technique is unlikely to be productive more than 4 hours after ingestion, unless gastric emptying has been delayed by opioid analgesics, anti­cholinergic agents, central nervous system de­pressants, and possibly salicylates. In such circumstances gastric lavage may be worthwhile up to 12 hours after ingestion.

It is said to be contraindicated after ingestion of corrosives and hydrocarbons such as paraffin because of the risks of perforation and lipoid pneumonia, respectively.

The patient must be correctly positioned head down in the left lateral position and a cuffed endotracheal tube inserted beforehand if the protective pharyngeal reflexes are depressed. It is essential to use a large bore tube (e.g. Jacques 30 gauge) and in adults lavage should be carried out with 300ml portions of warm tap water un­til the return is clear. Complications include pulmonary aspiration of stomach contents, and, rarely, oesophageal rupture.

Although gastric lavage is often unrewarding, large amounts of drug are occasionally re­covered. A common cause of failure is the use of too small a tube – an ordinary nasogastric tube is virtually useless. Large amounts of re­sidual drug have been found in the stomach postmortem after attempts at lavage with a nasogastric tube (Jenis et al. 1969), and in i case i large drug mass containing 25g of meproba­mate was removed by gastrotomy 40 hours after ingestion despite gastric lavage (Schwartz 1977).

Emetics

The comparative efficacy of induced emesis and gastric lavage is still debated. Neither guar­antees emptying of the stomach. Lavage is not always practicable in children because of the physical difficulty in passing a tube large enough to allow the passage of tablets, and emesis is probably preferable in young children. In 1 study in children poisoned with salicylates, emesis was claimed to be more effective than lavage (Boxer et al. 1969), but in another, only 10 to 15% of the amount of salicylate taken was recovered, even when emesis occurred within 1 hour of ingestion (Yaffe et al. 1970).

The major disadvantages are failure of eme­sis, particularly if central nervous system de­pressants have been taken, and toxicity, some­times fatal, from the retained emetic. Syrup of ipecac given with water is probably the best emetic, and is often effective within 15 to 30 minutes (Neuvonen et al. 1983).

Other agents which have been used include sodium chloride, copper sulphate, zinc sulphate, tartar emetic (antimony potassium tartrate), apomorphine and mustard. However, the over-enthusiastic use of sodium chloride and heavy metals can be ex­tremely dangerous and fatal poisoning with salt and copper sulphate has been reported (Gresham & Mashru 1982; Stein et al. 1976).

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