Lec 8 Decongestants & NSAIDs.pdf

Over the counter drugs Decongestants & NSAIDs  Dr. Mohammed Fareed  Decongestants Decongestants reduce nasal congestion by stimulating the alpha-adrenergic receptor sites on vascular smooth muscles which causes the dilated arterioles to constrict and thereby reduce the blood flow to engorged nasal...

Over the counter drugs Decongestants & NSAIDs  Dr. Mohammed Fareed  Decongestants Decongestants reduce nasal congestion by stimulating the alpha-adrenergic receptor sites on vascular smooth muscles which causes the dilated arterioles to constrict and thereby reduce the blood flow to engorged nasal vascular beds. Pseudoephedrine is the d-isomer of ephedrine and has only 25% of the adrenergic receptor activity of ephedrine. Both ephedrine and pseudoephedrine are stimulants of alpha as well as beta adrenergic receptors, Phenylpropanolamine is devoid of beta-adrenergic receptor activity. In fact in 2000, discontinuation of phenylpropanolamine (PPA) from all pharmaceutical products and has issued a public health warning concerning the risk of haemorrhagic stroke associated with phenylpropanolamine use, particularly among women. The dose of PPA used for appetite suppression is greater than the dose used in cough and cold preparations. compounds such as : naphazoline, oxymetazoline, tetrahydrozoline, and xylometazoline, which are powerful alpha2- adrenergic receptor stimulants.  Clinical Toxic Features 1. Toxicity usually manifests as CNS stimulation, hypertension, and tachycardia (bradycardia with phenylpropanolamine). Headache is common. Serious manifestations include seizures, dysrhythmias, cerebral haemorrhage, and psychosis. 1 2. Imidazoline decongestants (such as xylometazoline or oxymetazoline) cause CNS depression, hypotension, bradycardia, and respiratory depression. Imidazolines may also be used in combination with other sympathomimetics (e.g. phenylephrine or ephedrine), in which case, hypertension may be seen. Miosis may be present. Mydriasis has also occurred. 4. Chronic overuse may result in reactive vasodilation of the nasal mucosa. Acute psychosis and hypertension have been reported with chronic abuse. Signs and symptoms of phenylpropanolamine overdose: phenylpropanolamine has a propensity to cause significant hypertension, and may result in reflex bradycardia, extensive myocardial ischaemia, cerebral haemorrhage, or renal toxicity. Tachycardia can also occur. Psychiatric disturbances, particularly in children, have been reported after ingestion of phenylpropanolamine.  Treatment Because of hypertension, drowsiness and coma, emesis is not indicated even when nasal decongestants have been ingested. Activated charcoal and gastric lavage are also not routinely recommended, though they may be of value in phenylpropanolamine ingestions. Monitor serum creatine phosphokinase and renal function in severely symptomatic patients, and those with prolonged seizures or coma. 1. Seizures, agitation, and psychosis should be treated with IV diazepam. Refractory cases should be managed with barbiturates or neuromuscular blocking agents. Monitor for respiratory depression, hypotension, arrhythmias 2. Severe symptomatic palpitations, tremor, and associated anxiety may respond to propranolol, particularly in patients with combination overdose of phenylpropanolamine and other sympathomimetic agents. 2 However, propranolol may worsen hypertension in patients with singleingredient phenylpropanolamine overdose. 3. Persistent or highly elevated hypertension should be treated with nitroprusside or nifedipine. Nitroglycerin and phentolamine are possible alternatives. 4. Hypotension can be managed with isotonic fluids,Trendelenberg position, and dopamine infusions. 5. Dysrhythmias usually respond to standard doses of lignocaine or bretylium. Propranolol can also be used. Dialysis may be beneficial in phenylpropanolamine overdose.  NON-STEROIDAL ANTI-INFLAMMATORY DRUGS  ACETAMINOPHEN (N-ACETYL-PARAAMINOPHENOL, PARACETAMOL) INCIDENCE Poisoning cases with APAP exceed those of all other agents in this category (fivetimes greater incidence than with aspirin). It is the most common drug involved in overdose, registering approximately 60% of all analgesic exposures, and the second most common cause of liver failure in the U.S.  METABOLISM AND MECHANISM OF TOXICITY Hepatic glucuronide and sulfate conjugation (Reactions 1 and 2,) produce the inactive corresponding conjugates, which account for 95% of metabolism and elimination in urine. In addition, at therapeutic acute doses, the remaining 5% of the product is detoxified and eliminated in the minor cytochrome P450 oxidase pathway (Reaction 3). The result is the production of the reactive intermediate, Nacetyl-p-benzoquinoneimine (NAPQI) metabolite. Further conjugation by cellular glutathione results in the production of mercapturic acid and cysteine conjugates (Reaction 4). 3 With chronic use or with large doses, the glucuronide and sulfate conjugation metabolic routes (1 and 2) are saturated, and more importantly, glutathione stores are depleted (4). This leaves the cytochrome P450 oxidase pathway (Reaction 3) to accumulate toxic NAPQI metabolite. Binding of NAPQI to hepatocyte membranes and sulfhydril proteins accounts for the hepatotoxic sequelae. (Binding of NAPQI to hepatocyte membranes and sulfhydril proteins accounts for the hepatotoxic sequelae). (Binding of NAPQI to hepatocyte membranes and sulfhydril proteins accounts for the hepatotoxic sequelae). 4  SIGNS AND SYMPTOMS OF ACUTE TOXICITY (Note :Only arrow column wanted) :  CLINICAL MANAGEMENT OF ACUTE OVERDOSE Activated charcoal is beneficial if administered to an individual who presents within 1 to 2 h postingestion. At 8 h postingestion, activated charcoal, emetics, or gastric lavage are not necessary. N-acetylcysteine (NAC) is the antidote for acetaminophen poisoning. In its conversion to cysteine, NAC restores glutathione reserves by providing sulfhydril donors for the eventual detoxification of NAPQI. In addition, NAC increases sulfate conjugation, thereby preventing excess NAPQI production. NAC also acts as an antioxidant, enhancing oxygen utilization; this effect may be of benefit in patients with fulminant hepatic failure. Currently, the protocol is 140 mg/kg oral loading dose followed by 17 doses of 70 mg/kg every 4 h, for a total of 1330 mg/kg over 72 h. 5 The dose is continuous over the 72 h until the acetaminophen assay reveals a nontoxic level.  ACETYL SALICYLIC ACID  CLINICAL MANAGEMENT OF TOXICITY Activated charcoal and cathartics are recommended to effectively bind salicylates and to prevent intestinal obstruction due to concretions, respectively. Sodium bicarbonate administration enhances ASA elimination by alkalinizing the urine while simultaneously reversing metabolic acidosis. Other supportive measures include correcting the dehydration, maintaining kidney function (forcing fluids),rectifying electrolyte imbalance (especially potassium for hypokalemia that may result from bicarbonate infusion), and instituting supportive measures for hyperthermia, seizure control, and pulmonary edema. … END 6