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By C. Vak. University of Saint Mary.

Urinary retention is a well known adverse effect of drugs that have antagonist effects on muscarinic receptors generic 500 mg ciplox otc. In addition to the prototypic drug atropine order ciplox 500mg otc, M blockers include drugs used in Parkinson disease, such as benztropine. The symptoms of cholinergic excess seen in this child are indicative of exposure to insecticides such as the organophosphate parathion, which cause irreversible inhibition of acetylcholinesterase. Muscarinic receptors present in bronchiolar smooth muscle are of the M 3 subtype coupled via Gq proteins to phospholipase C. Tachyphylaxis, a rapid loss of pharmacologic activity, frequently occurs with indirect-acting sympathomimetics such as amphetamine, ephedrine, and pseudoephedrine. The signs and symptoms experienced by this boy are highly suggestive of the ingestion of a compound with strong muscarinic receptor blocking actions. The leaves and seeds of jimsonweed (Datura stramonium) contain anticholinergic compounds, including atropine, hyoscyamine, and scopolamine-approximately 50 seeds may cause severe toxicity. Although used primarily via inhalation for asthma, systemic effects of albuterol include vasodilation due to its ~2 receptor activation. Methoxamine and phenylephrine are (X- receptor activators causing vasoconstriction, which would result in reflex bradycardia. Ganglion blockers (mecamylamine) prevent autonomic reflexes, and a reflex increase in heart rate could not occur in the presence of a beta blocker (propranolol). A decrease in mean blood pressure, an increase in pulse pressure, plus a marked increase in heart rate are characteristic of a drug such as isoproterenol. A similar mechanism involving Gi protein inhibition of adenylyl cyclaseoccurs with activation of M2 receptors (see answer 6). Of the drugs listed, only isoproterenol causes a decrease in mean blood pres- sure, because it activates beta receptors and has no effect on alpha receptors. Prazosin is an alpha blocker, so one can antici- pate that this drug would antagonize any increases in blood pressure that result from acti- vation of (Xl receptors in the vasculature. Epinephrine (high dose), norepinephrine, and tyramine all exert pressor effects via activation of (Xl receptors. However, only epinephrine is active on ~2 receptors, and this action would be revealed by vasodilation and a reversal of its pressor effects following treatment with an alpha blocker-"epinephrine reversaL" Thus, drug #4 can be identified as epinephrine. Mydriasis and fixed far vision can be due to either muscarinic receptor antagonists or ganglionic blockade. The cholinesterase inhibitor (neostigmine) and alpha blocker (phentolaminelcause miosis. Ocular effects of the beta blocker (timolol) are restricted to decreased formation of aqueous humor by the ciliary epithelium. Mydriasis is associated with blockade of M receptors, and both micturition and sweating result from activation of such receptors. However, reflex bradycardia is not possible following pretreatment with an M blocker. This question is to remind you that indirect-acting sympathomimetics require innervation of the effector organ to exert effects. However, transplanted hearts retain receptors, including those (~l) responsive to direct-acting sympathomimetics. If symptoms improve with a single dose of edrophonium, then an increase in the dose of neostigmine or pyridostigmine is indicated. The effectiveness of labetalol in the management of hypertension and in severe hypertensive states appears to be due to a combination of antagonistic actions at both alpha and beta adrenoceptors. Labetalol is not a ~l selective blocking agent (unlike atenolol and metoprolol), and (unlike pindolol and acebutolol) it lacks intrinsic sympa- thomimetic activity. Labetalol is available for both peroral and parenteral use; unfortu- nately, it blocks ~2 receptors in bronchiolar smooth muscle. Only two of the listed drugs directly activate cardiac receptors: epinephrine and norepinephrine. This could occur only if agonist 3 was capable of ~l receptor activation in the heart. Direct cardiac stimulation could occur with norepinephrine (agonist 3) but not with methoxamine (agonist 2), which is a selective alpha adrenoceptor agonist. Explanations to Figures 11-4-2 through 11-4-11: Drug Identification from Effects on Heart Rate and Blood Pressure. Figure 11-4-2: The effects of Drug R are changed by treatment with either an alpha or beta- blocker, so Drug R must have activity at both receptors (choices C, D, and E are ruled out). A pressor dose of epinephrine would be "reversed" by an alpha- blocker, not just decreased!

Older studies in persons with mild hyperbilirubinemia (meeting the criteria for Gilbert syndrome ciplox 500mg discount, but not genetically determined) demonstrated a decreased clearance rate for drugs that are glucuronidated buy cheap ciplox 500mg on line. A more recent study in genotyped patients also found no difference in the glucuronide/ acetaminophen urinary ratio (21). A modest decrease (32%) in lamotrigine oral clearance was observed in persons with Gilbert’s syndrome (23). In general, these studies were conducted in a small number of Gilbert syndrome subjects. In a small study of etoposide and irinotecan, Ohtsu reported that all three patients receiving the combination had grade 3 or 4 tox- icities (one neutropenia, one hepatotoxicity, and one hyperbilirubinemia) (36). This is not unexpected because <25% of the dose is excreted as a direct quaternary ammonium glucuronide in urine. The formation of quaternary ammonium glucuronides appears to be highly species specific, with the highest activity in humans and monkeys. Lamotrigine, a novel triazine anticonvulsant, is extensively glucuronidated at the 2-position of the triazine ring in humans (>80% of the dose is excreted in human urine) (41). It is not significantly glu- curonidated in rats or dogs, but 60% of the dose is excreted in guinea pig urine as the 2-N-glucuronide (42). In contrast, valproic acid inhibits lamotrigine glucuronidation resulting in a two- to threefold increase in half-life (44). Lamotrigine had a small, but significant effect (25% increase) on the apparent oral clearance of valproic acid (44). Regioselectivity in the glucur- onidation of quercetin was also altered between variants. Catalytic efficiencies for substrates such as trans-androsterone, imipramine, cyproheptadine, and tigoge- nin also changed (49). Consequently, induction interactions are likely to occur and have been demonstrated in humans as demonstrated by lamotrigine interactions with inducing anticonvulsants. Serotonin appears to be a highly selective endogenous substrate for this enzyme (53). Serotonin glucuronidation was doubled in microsomes from persons with moderate-to-heavy alcohol use (54). Consequently, the mechanism of induction by oral contraceptives, phenytoin, and rifampin is unclear and may involve multiple enzymes. Propofol clearance is greater than liver blood flow, also suggesting that extrahepatic metabolism is important for this compound. A number of pharmacodynamic interactions have been reported between propofol and benzodiazepines or opoids such as fentanyl and alfentanil (68–70). Phar- macokinetic interaction studies in humans with fentanyl or alfentanil revealed a modest decrease in propofol clearance (20–50%). The 7-O-glucuronide is the predominant conjugate formed in vivo and is the major excretory metabolite of mycophenolate (90% of the dose in human urine). The two regulatory region mutations are more common appearing in >15% of Caucasians and may result in increased protein expression. In a population of 95 kidney transplant recipients, (83) 16/95 carried only the –275 T>A mutation, 12/95 had only the –2152 C>T mutation, and 11/ 95 carried both mutations, although Innocenti et al. Allele frequencies were 60% in Japanese (n ¼ 87), 39% in Caucasians (n ¼ 50), and 44% in African Americans (n ¼ 50). Innocenti found similar frequencies [53% in Asians (n ¼ 200) and 39% in Caucasians (n ¼ 254)] (84). In vitro, the enzyme was shown to catalyze conjugation at both the phenolic hydroxyl at the 7- position and the carboxylic acid moiety to form an acyl glucuronide. These data suggest that the Caco-2 cell system may not be the optimal model to predict small intestinal glucur- onidation. The very low bioavailability of raloxifene in humans (2%) is therefore 100 Remmel et al. The Vmax values for the M59I variant were about half of wild type for 17b-estradiol glucuronidation with a similar Km value (93,94). This enzyme had activity toward several steroidal substrates, including estriol and androsterone, with low activity for the bile acid and hyodeoxycholic acid. Morphine glucuronidation has been well studied; however, relatively few clinical drug-drug interaction with morphine have been reported. However, morphine-6-glucuronide has poor ability to cross the blood-brain barrier, with a permeability coefficient in rats that 1/57 that of morphine. Morphine-6-glucur- onide has potency similar to the analgesic effects of morphine when administered to rats on a mg/kg basis. In humans, both morphine-3-glucuronide (lacking analgesic activity) and morphine-6- glucuronide are present in higher concentrations in plasma than morphine at steady state. The data did not fit to a simple hyperbolic fit expected of a competitive inhibitor of single enzyme. Drug interaction studies with lorazepam and clofibric acid in humans have been reported and are summarized in Table 5.

Counselling If applicable 500mg ciplox with amex, the patient should be accompanied home by a responsible adult and should not drive or operate machinery for 24 hours buy generic ciplox 500mg line. This assessment is based on the full range of preparation and administration options described in the monograph. Diazoxide 15mg/mL solution in 20-mL ampoules * Diazoxide is a benzothiadizine analogue and is related structurally to the thiazide diuretics. Inspect visually for particulate matter or discolor- ation prior to administration and discard if present. Technical information Incompatible with Not relevant Compatible with Flush: NaCl 0. Monitoring Measure Frequency Rationale Blood pressure Continuous * Monitor response; maximum hypotensive effects initially, reducing generally occur within less than 5 minutes. Blood glucose * Hyperglycaemia; may be severe in patients with pre- existing carbohydrate metabolic disorders. Additional information Common and serious Injection/infusion-related: Local: Extravasation causes tissue damage. Single doses of 300mg have been associated with angina and with myocardial and cerebral infarction. Pharmacokinetics Plasma elimination half-life ranges from about 20--45 hours but values of up to 60 hours have been reported and may be prolonged in renal impairment. A response usually occurs within 5 minutes and usually persists for up to 4 hours. Plasma half-life is at least 3 times longer than the hypotensive action, so accumulation is likely. Counselling Patients should be warned to expect pain or a feeling of warmth along the injected vein and to report severe sensations. This assessment is based on the full range of preparation and administration options described in the monograph. Maximum duration of parenteral treatment is 48 hours; oral or rectal therapy should be instituted as soon as possible if necessary. Dose in renal impairment: adjusted according to creatinine clearance:1 * CrCl >20--50mL/minute: dose as in normal renal function. Intermittent or continuous intravenous infusion For dilution of Voltarol and Goldshield products, NaCl 0. Inspect visually for particulate matter or discoloration prior to administration and discard if present. Inspect visually for particulate matter or discolor- ation prior to administration and discard if present. Technical information Incompatible with No information Compatible with Flush: NaCl 0. Additional information Common and serious Immediate: Anaphylaxis and other hypersensitivity reactions may occur. This assessment is based on the full range of preparation and administration options described in the monograph. Its use arises from the property of cobalt salts to form a relatively non-toxic stable ion-complex with cyanide. Dicobalt edetate is toxic and potentially fatal in the absence of cyanide poisoning. Pre-treatment checks * Must only be used in cases of confirmed severe cyanide poisoning. If the patient is fully conscious, it is unlikely that the extent of poisoning warrants the use of dicobalt edetate injection. Biochemical and other tests Nil Doses of cyanide poisoning antidotes1 (see relevant entries) Itisessentialtoconsult apoisonsinformationservice,e. Severe poisoning (coma, fixed dilated pupils, cardiovascular collapse, respiratory failure, cyanosis): If dicobalt edetate is available: As well as other supportive measures: * Give 300mg (20mL) of 1. If a second dose of dicobalt edetate is given, there is "risk of cobalt toxicity but only if the diagnosis is not cyanide poisoning. Inspect visually for particulate matter or discoloration prior to administration and discard if present. Technical information Incompatible with Not relevant Compatible with Not relevant pH 4--7. Dicobalt edetate | 245 Monitoring Measure Frequency Rationale Signs of Throughout treatment * May cause anaphylactoid reactions, particularly hypersensitivity in overdose (or in the absence of cyanide). Additional information Common and serious Immediate: Anaphylactic reactions including facial and laryngeal oedema undesirable effects (facilities for intubation and resuscitation should be immediately available). This assessment is based on the full range of preparation and administration options described in the monograph. Wolff--Parkinson--White syndrome; ventricular tachycardia or fibrillation; hypertrophic cardiomyopathy (unless concomitant atrial fibrillation and heart failure -- but with caution). The dose may alternatively be given in divided doses, each over 10 to 20 minutes, with about 50% of the total dose given initially and additional fractions (usually 25%) given at intervals of 6 to 8 hours if still indicated. Commence oral maintenance therapy on the following day adjusted according to age, lean bodyweight and renal function.