Answers
John D Firth, Professor Ian Gilmore in MRCP Part 2 Self-Assessment, 2018
Aspirin in excess causes symptoms of nausea, vomiting, headache, confusion and tinnitus or hearing difficulties. Whilst the co-codamol and codeine phosphate could cause confusion, they would not cause the tinnitus. All analgesics taken for a prolonged period of time can lead to an analgesic-induced headache. AReactions to NAC are well recognized and are not related to hypersensitivity. NAC can almost always be safely restarted and the full treatment dose safely administered after symptomatic treatment. Oral methionine may be an alternative but is definitely second line. IV chlorpromazine would make hypotension worse. Withholding treatment and waiting more than 12 hours would expose the patient to risk of liver failure. ARizatriptan is not used as prophylaxis against migraine. It is a 5HT1 agonist and may be useful in the treatment of acute attacks, for which it is available as either tablets or ‘melt wafers’ that dissolve on the tongue. Propranolol and pizotifen are licensed for use as prophylaxis against migraine. Pizotifen may cause drowsiness and weight gain. Sodium valproate and amitriptyline are unlicensed for migraine prophylaxis but can be effective in some patients. CAbout 25% of patients who stop their anti-epilepsy treatment will relapse within a year of starting to taper down their medication. The likelihood of seizure is greatest during withdrawal and in the subsequent 6 months. The DVLA recommends that patients should not drive during this period. Doses of drugs such as carbamazepine, lamotrigine, phenytoin, sodium valproate and vigabatrin should be reduced by about 10% every 2–4 weeks. Barbiturates, benzodiazepines and ethosuximide should be tapered more slowly by reducing dosage by about 10% every 4–8 weeks.
Substrates of Human CYP2D6
Shufeng Zhou in Cytochrome P450 2D6, 2018
CYP2D6 plays an important role in the metabolism of many indolealkylamines agents, which are 5-hydroxytryptamine (5-HT/serotonin) analogs that mainly act on the serotonin system (Yu 2008). Structurally, this group of compounds contains an indole moiety and a basic nitrogen atom, which are connected by an alkyl chain usually of two carbons in length. They mainly act on the 5-HT receptors, and some indolealkylamines such as ergotamine and a series of triptans including sumatriptan, zolmitriptan, naratriptan, almotriptan, frovatriptan, and rizatriptan have been developed for the clinical treatment of migraine (Saper and Silberstein 2006). However, many other indolealkylamine agents are widely abused compounds in developed countries although some have demonstrated therapeutic potential in psychopharmacotherapy. These include the notorious lysergic acid amides such as D-lysergic acid diethylamide and ergine; tryptamine derivatives such as psilocybin (O-phosphoryl-4-hydroxy-N,N-dimethyltryptamine), N,N-dimethyltryptamine (DMT), bufotenine (5-hydroxy-dimethyltryptamine), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), and 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT, “Foxy,” or “Foxy Methoxy”); and β-carbolines such as harman, harmaline, harmine, and ibogaine (Yu 2008). All these compounds produce hallucinogenic and stimulant activities and high doses of administration will cause mydriasis, nausea, jaw clenching, and overt hallucinations with auditory and visual distortions. Structurally, DMT, psilocybin (a prodrug), 5-MeO-DMT, and bufotenine are analogous to 5-HT and tryptamine. DMT is created in small amounts by the human body during normal metabolism by the enzyme tryptamine-N-methyltransferase. Like tryptamine (Airaksinen and Kari 1981; Yu et al. 2003a), tryptamine derivatives including DMT, bufotenine, and 5-MeO-DMT are excreted primarily via oxidative deamination, which is predominantly catalyzed by MAO-A (Figure 3.108) (Sanders-Bush et al. 1976; Suzuki et al. 1981; Szara and Axelrod 1959). However, there are some species differences in the metabolism of these tryptamine derivatives. DMT and 5-MeO-DMT are metabolized through deamination, N-demethylation, O-demethylation, and N-oxygenation, and N-oxide is the major metabolite in rat tissues (Sitaram et al. 1987a, b). In contrast, oxidative deamination and O-demethylation followed by glucuronidation or deamination are the major metabolic pathways for 5-MeO-DMT in rats (Agurell et al. 1969). In human liver microsomes and cultured hepatocytes, 5-MeO-DMT undergoes extensive deamination and O-demethylation, with the latter reaction being primarily catalyzed by CYP2D6 and resulting in toxic bufotenine (Yu et al. 2003c).
Application of Bioresponsive Polymers in Drug Delivery
Deepa H. Patel in Bioresponsive Polymers, 2020
Poloxamers have been one of the most researched thermoresponsive polymers. In one of the study, Majithiya et al. developed a composite gel based on Poloxamer 407 and Carbopol 934P for sumatriptan succinate in management of migraine. The transition temperatures were below 30°C. The gel showed mucoadhesive characteristics and enhanced permeability and induced no cellular toxicity [52]. Zaki et al. also worked on Polaxamer 407 but with polyethylene glycol and multiple mucoadhesive polymers for metoclopromide. The inclusion of mucoadhesive polymers modified the rheological properties and increased the residence time as evidenced by longer mucociliary transport time. The formulation also ensured a faster Tmax compared to oral solution [53]. Ketorolac tromethamine nasal sprays gave insufficient nasal residence time to limit their applicability. Another study on thermoresponsive hydrogel of Poloxamer 407 and Carrageenan for ketoraolac ensured higher nasal retention in vivo studies (54). Smart polymer-based hydrogels increased the residence time, but they may be exploited with other aims also. Rizatriptan benzoate used in the treatment of migraine suffers from extensive hepatic metabolism upon oral administration. Hence, Kempwade and Taranalli explored nasal delivery as an alternate to escape the first-pass metabolism. Thermo-reversible gels comprised of Poloxamer 407 and Carbopol were developed and investigated. Superior permeation and no toxicity of the developed formulation were observed [55]. Qian et al. formulated tacrine in a Pluronic F-127 (20%, w/v) in situ gel for the intranasal delivery. The formulation was rationalized by its low oral bioavailability (17–24%) and dose-dependent hepatotoxicity. In vivo studies revealed 2–3 fold higher peak plasma concentration (Cmax), a significantly higher tacrine exposure in the brain and reduction in drug’s metabolites after intranasal administration of the gel, compared to the oral solution [56]. It is practically impossible for the hydrophilic molecules to gain entry into the brain by crossing blood-brain barrier. One of the approaches for direct brain targeting is through nasal cavity. The nasal cavity offers direct transport of drugs to brain through olfactory and trigeminal nerve cells. Gabal et al. loaded anti-Parkinsonism drug, ropinirole into nanostructured lipid carriers and integrated them in Poloxamer 188 in situ gels.
A review of rizatriptan, a quick and consistent 5-HT
Published in Expert Opinion on Pharmacotherapy, 2004
Rizatriptan is a second-generation triptan marketed as 5 and 10 mg tablets and rapidly disintegrating wafer formulations. In > 5000 acute migraine patients enrolled in short-term trials and almost 1800 patients in long-term, open-label trials treating ~ 47,000 attacks, rizatriptan was effective and well-tolerated. Controlled head-to-head data and a meta-analysis of 53 randomised, placebo-controlled trials of oral triptans in > 24,000 patients have shown that rizatriptan 10 mg offers efficacy advantages over oral sumatriptan 50 and 100 mg and other oral triptans, both in terms of speed of onset of action and consistency. These advantages may reflect its improved pharmacological profile over sumatriptan in terms of higher oral bioavailability and a shorter time to maximum concentration. The wafer formulation offers the convenience of being administered without water. As a result of its superior efficacy profile and generally good tolerability, rizatriptan can be considered as a first-line treatment for acute migraine.
A review of the 5-HT1B/1D agonist rizatriptan: update on recent research and implications for the future
Published in Expert Opinion on Pharmacotherapy, 2008
Background: Among the 5-HT1B/1D agonists or ‘triptans,’ which are considered first-line therapy for acute migraine, rizatriptan has emerged as one of the most efficacious. Objective: Several comprehensive reviews of rizatriptan are available in the literature; the aim of this paper is to review the most current research with rizatriptan. Methods: The scope of the review addresses current topics of clinical interest, including studies of time to pain relief, effect of early administration, use in combination with other drugs, and tolerability updates, as well as trials of rizatriptan in certain subpopulations such as patients with menstrual migraine, patients with motion sickness and pediatric patients. Conclusion: In the context of these newly available data, the potential for expansion of the role of rizatriptan in the clinic is evaluated.
Efficacy and tolerability of rizatriptan 10 mg compared with sumatriptan 100 mg: an evidence-based analysis
Published in Expert Review of Neurotherapeutics, 2010
Acute migraine attacks have a strong impact on quality of life and require immediate therapeutic intervention to achieve rapid pain relief. The introduction of triptans into the market in 1993 has increased the therapeutic options in migraine patients considerably. The seven currently available triptans show many similar characteristics but there are also some clinically relevant pharmacological differences. Rizatriptan 10 mg has demonstrated, in a head-to-head study, higher response rates and a more rapid onset of action than sumatriptan 100 mg, together with a favorable tolerability profile. Meta-analyses of double-blind placebo-controlled studies confirmed the superior efficacy of rizatriptan. Owing to the limited efficacy of sumatriptan, a more effective triptan treatment is needed in the majority of patients with acute migraine attacks.
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