CNS side effects

Activation of immunophilin receptors in the CNS is thought to be involved in certain aspects of AIDS dementia and the CNS side effects seen with the immunosupressants, FK 506 and cyclophilin. FK 506 and related compounds also have antiischemic effects. 

The Class I agents have many similar side effects and toxicities. The anticholinergic side effects include dry mouth, constipation, and urinary hesitancy and retention. Common gastrointestinal (GI) side effects include nausea, vomiting, diarrhea, and anorexia. Cardiovascular adverse effects are hypotension, tachycardia, arrhythmias, and myocardial depression, especially in patients with congestive heart failure. Common central nervous system (CNS) side effects are headache, dizziness, mental confusion, hallucinations, CNS stimulation, paraesthesias, and convulsions. 

More recently, the utility of the indole group as a scaffold for cannabinoid agonists has been demonstrated by a number of new patent applications appearing in the literature (286)-(290) [187-190]. Of particular note is compound (286) that is reported to have 18-fold selectivity for the CBi receptor (CBp Ki — 0.08 nM CB2 Ki — 1.44nM). In addition to the indole scaffold, a number of patent applications by AstraZeneca claim indole-like scaffolds such as benzimidazoles (289) [191-193] and azaindoles (290) [194]. Although these compounds bind to both CBi and CB2 receptors, the inventors claim that they may be useful in treating diseases without the associated CNS side effects. 

In the early clinical trials of Pravadoline (248), the Sterling-Winthrop Research group observed CNS side effects. In an effort to circumvent these issues, indenes were explored as an alternative core [197]. The rationale behind this approach came from the observation that sulindac (308), an indene analogue of indomethacin (309), had anti-inflammatory properties comparable to (309) but without the CNS-associated side effects. 

Receptor subtype selective CB2 agonists are seen as potential candidates for the treatment of a variety of diseases, including pain-related indications. The promise of useful therapeutic effects without unwanted CNS side effects makes the development of CB2 selective compounds a particularly attractive... 

Most of the antiemetic clinical trials in the last decade have involved metoclopramide (1) either as a single agent or in combination with other drugs. Similarly, most of the chemical modification studies have been designed to optimize antiemetic and/or gastroprokinetic properties of metoclopramide and to eliminate undesirable CNS side-effects which are the consequence of its dopamine D2 receptor blockade [1-3]. 

Control can be achieved in most patients with 200 to 300 mg given every 8 hours. If satisfactory response is not achieved at 300 mg every 8 hours, and the patient tolerates mexiletine well, try 400 mg every 8 hours. The severity of CNS side effects increases with total daily dose do not exceed 1200 mg/day. 

Intrathecal Management of severe spasticity of spinal cord origin in patients who are unresponsive to oral baclofen therapy or experience intolerable CNS side effects at effective doses. Intended for use by the intrathecal route in single bolus test doses (via spinal catheter or lumbar puncture) and, for chronic use, only in implantable pumps approved by the FDA specifically for the administration of baclofen into the intrathecal space. 

Reserpine also interferes with the neuronal storage of a variety of central transmitter amines such that significant depletion of norepinephrine, dopamine, and 5-hydroxytryptamine (serotonin) occurs. This central transmitter depletion is responsible for the sedation and other CNS side effects associated with reserpine therapy. The depletion of brain amines also may contribute to the antihypertensive effects of reserpine. 

Indomethacin (Indocin) is used in the treatment of acute gouty arthritis, rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis. It is not recommended for use as a simple analgesic or antipyretic because of its potential for toxicity. While indomethacin inhibits both COX-1 and COX-2, it is moderately selective for COX-1. It produces more CNS side effects than most of the other NSAIDs. Severe headache occurs in 25 to 50% of patients vertigo, confusion, and psychological disturbances occur with some regularity. GI symptoms also are more frequent and severe than with most other... 

Sulindac (Clinoril) is chemically related to indomethacin and is generally used for the same indications. It is a prodrug that is metabolized to an active sul-hde metabolite and an inactive metabolite. The most frequently reported side effects are GI pain, nausea, diarrhea, and constipation. The incidence of these effects is lower than for indomethacin, presumably because sulindac is a prodrug and thus the active metabolite is not highly concentrated at the gastric mucosa. As with indomethacin, a rather high incidence of CNS side effects (dizziness, headache) also occurs. 

Ipratropium is virtually devoid of the CNS side effects associated with atropine. The most prevalent peripheral side effects are dry mouth, headache, nervousness, dizziness, nausea, and cough. Unlike atropine, ipratropium does not inhibit mucociliary clearance and thus does not promote the accumulation of secretions in the lower airways. 

The inhibition of MAO enzymes increases the concentrations of these neurotransmit-ters at storage sites throughout the CNS. Side effects of MAOIs include hypotensive effects from the inhibition of central vasomotor centers and cholinergic effects. 

CNS effects. CNS side effects usually occur during titration and early in therapy, then... 

CNS side effects (seizures, respiratory depression, decreased level of consciousness, coma, death)... 

Several nonsedative Hj inhibitors have been marketed—for example, astemizole (4.149) and terfenadine (4.150). They are quite polar molecules and therefore cannot cross the blood-brain barrier to reach central histamine receptors. This is a good example of drug design exploiting knowledge of the pharmacokinetic processes to preclude undesirable CNS side effects. 

CNS side effects include confusion, anxiety, lethargy, nausea and vomiting. GIT related effect is constipation. Other side effects are urinary retention, dry mouth, miosis, dysphoria, hypotension, skin rash, itching and urticaria. Tolerance, drug dependence and drug abuse are the main drawbacks of morphine. 

CNS side effects include lethargy, drowsiness, increase in REM sleep, restlessness, excitement and impaired psychomotor functions. 

CNS side effects include dizziness, mental confusion, tremors, twitching, visual disturbances, convulsion and respiratory depression. CVS toxicity includes hypotension, cardiac arrhythmias and bradycardia. Other side effects include allergic dermatitis, asthma, anaphylactic shock etc. 

It also causes miosis, salivation, increased gastric acid secretion. CNS side effects include lethargy, apathy, psychic depression which may result in suicidal tendencies and weight gain. 

CNS side effects include nystagmus and hallucinations and some of the newer compounds can cause disulfiram like reaction. 

Adverse reactions include vomiting, dyspepsia, flatulence, jaundice, palpitations, chest pain. Allergic reactions include rash, photosensitivity and angioedema. CNS side effects are headache, dizziness, vertigo and fatigue. 

Dopamine does not cross the blood-brain barrier and so there are no CNS side effects when given intravenously. Tachyarrhythmias, myocardial ischaemia, headache, nausea and vomiting may occur. Interactions... 

An overdosage of local anesthetics can produce dose-dependent central nervous system (CNS) side effects such as insomnia, visual and auditory disturbances, nystagmus, shivering, tonic-clonic convulsions, and finally fatal CNS depression. The initial CNS excitation and convulsions may be brought under control by diazepam or thiopental. 

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