Anticholinergic activity

Amantadine is less effective than levodopa in the treatment of Fhrkinson s disease but more effective than die anticholinergics. Amantadine may be given alone or in combination witii an antiparkinsonism drug witii anticholinergic activity. Amantadine is also used as an antiviral drug (see Chap. 14). 

Drugp with anticholinergic activity inhibit acetylcholine (a neurohormone produced in excess in Fhrkinson s disease) in the CNS. Dru with anticholinergic activity are generally less effective than levodopa... 

Frequently seen adverse reactions to dragp with anticholinergic activity include dry mouth, blurred vision, dizziness, mild nausea, and nervousness. These may become less pronounced as therapy progresses. Other adverse reactions may include skin rash, urticaria (hives), urinary retention, dysuria, tachycardia, muscle weakness, disorientation, and confusion. If any of these reactions are severe, the drug may be discontinued for several days and restarted at a lower dosage, or a different antiparkinsonism drag may be prescribed. 

The antiemetics and antivertigo drug may have additive effects when used with alcohol and other CNS depressants such as sedatives, hypnotics, antianxiety drugp, opiates, and antidepressants. There may be additive anticholinergic effects (see Chap. 25) when administered with drag s that have anticholinergic activity such as the antihistamines, antidepressants, pheno-thiazines, and disopyramide The antacids decrease absorption of the antiemetics. 

The antidiarrheal drugs cause an additive CNS depression when administered with alcohol, antihistamines, narcotics, and sedatives or hypnotics. There are additive cholinergic effects when administered with other drugp having anticholinergic activity, such as antidepressants or antihistamines. Concurrent use of the antidiarrheals witii a monoamine oxidase inhibitor increases the risk of a hypertensive crisis. 

Benzilate esters of piperidinols, as well as those of acyclic aminoalcohols, show similar anticholinergic activity. For example, ester interchange between methyl benzilate and N-methyl-4-piperidinol, followed by quaternization of the resulting ester... 

Biological activity in this series shows considerable tolerance for modification in the ester moiety as well. Esters in which one of the aromatic rings is fully reduced still show good anticholinergic activity. One such agent, propenzolate (66), is prepared by displacement of halogen from N-methyl-3-chloropiperidine (64) by the sodium salt of acid... 

DIBENZOCYCLOHEPTANES AND DIBENZOCYCLOHEPTENES Drugs in this structural class have effected a revolution in the treatment of severely depressed patients such that deinstitutionalization is a feasible public policy. The compounds often show other CNS activities which depend on the length of the side chain. One-carbon chains generally lead to anticonvulsant activity amines separated from the nucleus by three carbons usually donvey antidepressant activity. Selected examples possess significant anticholinergic activity. 

Many tricyclic tranquilizers and antidepressants exhibit some measure of anticholinergic activity. 

It is of interest to note that attachment of a basic side chain on carbon of an isomeric dibenzazepine affords a compound in which anticholinergic activity predominates, elantrine (50). Reaction of anthra-quinone (45) with the Grignard reagent from 3-chloro-N,N-dimethylaminopropane in THF in the cold results in addition to but one of the carbonyl groups to yield hydroxyketone 46. This is then converted to oxime 47 in a straightforward manner. Treatment of that intermediate with a mixture of phosphoric and polyphosphoric acids results in net dehydration of... 

McShane R, Keene J, Gedling K et al. (1997) Do neuroleptic drugs hasten cognitive decline in dementia Prospective study with necropsy follow up. BMJ 314(7076) 266-270 Mortimer AM, Shepherd CJ, Rymer M et al. (2005) Primary care use of antipsychotic drugs an audit and intervention study. Ann Gen Psychiatry 4 18 DOI 10.1186/1744-859X-4-18 Mulsant BH, Pollock BG, Kirshner M et al. (2003) Serum anticholinergic activity in a community-based sample of older adults relationship with cognitive performance. Arch Gen Psychiatry 60(2) 198-203... 

Evidence that central muscarinic receptors are supersensitive in depressed patients and that chronic antidepressant treatments normalize the supersensitivity of these receptors. This effect does not depend on any intrinsic anticholinergic activity of the antidepressant (i.e. it is an indirect, adaptive effect). 

Mianserin was the first of the second-generation antidepressants to be developed. It lacked the amine reuptake inhibitory and MAOI actions of the first-generation drugs and also lacked the cardiotoxicity and anticholinergic activity of the TCAs. However, it was sedative (antihistaminic), caused postural hypotension (alpha-1 blockade) and also caused blood dyscrasias and agranulocytosis in a small number of patients. This has limited the use of mianserin in recent years. 

The cycloalkylamine salts of 5-cyano-l-uracilacetic acid and analogues, exemplified by (LI), are claimed to produce marked inhibition of gastric secretion with virtually no anticholinergic activity [378]. This activity is not inherent in the free acetic acid nor in the amine. There is no distinction between optical isomers of the longer chain acids. The pyrimidine portion can be prepared by the treatment of a-cyano-/3-ethoxy-A -(ethoxycarbonyl)acrylamide with alanine or related derivatives [301,302]. 

Thus, the anticholinergic activity of the alkaloid hyoscyamine is almost entirely confined to the (—)-isomer, and the (+)-isomer is almost devoid of activity. The racemic ( )-form, atropine, has approximately half the activity of the laevorotatory enantiomer. An anticholinergic drug blocks the action of the neurotransmitter acetylcholine, and thus occupies the same binding site as acetylcholine. The major interaction with the receptor involves that part of the molecule that mimics acetylcholine, namely the appropriately positioned ester and amine groups. The chiral centre is adjacent to the ester, and also influences binding to the receptor. 

Bupropion is an a-aminoketone that is structurally related to amphetamines, and it exhibits unique activity comparable to that of other antidepressants. It is believed that bupropion restores the total amount of norepinephrine in the body. This compound is a poor reuptake inhibitor of dopamine, and does not exhibit anticholinergic activity or inhibit MAO. Its efficacy as an antidepressant is comparable to that of tricyclic antidepressants, and as a serotonin uptake inhibitor it is comparable to fluoxetine. It is preferable to use amoxapine. Synonyms of bupropion are amphebutamon and wellbutrin. 

These drugs have weaker anticholinergic activity than atropine however, they have a significantly more expressed antispastic action. They are used for treating so-called irritable bowel syndrome and diarrhea. 

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