What are antimuscarinic drugs used for?
Anticholinergic, or antimuscarinic, drugs have been used for the treatment of more or less specified gastrointestinal diseases or complaints for many centuries, first in herbal preparations (including belladonna), and in modern times as synthetic tertiary or quaternary compounds, with atropine being … Antimuscarinic drugs
How do anti-antimuscarinics work?
Antimuscarinics cause the airways to relax by blocking nerve impulses which tell the smooth muscles in the airways to contract. Another effect of LAMAs (long-acting muscarinic antagonists) is that they can reduce the amount of mucus produced.
How safe are antimuscarinic drugs?
How safe are antimuscarinic drugs? Antimuscarinic drugs are associated with the common anticholinergic adverse effects of dry mouth, constipation, blurred vision, and somnolence. Although these are not life threatening, they may be associated with poor compliance or persistence with treatment.
What is the difference between antimuscarinic and muscarinic?
The prefix “anti” means “against”, while “muscarinic” means “relating to the parasympathetic effects,” since antimuscarinics work by inhibiting the parasympathetic nervous system. Join millions of students and clinicians who learn by Osmosis!
What does an antimuscarinic do?
Antimuscarinics help by decreasing the motility of smooth muscle cells in the urinary tract and increasing the tone of the sphincters controlling urination.
How long does it take for antimuscarinics to work?
You'll usually take solifenacin once a day. Common side effects include dry mouth and blurred vision. You will usually take this medicine long term to help keep your symptoms under control. Solifenacin starts to work within 3 to 8 hours, but it can take up to 4 weeks to reach its full effect.
How do antimuscarinics work in incontinence?
Acetylcholine is the primary contractile neurotransmitter in the human detrusor, and antimuscarinics exert their effects on OAB/DO by inhibiting the binding of acetylcholine at muscarinic receptors M(2) and M(3) on detrusor smooth muscle cells and other structures within the bladder wall.
What are some antimuscarinic drugs?
Antimuscarinic agents (such as propantheline bromide, hyoscyamine, and oxybutynin) and muscarinic receptor antagonists (such as darifenacin, solifenacin, and trospium) are used for the suppression of detrusor activity. Cholinergic agonists (bethanechol) can be used to increase detrusor activity.
What is the new drug for incontinence?
Mirabegron (Myrbetriq) Mirabegron is a medication approved to treat certain types of urinary incontinence. It relaxes the bladder muscle and can increase how much urine the bladder can hold. It might also increase the amount you're able to urinate at one time.
What is the best medication for overactive bladder?
Medications that relax the bladder can be helpful for relieving symptoms of overactive bladder and reducing episodes of urge incontinence. These drugs include: Tolterodine (Detrol) Oxybutynin, which can be taken as a pill (Ditropan XL) or used as a skin patch (Oxytrol) or gel (Gelnique)
What are 3 treatment options for incontinence?
Incontinence products absorbent products, such as pants or pads. handheld urinals. a catheter (a thin tube that is inserted into your bladder to drain urine) devices that are placed into the vagina or urethra to prevent urine leakage – for example, while you exercise.
How do I train my bladder to empty completely?
Techniques for Complete Bladder EmptyingTimed voids. ... Double void. ... Drink plenty of fluids. ... Have a bowel movement every day. ... Comfort and privacy are necessary to empty completely. ... Leaning forward (and rocking) may promote urination.More items...
How do antimuscarinics work for overactive bladder?
Antimuscarinic agents are the predominant pharmacological treatment for patients with overactive bladder (OAB). These drugs are thought to act primarily through antagonism at muscarinic M3 receptors located at neuromuscular junctions in the human bladder detrusor muscle.
Do antimuscarinics cause urinary retention?
Undeniably, high doses of antimuscarinics can produce urinary retention, but in the dose range needed for beneficial effects in OAB, there is little evidence for a significant reduction of the voiding contraction.
What are antimuscarinic side effects?
Common adverse effects of antimuscarinic drugs include dry mouth, constipation, urinary retention, agitation, drowsiness, and blurred vision. There is no evidence as to what extent these occur in people in the terminal phase of illness.
What are the 4 most common anticholinergic drugs?
It was found the most common anticholinergic drug classes used by the elderly in the study were: tricyclic antidepressants (for example: amitriptyline) first generation antihistamines (for example: chlorpheniramine, diphenhydramine) overactive bladder antimuscarinics (for example: oxybutynin)
How long does it take for tablets to work?
In general, it typically takes approximately 30 minutes for most medications to dissolve. When a medication is coated in a special coating – which may help protect the drug from stomach acids – often times it may take longer for the therapeutic to reach the bloodstream.
What are 3 treatment options for incontinence?
Incontinence products absorbent products, such as pants or pads. handheld urinals. a catheter (a thin tube that is inserted into your bladder to drain urine) devices that are placed into the vagina or urethra to prevent urine leakage – for example, while you exercise.
What are antimuscarinic side effects?
Common adverse effects of antimuscarinic drugs include dry mouth, constipation, urinary retention, agitation, drowsiness, and blurred vision. There is no evidence as to what extent these occur in people in the terminal phase of illness.
What does antimuscarinic mean in medical terms?
(an'tē-mŭs'kă-rin'ik), Inhibiting or preventing the actions of muscarine and muscarinelike agents, or the effects of parasympathetic stimulation at the neuroeffector junction (for example, atropine).
What is antimuscarinic medication?
Antimuscarinic medications are a group of anticholinergic agents, specifically known for blocking the activity of muscarinic receptors. These recep...
What does antimuscarinic mean?
The prefix “anti” means “against”, while “muscarinic” means “relating to the parasympathetic effects,” since antimuscarinics work by inhibiting the...
How do antimuscarinic medications work?
Antimuscarinic medications work by blocking muscarinic receptors from the action of acetylcholine, the chief chemical messenger controlling parasym...
Are anticholinergics and antimuscarinics the same?
Antimuscarinics are a subtype of anticholinergic drugs. Anticholinergics refer to agents that block cholinergic receptors, or acetylcholine recepto...
Do all antimuscarinic drugs cross the blood-brain barrier?
Some antimuscarinic medications can cross the blood-brian barrier, which is a highly selective barrier of cells that surround the blood vessels pas...
What are antimuscarinics used for?
Antimuscarinic medications can be prescribed for a variety of different reasons. One of the more common cases is in individuals with overactive bla...
What are the potential side effects of antimuscarinics?
Antimuscarinic medications have several potential side effects that often correspond to the various receptors targeted for treatment. Adverse effec...
What are the most important facts to know about antimuscarinic drugs?
Antimuscarinic medications are a specific group of anticholinergic drugs that block muscarinic receptors from the action of acetylcholine. This lea...
How long does atropine last in the eye?
Atropine has a duration of action in the eye of 7-10 days. Tropicamide can induce a transient rise in intraocular pressure, and its use is contraindicated in patients with narrow angle glaucoma for this reason. Cycloplegia (Focused for far vision). This is a second effect of antimuscarinic “eye drops”.
Why are older people more sensitive to antimuscarinic drugs?
Older adults are known to be more sensitive to the effects of antimuscarinic drugs, and this may be due to a combination of age-related changes in pharmacokinetics (reduced renal & hepatic clearance of drugs), increased permeability of the blood-brain-barrier to drugs, and reduced cholinergic neurotransmission in the brain (Campbell et al, 2009).
What is the best antidote for cholinesterase poisoning?
Atropine is an effective antidote used in the treatment of cholinesterase poisoning, overdose by a muscarinic agonist (e.g. pilocarpine, carbachol), or poisoning caused by consumption of mushrooms or other fungi containing significant amounts of muscarine.
What is belladonna alkaloid?
ATROPINE . Atropine is a naturally occurring “ belladonna alkaloid” that can be extracted from plants such as deadly nightshade ( Atropa belladonna ), Jimson weed & mandrake. It is a competitive antagonist of all five known muscarinic receptors (m1-m5), and when administered systemically, it antagonizes the “rest and digest” effects produced by the parasympathetic nervous system. It has numerous medical uses, including temporary relief from bradycardia or AV-block, as an antidote for cholinesterase poisoning or poisoning by mushrooms containing muscarine.
What are the therapeutic uses of antimuscarinics?
By the end of the self study you should be able to: Explain the therapeutic uses of antimuscarinics for treating bronchoconstriction, excessive salivation, motion sickness, AV block, intestinal spasticity / diarrhea & urinary incontinence.
How long does physostigmine last?
The half-life of physostigmine is 15 minutes, but its effects last significantly longer; additional smaller doses may need to be given if agitated delirium reoccurs. Most patients don't require physostigmine for more than 6-7 hours after the initial dose.
What happened to a 13 year old girl?
A 13 year old young woman is brought to the emergency department by ambulance with a chief medical complaint of altered mental status. Her older brother had called 911 after finding her in the front yard of their home speaking incoherently and unaware of her surroundings. In the emergency department it was determined that ...
What is antimuscarinic medicine?
Anticholinergic, or antimuscarinic, drugs have been used for the treatment of more or less specified gastrointestinal diseases or complaints for many centuries , first in herbal preparations (including belladonna), and in modern times as synthetic tertiary or quaternary compounds, with atropine being ….
What is the name of the drug that is used to treat gastrointestinal problems?
Anticholinergic, or antimuscarinic, drugs have been used for the treatment of more or less specified gastrointestinal diseases or complaints for many centuries, first in herbal preparations (including belladonna), and in modern times as synthetic tertiary or quaternary compounds, with atropine being a pharmacological standard.
Does M1 reduce gastric acid?
The M1-selective antimuscarinic drugs, pirenzepine and telenzepine, moderately reduced gastric acid and pep sin secretion without inhibiting smooth-muscle activity as do non-selective antimuscarinics. They hasten peptic ulcer healing and improve the symptoms of reflux esophagitis.
Can H2 antagonists be used in vagotomy?
In combination with H2-antagonists they abolish gastric acid secretion almost completely and can, therefore, be used in high risk peptic conditions. Long-term trials have to show whether they can form a medical alternative to parietal cell vagotomy.
What is the treatment for urinary incontinence?
The treatment of urinary incontinence concerns the first group. Antimuscarinic drugs reduce involuntary detrusor contractions and increase bladder capacity (BMA/RPSGB, 2004). They exert their antagonistic effect at postganglionic cholinergic nerve endings at muscarinic receptor sites in the parasympathetic nervous system (see Figure).
What is the drug that interrupts parasympathetic nerve impulses?
Antimuscarinic drugs interrupt parasympathetic nerve impulses by competing with the neurotransmitter acetylcholine at muscarinic receptor sites (Williams et al, 1998).
What is involuntary urine leakage?
Urinary incontinence is defined as an involuntary leakage of urine and may have multiple causes (Edmunds, 2003).
What are the side effects of antimuscarinic drugs?
Side-effects include: dry mouth; constipation; blurred vision; drowsiness; nausea; vomiting; abdominal discomfort (BMA/RPSGB, 2004); difficulty micturating; palpitations; skin reactions. Restlessness, disorientation and hallucinations may also occur as a result of central nervous system stimulation. A decreased ability to sweat can predispose to heat exhaustion.
What are anticholinergic drugs?
Anticholinergic drugs may be classified into three groups: - Those used for smooth muscle relaxation, antispasmodics and antisecretory properties. - Those used for their effects on the central nervous system and treatment of parkinsonism. - Those used in ophthalmology.
Why do the sympathetic and parasympathetic systems counterbalance each other?
The parasympathetic and sympathetic system counterbalance each other in order to maintain physiological equilibrium. As such the depression of one part of the system will produce an end result comparable with that of stimulating the opposite part (Hopkins et al, 1999).
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What is antimuscarinics used for?
Antimuscarinics are generally used in psychiatry to treat the extrapyramidal side effects of antipsychotic medications.
What are the side effects of antimuscarinics?
Side effects of antimuscarinics include constipation, transient bradycardia (followed by tachycardia, palpitations, and arrhythmias), reduced bronchial secretions, urinary urgency and retention, dilation of the pupils with loss of accommodation, photophobia, dry mouth, flushing, and dryness of the skin. Side effects that occur occasionally include confusion (particularly in the elderly), nausea, vomiting, and giddiness.
What is methanthelinium used for?
Methanthelinium has been used as an adjunct in the treatment of peptic ulcer disease and in gastrointestinal disorders associated with smooth muscle spasm and in the management of urinary incontinence Parfitt (1999).
What is the treatment for OAB?
Antimuscarinic agents are the predominant pharmacological treatment for patients with overactive bladder (OAB). These drugs are thought to act primarily through antagonism at muscarinic M3 receptors located at neuromuscular junctions in the human bladder detrusor muscle.
What is the treatment for an overactive bladder?
Antimuscarinic drugs for overactive bladder and their potential effects on cognitive function in older patients. Antimuscarinic agents are the predominant pharmacological treatment for patients with overactive bladder (OAB). These drugs are thought to act primarily through antagonism at muscarinic M3 receptors located at neuromuscular junctions in ...
Where are the M3 receptors located?
These drugs are thought to act primarily through antagonism at muscarinic M3 receptors located at neuromuscular junctions in the human bladder detrusor muscle. Several of these drugs have been shown to be efficacious in ameliorating the symptoms of OAB in older patients, but most currently available agents lack selectivity for ...
Which system exerts a major influence on cognitive processes?
A review of the literature shows that the cholinergic system in the central nervous system (CNS) exerts a major influence on cognitive processes, in particular memory via M1 cholinergic receptors. In addition, recent evidence suggests a role for M2 receptors in mediating cognitive function.
Is memory loss a concern for OAB?
Thus, cognitive dysfunction (including memory loss) during treatment with nonselective antimuscarinic agents for OAB is of growing concern, particularly in older patients and those with mild cognitive impairment or dementia.
What are antimuscarinics used for?
Antimuscarinics are predominantly used in the management of COPD and occasionally used to treat asthma. Antimuscarinics cause the airways to relax by blocking nerve impulses which tell the smooth muscles in the airways to contract. Another effect of LAMAs (long-acting muscarinic antagonists) is that they can reduce the amount of mucus produced.
How long can ipratropium be nebulised?
Ipratropium – inhaler and can be nebulised (3-6 hours).
What are the effects of lanas?
Another effect of LAMAs (long-acting muscarinic antagonists) is that they can reduce the amount of mucus produced. They can be used as additional management for chronic symptoms . The duration of effect of available LAMAs varies considerably.
Can antimuscarinics cause dry mouth?
Dry mouth – a commonly reported side effect from antimuscarinics. This can be minimised in some case by changing the type of inhaler device.
What is overactive bladder?
Overactive bladder is the term used to describe the symptom complex of urinary urgency, usually accompanied by frequency and nocturia, with or without urge urinary incontinence, in the absence of urinary tract infection or other obvious pathology. 1
How well do antimuscarinic drugs work?
Several antimuscarinic drugs are licensed and available in the UK. These have all been recently recommended by the International Consultation on Incontinence 7 to treat overactive bladder syndrome (box 1) and all have level I evidence 8 and a grade A recommendation (see box 2 for definitions). 9
What are the precautions?
Hepatic or renal impairment—As antimuscarinic drugs undergo both hepatic metabolism and renal excretion, the dose may need to be decreased in such patients
How cost effective are antimuscarinic drugs?
In a recent assessment of cost effectiveness of all antimuscarinic therapies within the UK National Health Service, solifenacin was associated with the highest quality adjusted life year (QALY) gain in terms of urinary urgency, frequency, and incontinence. Solifenacin was found to be more cost effective than fesoterodine, tolterodine, and propiverine, though not oxybutynin. 24 A cost utility analysis comparing solifenacin and tolterodine found that solifenacin was less expensive and more effective than tolterodine: solifenacin was found to have an incremental cost of £8087 per QALY, and the one year costs were £509 with solifenacin compared with £526 for tolterodine. 25
How do antimuscarinic drugs compare with conservative therapy and other drugs?
Antimuscarinic drugs may be a useful addition to non-drug therapy in the management of overactive bladder. In a Cochrane review of 13 trials including 1770 patients, symptomatic improvement was more common among those taking antimuscarinic drugs compared with bladder retraining (relative risk 0.73 (0.59 to 0.90)), and combination treatment was also associated with more improvement than bladder training alone (0.55 (0.32 to 0.93)). Similarly there was a trend towards greater improvement with a combination of antimuscarinic drugs with bladder retraining compared with antimuscarinics alone (relative risk 0.81 (0.61 to 1.06)), although this was not significant. 26
What causes detrusor overactivity?
Although the cause of detrusor overactivity is unknown, there is evidence to support both neurogenic and myogenic causes . 4 5 Antimuscarinic drugs used to treat overactive bladder (see box 1) act by blocking muscarinic receptors at the neuromuscular junction and thus prevent acetylcholine mediated bladder contraction.
What is the box 1 of the urinary system?
Box 1: Antimuscarinic drugs used to treat overactive bladder. Based on level I evidence for all these drugs, the International Consultation on Incontinence has made grade A recommendations for their use in overactive bladder syndrome. 7 (See box 2 for definitions of levels of evidence and recommendations)
How much does OAB cost?
OAB costs an estimated US$12 billion annually in the US, with US$9 billion incurred in the community (Basra and Kelleber 2007). The estimate includes both the direct costs of care, protective undergarments, and treatment as well as consequential costs, such as those resulting from urinary tract infections and falls due to urgency to get to the bathroom. There are intangible costs such as pain, suffering, and poor quality of life. The negative impacts on health, the ability to function, and quality of life have been well-documented. The elderly with OAB and subsequent incontinence are more likely to be admitted to nursing homes. Thom et al (1997)found at least a 2-fold increase in risk of admission to a nursing facility for patients with incontinence. Urinary incontinence can lead to anxiety, negative self-image, and isolation (Basra and Kelleber 2007). OAB places individuals at risk for other forms of morbidity. Problems associated with OAB include skin ulceration and urinary tract infections. Nocturia, waking up more than one time per night to void, is common with OAB and is among the most bothersome of lower urinary tract symptoms (Ohelke 2005). In addition to sleep interruption and resulting fatigue, patients with nocturia may be more likely to suffer from falls and fractures, which are associated with high morbidity in elderly patients (33% of patients do not survive beyond 1 year after a hip fracture) (Reeves et al 2006).
What is the best medication for OAB?
There are many medications available for the management of uncomplicated OAB. Several agents previously used include propantheline, hyoscyamine, and imipramine. Propantheline bromide is a non-selective muscarinic receptor antagonist with low or varying bioavailability, with less frequent dosing and a larger side-effect burden (Nabi et al 2006). It is no longer applied for the treatment of OAB. Hyoscyamine sulfate, another muscarinic receptor antagonist, may be useful in patients with intermittent symptoms (Malone and Okano 1999). Its side effect profile includes prominent anticholinergic side effects. Imipramine, a tricyclic antidepressant, is not routinely recommended for the treatment of OAB, but may be useful for stress incontinence or mixed urge – stress incontinence due to its effect on bladder neck tone (Wein 1998). Imipramine is associated with potentially serious CNS side effects and cardiotoxicity. More frequently prescribed agents for the treatment of OAB are oxybutynin, which has a mixed action, and tolterodine. Three additional drugs were approved by the US Food and Drug Administration in 2004 to treat the symptoms of OAB: trospium, which has been in use in Europe for the treatment of OAB, darifenacin, and solifenacin (Lam and Hilas 2007).
What is the best antimuscarinic for bladder?
Choice of antimuscarinic agents for overactive bladder in the older patient: focus on darifenacin
What is an overactive bladder?
Overactive bladder (OAB) is a problem characterized by urgency; a sudden desire to urinate that cannot be postponed. According to the International Continence Society (ICS) “urgency, with or without urge incontinence, usually with frequency and nocturia, can be described as the overactive bladder syndrome, urge syndrome, or urgency-frequency syndrome. These terms can be used if there is no proven infection or obvious pathology.”( Wein and Rovner 2002). It can be associated with frequency and nocturia, and it may occur with urinary incontinence. OAB affects approximately 16% of the adult population in the US and the prevalence increases with age (Wein and Rovner 2002; Beneton and De Parisot 2003).
What are the interventions for OAB?
Once these discreet diagnoses have been ruled out, treatment of uncomplicated OAB can begin. Behavioral intervention should always include patient education. Timed voiding in infrequent voiders or in patients with prior central nervous system injury (eg, stroke), decreased fluid consumption in those with polydypsia or night-time fluid intake, caffeine modification, and proper time of diuretic administration are all obvious places to start. Biofeedback pelvic floor muscle retraining can be used to relax any contributory pelvic floor muscle spasm and to educate patients on manipulation of bladder inhibitory reflexes. Unfortunately no peer-reviewed publication specifically exists for the use of biofeedback in OAB. However, a meta-analysis by Berghmans et al assessing the efficacy of biofeedback in urge urinary incontinence found that almost all studies had positive results in favor of biofeedback but better constructed studies were needed to really evaluate its efficacy (Berghmans et al 2000).
What neurotransmitter is responsible for bladder contraction?
There is a complex interplay of neurotransmitters and receptors leading to normal bladder function. Acetylcholine, by acting on muscarinic receptors within the bladder, is the primary neurotransmitter in bladder contraction (Yamanishi et al 2001). Contraction occurs as a result of increased parasympathetic outflow and relaxation of sympathetic inhibition. There are 5 known muscarinic subtypes (M1 to M5) that are distributed throughout the human body (Table 1). The muscarinic receptor subtypes are located in smooth muscle (bladder), exocrine glands, the nervous system, and the heart. M2 receptors are the predominant subtype within the healthy detrusor muscle; activation of M2 receptors inhibits sympathetically mediated detrusor relaxation. M2 receptors are also located in the heart and central nervous system (CNS). M3 receptors are responsible for detrusor smooth muscle contraction and also have an exocrine function in the salivary glands (Pontari et al 2004). The muscarinic receptor antagonists used to treat OAB may affect these receptors to varying levels. The use of muscarinic receptor antagonists is associated with a spectrum of outcomes in both efficacy and side-effect profile.
What are the side effects of antimuscarinic agents?
Side effects of antimuscarinic agents can include changes in blood pressure, pulse rate or ECG when beginning treatment. Dizziness and blurred vision are occasionally reported as well. The most common side effect is dry mouth (Lam and Hilas 2007). Constipation and dyspepsia are also reported. Dizziness and somnolence are common CNS side effects. On the whole, side effects are transient and tolerable – although constipation is one of the common side effects, the use of laxatives and stool softeners is rarely necessary (Anon 2007). Adverse events or side effects infrequently lead to withdrawal of treatment.
What is the MRA?
Metabotropic acetylcholinergic receptors. A muscarinic receptor antagonist ( MRA) is a type of anticholinergic agent that blocks the activity of the muscarinic acetylcholine receptor. The muscarinic receptor is a protein involved in the transmission of signals through certain parts of the nervous system, and muscarinic receptor antagonists work ...
What are the two most commonly used anticholinergics?
Most muscarinic receptor antagonists are synthetic chemicals; however, the two most commonly used anticholinergics, scopolamine and atropine, are belladonna alkaloids, and are naturally extracted from plants such as Atropa belladonna, the deadly nightshade.
What is the effect of atropine on the heart?
Atropine acts on the M2 receptors of the heart and antagonizes the activity of acetylcholine. It causes tachycardia by blocking vagal effects on the sinoatrial node. Acetylcholine hyperpolarizes the sinoatrial node, which is overcome by MRA and thus increases the heart rate.
What are muscarinic antagonists used for?
Drugs with muscarinic antagonist activity are widely used in medicine, in the treatment of low heart rate, overactive bladder, respiratory problems such as asthma and COPD, and neurological problems such as Parkinson's disease and Alzheimer's disease.
What is the function of muscarinic antagonists?
Notably, muscarinic antagonists reduce the activation of the parasympathetic nervous system. The normal function of the parasympathetic system is often summarised as "rest-and-digest", and includes slowing of the heart, an increased rate of digestion, narrowing of the airways, promotion of urination, and sexual arousal.
What are the antagonists of vasodilation?
Important muscarinic antagonists include atropine, Hyoscyamine, hyoscine butylbromide and hydrobromide, ipratropium, tropicamide, cyclopentolate, and pirenzepine .
Why is Belladonna called Belladonna?
The name "belladonna", Italian for "beautiful lady", is thought to derive from one of the antimuscarinic effects of these alkaloids: they were used by women for cosmetic purposes, to promote dilation of the pupils. Muscarinic antagonist effects and muscarinic agonist effects counterbalance each other for homeostasis .
Cholinergic-Blocking Drugs
Pharmacokinetics
Pharmcodynamics
Cautions and Contraindications
Adverse Reactions/Side-Effects
Drug Interactions
Key Points
- - Anticholinergic drugs are drugs that block the effects of acetylcholine at cholinergic receptor sites - Antimuscarinic drugs block acetylcholine at muscarinic receptors sites - Antimuscarinic drugs are indicated for urinary frequency, bladder instability, and nocturnal enuresis - Antimuscarinic drugs act by reducing the contractile activity of th...