Antispasmodics and Spasmolytic Drugs.pdf

ANTISPASMODICS AND SPASMOLYTIC DRUGS ANTISPASMODICS Spasm means a sudden, brief, unintended (involuntary), and usually painful contraction of a muscle or group of muscles. Muscle spasm (cramps) is not always related to an underlying condition. It may be caused by: Dehydr...

ANTISPASMODICS AND SPASMOLYTIC DRUGS ANTISPASMODICS Spasm means a sudden, brief, unintended (involuntary), and usually painful contraction of a muscle or group of muscles. Muscle spasm (cramps) is not always related to an underlying condition. It may be caused by: Dehydration Vigorous exercise Physical labour Certain medications It may however signify an underlying health condition. These conditions include heat exhaustion, liver cirrhosis, neuropathies, lockjaw, lumbar spinal stenosis Spasmodic means occurring in briefs, irregular bursts. Hence, antispasmodics, chiefly of a drug are used to relieve spasm of involuntary muscle Antispasmodics: These are a broad group of medicines that act on the neurotransmitter, acetylcholine. They are also called anticholinergics. By blocking the action of acetylcholine, anticholinergics prevent impulses from the parasympathetic nervous system from reaching smooth muscle and causing contractions, cramps or spasms. Anticholinergics are used in the treatment of some gastrointestinal and bladder conditions. They may also be used in the treatment of some respiratory or movement disorders. Anticholinergics block acetylcholine from binding to its receptors on certain nerve cells. They inhibit actions called parasympathetic nerve impulses. These nerve impulses are responsible for involuntary muscle movements in the: gastrointestinal tract, lungs, urinary tract, other parts of the body. The nerve impulses help control functions such as salivation, digestion, urination and mucus secretion. Blocking acetylcholine signals can decrease involuntary muscle movement, digestion, mucus secretion. That’s why these drugs can cause certain side effects, such as, urinary retention, having a dry mouth, etc. The anticholinergics are muscarinic antagonists, often referred to as parasympatholytic, because they selectively block the effects of parasympathetic nerve activities. They are all competitive antagonists, and their chemical structures usually contain ester and basic groups in the same relationship as acetylcholine. Atropine and hyoscine are two naturally occurring compounds in this group. Effects of antispasmodics/anticholinergics/muscarinic antagonists i. Inhibition of secretion: Salivary, bronchial, lacrimal and sweat glands ii. Effects on heart rate: Atropine causes tachycardia through the block of cardiac muscarinic receptors. iii. Effects on the eye: The pupil is dilated by atropine administration (mydriasis). It becomes unreactive to light under this condition. Relaxation of the ciliary muscle causes paralysis of accommodation (cycloplegia). This causes impairment of near vision, and can be dangerous in patients with narrow angle glaucoma. iv. Effects on the gastrointestinal tract: Gastrointestinal tract motility is inhibited by atropine, because excitatory transmitters other than acetylcholine are important in normal function of of the myenteric plexus. v. Effects of other smooth muscles: Bronchial, biliary and urinary tract smooth muscles are all relaxed by atropine. Reflex bronchoconstriction during anaesthesia is prevented be atropine. vi. Effects on the central nervous system: Atropine produces mainly excitatory effects on the CNS. At low doses it causes mild restlessness and at high doses agitation and disorientation. Uses Anticholinergics are used to treat a variety of conditions. These include chronic obstructive pulmonary disease (COPD), overactive bladder and incontinence, gastrointestinal disorders, such as diarrhea, asthma, dizziness and motion sickness, poisoning caused by toxins such as organophosphates or muscarine, which may be found in some insecticides and poisonous mushrooms, symptoms of Parkinson’s disease, such as abnormal involuntary muscle movement Anticholinergics can also be used as muscle relaxants during surgery to assist with anesthesia. They help to keep the heartbeat normal, relax the person, decrease saliva secretions. Overdose and concurrent use with alcohol Using too much of an anticholinergic drug can result in unconsciousness or even death. These effects can also happen if you take anticholinergics with alcohol. Signs of an overdose include dizziness, severe drowsiness, fever, severe hallucinations, confusion, trouble breathing, clumsiness and slurred speech, fast heartbeat, flushing and warmth of the skin. Examples of anticholinergics The anticholinergics include atropine (Atropen), belladonna alkaloids, benztropine mesylate (Cogentin), clidinium, cyclopentolate (Cyclogyl), darifenacin (Enablex), dicylomine, fesoterodine (Toviaz), flavoxate (Urispas), glycopyrrolate, homatropine hydrobromide, hyoscyamine (Levsinex), ipratropium (Atrovent), orphenadrine, oxybutynin (Ditropan XL), propantheline (Pro-banthine), scopolamine, methscopolamine, solifenacin (VESIcare), tiotropium (Spiriva), tolterodine (Detrol), trihexyphenidyl, trospium. Acetylcholine Acetylcholine is the neurotransmitter at neuromuscular junctions, at synapses in the ganglia of the visceral motor system, and at a variety of sites within the central nervous system. Whereas a great deal is known about the function of cholinergic transmission at the neuromuscular junction and at ganglionic synapses, the actions of ACh in the central nervous system are not as well understood. Acetylcholine is synthesized in nerve terminals from acetyl coenzyme A (acetyl CoA, which is synthesized from glucose) and choline, in a reaction catalyzed by choline acetyltransferase (CAT). The presence of CAT in a neuron is thus a strong indication that ACh is used as one of its transmitters. Choline is present in plasma at a concentration of about 10 mM, and is taken up into cholinergic neurons by a high-affinity Na+/choline transporter. About 10,000 molecules of ACh are packaged into each vesicle by a vesicular ACh transporter. In contrast to most other small-molecule neurotransmitters, the postsynaptic action of ACh at many cholinergic synapses (the neuromuscular junction in particular) are not terminated by reuptake but by a powerful hydrolytic enzyme, acetylcholinesterase (AChE). This enzyme is concentrated in the synaptic cleft, ensuring a rapid decrease in ACh concentration after its release from the presynaptic terminal. AChE has a very high catalytic activity (about 5000 molecules of ACh per AChE molecule per second) and hydrolyses ACh into acetate and choline. As already mentioned, cholinergic nerve terminals typically contain a high-affinity, Na+-choline transporter that takes up the choline produced by ACh hydrolysis. Among the many interesting drugs that interact with cholinergic enzymes are the organophosphates. Compounds such as diphenyl trichloroethane (DTT) and the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) were originally developed as insecticides. This group also includes some potent chemical warfare agents. One such compound is the nerve gas “Sarin,” which was made notorious a few years ago after a group of terrorists released this gas in Tokyo's underground rail system. Organophosphates can be lethal to humans (and insects) because they inhibit AChE, causing ACh to accumulate at cholinergic synapses. This build-up of ACh depolarizes the postsynaptic cell and renders it refractory to subsequent ACh release, causing, among other effects, neuromuscular paralysis SPASMOLYTIC DRUGS Certain chronic diseases of the CNS (eg, cerebral palsy, multiple sclerosis, stroke) are associated with abnormally high reflex activity in the neuronal pathways that control skeletal muscle; the result is painful spasm. Bladder control and anal sphincter control are also affected in most cases and may require autonomic drugs for management. In other circumstances, acute injury or inflammation of muscle leads to spasm and pain. Such temporary spasm can sometimes be reduced with appropriate drug therapy. The goal of spasmolytic therapy in both chronic and acute conditions is reduction of excessive skeletal muscle tone without reduction of strength. Reduced spasm results in reduction of pain and improved mobility. Drugs for Chronic Spasm Classification: The spasmolytic drugs do NOT resemble ACh in structure or effect. They act in the CNS and in one case in the skeletal muscle cell rather than at the neuromuscular end plate. The spasmolytic drugs used in treatment of the chronic conditions mentioned previously include diazepam, a benzodiazepine; baclofen, a γ-aminobutyric acid (GABA) agonist; tizanidine, a congener of clonidine; and dantrolene, an agent that acts on the sarcoplasmic reticulum of skeletal muscle agents are usually administered by the oral route. Refractory cases may respond to chronic intrathecal administration of baclofen. Botulinum toxin injected into selected muscles can reduce pain caused by severe spasm and also has application for ophthalmic purposes and in more generalized spastic disorders (eg, cerebral palsy). Gabapentin and pregabalin, antiseizure drugs, have been shown to be effective spasmolytics in patients with multiple sclerosis. Mechanisms of action: The spasmolytic drugs act by several mechanisms. Three of the drugs (baclofen, diazepam, and tizanidine) act in the spinal cord. Baclofen acts as a GABAB agonist at both presynaptic and postsynaptic receptors, causing membrane hyperpolarization. Presynaptically, baclofen, by reducing calcium influx, decreases the release of the excitatory transmitter glutamic acid; at postsynaptic receptors, baclofen facilitates the inhibitory action of GABA. Diazepam facilitates GABA-mediated inhibition via its interaction with GABAA receptors. Tizanidine, an imidazoline related to clonidine with significant α2 agonist activity, reinforces presynaptic inhibition in the spinal cord. All 3 drugs reduce the tonic output of the primary spinal motoneurons. Dantrolene acts in the skeletal muscle cell to reduce the release of activator calcium from the sarcoplasmic reticulum via interaction with the ryanodine receptor (RyR1) channel. Cardiac muscle and smooth muscle are minimally depressed. Dantrolene is also effective in the treatment of malignant hyperthermia, a disorder characterized by massive calcium release from the sarcoplasmic reticulum of skeletal muscle. Though rare, malignant hyperthermia can be triggered by general anesthesia protocols that include succinylcholine or tubocurarine. In this emergency condition, dantrolene is given intravenously to block calcium release. Toxicity: The sedation produced by diazepam is significant but milder than that produced by other sedative-hypnotic drugs at doses that induce equivalent muscle relaxation. Baclofen causes somewhat less sedation than diazepam, and tolerance occurs with chronic use withdrawal should be accomplished slowly. Tizanidine may cause asthenia, drowsiness, dry mouth, and hypotension. Dantrolene causes significant muscle weakness but less sedation than either diazepam or baclofen. Drugs for Acute Muscle Spasm Many drugs eg, cyclobenzaprine, metaxalone, methocarbamol, orphenadrine are promoted for the treatment of acute spasm resulting from muscle injury. Most of these drugs are sedatives or act in the brain stem. Cyclobenzaprine, a typical member of this group, is believed to act in the brain stem, possibly by interfering with polysynaptic reflexes that maintain skeletal muscle tone. The drug is active by the oral route and has marked sedative and antimuscarinic actions. Cyclobenzaprine may cause confusion and visual hallucinations in some patients. None of these drugs used for acute spasm is effective in muscle spasm resulting from cerebral palsy or spinal cord injury. Patients with renal failure often have decreased levels of plasma cholinesterase, thus prolonging the duration of action of mivacurium or succinylcholine. Bibliography Brunton LL, Lazo JS and Parker KL, editors; Goodman and Gilman’s The Pharmacological Basis of therapeutics, 11th ed. McGraw-Hill, 2006. Katzung BG, editor: Basic & Clinical Pharmacology, 10th ed. McGraw-Hill, 2007. Purves D, Augustine GJ, Fitzpatrick D, et al., editors. Neuroscience. 2nd edition. Sunderland (MA): Sinauer Associates; 2001. Acetylcholine. Available from: https://www.ncbi.nlm.nih.gov/books/NBK11143. Rang HP et al., Pharmacology 5th ed. Churchill Livingstone, 2003. Trevor AJ et al. editors: Pharmacology Examination & Board Review 10th ed. McGraw-Hill, 2013.