Centrally Acting Antispastic Drugs

Few points on centrally acting antispastic medications,pharmacokinetics and sideffects

1. Centrally Acting Antispastic Drugs

2. Introduction A   muscle relaxant  is a drug which affects  skeletal muscle  function and decreases the  muscle tone used to alleviate symptoms such as muscle  spasms, pain, and  hyperreflexia. Muscle Relaxants classified as: 1. Neuromuscular Junction Blockers 1.1. depolarizing 1.2. Nondepolarizing muscle relaxant   2. Spasmolytics

3. 1. Neuromuscular Junction Blockers Can be; 1.1. Depolarizing 1.2. Nondepolarizing Muscle Relaxants Neuromuscular blockers act by interfering with transmission at the neuromuscular end plate and have no  central nervous system (CNS) activity. Important for induction of muscle paralysis as part of preoperative general anesthesia.

4. 2. Spasmolytics Spasmolytics , also known as "centrally acting" muscle relaxants Used to alleviate  musculoskeletal pain and spasms and to reduce  spasticity Both neuromuscular blockers and spasmolytics are often called muscle relaxants It is often associated with cerebral palsy, multiple sclerosis, and stroke. The generation of the neuronal Signals in motor neurons that cause muscle contractions are dependent on the: balance of synaptic excitation and inhibition the motor neuron receives

5. What is muscle spasm? Muscle spasms is defined as an involuntary muscular contraction A painful muscle spasm is typically referred to as a muscle cramp Spasticity is defined as a muscle tone disorder characterized by hyperactive tonic stretch reflexes thought to arise from an im balance of excitatory and inhibitory neurotransmitters

6. Cont’d… Spasmolytic agents generally work by either enhancing the level of inhibition , or r educing the level of excitation Inhibition is enhanced by mimicking or enhancing the actions of endogenous inhibitory substances, such as  GABA The mechanisms underlying clinical spasticity appear to involve not only the stretch reflex arc itself but also H igher centers in the central nervous system (ie, upper motor neuron lesion), with damage to descending pathways in the spinal cord resulting in hyperexcitability of the alpha motoneurons in the cord.

7. Baclofen Baclofen has commonly been used for its muscle relaxant effects in the treatment of spasticity Baclofen   is as effective as diazepam in reducing spasticity Causes much less sedation Mechanism Of Action Acts as a GABA  agonist at GABA B  receptors in the brain and spinal cord Potassium Ion Conductance Hyperpolarization calcium ion influx   Release of excitatory neurotransmitters substance P

8. Baclofen also inhibits neural function presynaptically Reducing the in both the brain and spinal cord It may also reduce pain in patients by inhibiting the release of  substance P  in the spinal cord, as well Studies have confirmed that intrathecal administration of baclofen can control severe spasticity and muscle pain that is not responsive to medication by other routes of administration Partial tolerance to the effect of the drug may occur after several months of therapy, but can be overcome by upward dosage adjustments to maintain the beneficial effect Cont’d…

9. Pharmacokinetics Metabolized in the liver and excreted in the urine Baclofen can be administered orally as well as intrathecally Baclofen is rapidly and effectively absorbed after oral administration It is lipophilic and able to penetrate the blood-brain barrier Approximately 35% of the drug is excreted unchanged in the urine and feces side effects Common are weakness, sedation, and dizziness At higher doses, baclofen can cause seizures, ataxia, and hallucinations Abrupt withdrawal should be avoided because it can precipitate seizures and hallucinations Cont’d…

10. Diazepam The   benzodiazepines , such as   diazepam , interact with the  GABA A   receptor  in the central nervous system Its action in reducing spasticity is at least partly mediated in the spinal cord because it is somewhat effective in patients with cord transection While it can be used in patients with muscle spasm of almost any origin Produces sedation in most individuals at the doses required to reduce muscle tone

11. Tizanidine Clonidine   and other imidazoline compounds have also been shown to reduce muscle spasms by their central nervous system activity.  T izanidine   is an agonist at  α 2 adrenergic receptor Reduces spasticity at doses that result in significantly less hypotension   than clonidine  Neurophysiologic studies show that it depresse s excitatory feedback from muscles that would normally increase muscle tone, therefore minimizing spasticity   Several clinical trials indicate that tizanidine has a similar efficacy to other spasmolytic agents, such as diazepam and baclofen, with a different spectrum of adverse effects

12. Tizanidine is a centrally acting muscle relaxant that, through its alpha-2 adrenergic agonist properties Thought to prevent the release of excitatory amino acids by suppressing polysynaptic excitation of spinal cord interneurons Even though tizanidine’s pharmacologic effect is similar to another alpha-2 agonist like clonidine , but It possesses only a fraction of its blood pressure–lowering effect Cont’d…

13. Other Centrally Acting - Spasmolytic Drugs Gabapentin A n antiepileptic drug that has shown considerable promise as a spasmolytic agent in several studies involving patients with multiple sclerosis Pre gabalin is a new analog of gabapentin that may also prove useful Progabide and glycine H ave also been found in preliminary studies to reduce spasticity Progabide is a GABA A and GABA B agonist and has active metabolites, including GABA itself

14. Glycine I s another inhibitory amino acid neurotransmitter It appears to possess pharmacologic activity when given orally and readily passes the blood-brain barrier Idrocilamide and riluzole N ewer drugs for the treatment of amyotrophic lateral sclerosis H ave spasm-reducing effects, possibly through I nhibition of glutamatergic transmission in the CNS Cont’d…

15. Spasmolytic Drugs Side Effects Because of the enhancement of inhibition in the CNS most spasmolytic agents have the side effects Sedation Drowsiness and Dependence with long-term use Several of these agents also have abuse potential, and their prescription is strictly controlled!!!

16. The most commonly used muscle relaxant for non spasticity-related muscle pain Structurally, it resembles tricyclic anti-depressants(TCAs) Its therapeutic effect is centrally mediated and carries no direct peripheral action on the affected muscles Its main pharmacologic action occurs at the brainstem and spinal cord levels and is partially explained by a depressant effect on the descending serotonergic neurons Cyclobenzaprine

17. Methocarbamol It is a centrally acting muscle relaxant that suppresses spinal polysynaptic reflexes and has no direct effect on skeletal muscle Orphenadrine Structurally related to diphenhydramine and carries relativelystronger anticholinergic and weaker sedative properties Its exact mechanism of action is unknown Common side effects include drowsiness and dizziness, followed by other central nervous system effects such as agitation, hallucinations, and euphoria Cont’d…

18. Quinine Antimalarial , antipyretic, analgesic, and muscle relaxant effects Prescribed for the R x of nocturnal leg muscle cramps Increase the refractoriness of muscle and to decrease the excitability of the neuromuscular endplate Metaxalone Metaxalone is a centrally acting muscle relaxant with an unknown mechanism It is metabolized in the liver and excreted through the kidneys in the form of metabolites Cont’d…

19. Carisoprodol Carisoprodol is still a commonly prescribed muscle relaxant that should caution owing to the Potentially addictive properties of its main metabolite, meprobamate Carisoprodol produces its muscle relaxant effect by depressing the interneuronal activity at the Spinal cord level aswell as in the descending tracts of the reticular formation It is not recommended in the pediatric age population Cont’d…

20. Botulinum toxin type A, B These neurotoxins exert their pharmacologic effect at the neuromuscular junction (NMJ) Prevent the calcium-dependent release of acetylcholine Producing a state of temporary drug-induced denervation The therapeutic effect can take up to 1 week to take place fully and can last up to 3 months, at which point repeat injections can be considered Caution should be exercised in using appropriate botulinum dosing to avoid functionally limiting muscle weakness

21. Benzodiazepines (diazepam, lorazepam, clonazepam, etc) Diazepam has commonly been used in the treatment of muscle spasm especially in the acute setting It belongs to a group of compounds called benzodiazepines known for their potent anxiolytic , sedative, as well as muscle Mechanism of action Their main mechanism of action is through central potentiation of the inhibitory g- aminobutyric acid (GABA) effect through presynaptic Facilitation of GABA release

22. Antispastic agents Antispastic drugs are principally used for the treatment of spasticity observed in disease states with upper motor neuron pathology such as Stroke Spinal cord injury Traumatic brain injury, and Multiple sclerosis All but two of these agents exert their clinical effect through centrally mediated mechanisms

23. Dantrolene Dantrolene reduces muscle spasms by inhibiting the release of calcium from the sarcoplasmic reticulum and does not directly affect the CNS Because dantrolene tends to produce greater muscle weakness than baclofen, It should not be the first-line agent for patients who are capable of ambulation

24. End of discussion…….! relax