Define Muscle relaxants Classification and pharmacology properties . Toxicology of muscle relaxants How to investigate muscle relaxant toxicity and managing.

1. Khaled A. Alrasheedi
PharmD, Clinical Toxicologist

2. At the end of the lecture we will be
able to know :
• Define Muscle relaxants
• Classification and pharmacology properties .
• Toxicology of muscle relaxants
• How to investigate muscle relaxant toxicity and
managing.

3. Defenation
• Medications that act as central nervous system depressants
and have sedative and musculoskeletal relaxant properties.
• Used in addition to rest, physical therapy, and other
measures to relieve discomfort, muscle relaxants are
beneficial for short-term use for acute, painful
musculoskeletal conditions.

4. Pharmacology of Muscle Relaxant
• Classification
 Peripherally acting (Neuromuscular blockers).
 Succinylcholine ( Ach Agonist )
 Centrally acting skeletal muscle relaxants
 e.g. Baclofen ( GABAB receptors agonist )
 - Diazepam ( GABAA receptors agonist )
 Direct acting skeletal muscle relaxants
▫ e.g. Dantrolene ( act directly by interfering
release of calcium )

5. Pharmacokinetics
 Absorption :
• Baclofen is rapidly and completely absorbed from the
gastrointestinal tract with therapeutic dosing. And Penetration
of the blood-brain barrier is limited at therapeutic doses.
• Carisoprodol is rapidly absorbed after ingestion.
• Cyclobenzaprine is slowly but completely absorbed after ingestion.
 Metabolism of the muscle relaxants is primarily hepatic, and
elimination is primarily renal.

6. Common Clinical Uses
• Peripherally acting (Neuromuscular blockers)
1- Adjuvant in general anesthesia
2- Intubation and endoscopies
• Centrally acting skeletal muscle relaxants
1- Acute muscle spasm
2- Anxiety and tension
• Direct acting skeletal muscle relaxants
1- Manage spasticity
2- Malignant Hyperthermia

7. Choice of Agent
• Therapeutic selection of a neuromuscular blocking agent should be
based on achieving a pharmacokinetic profile consistent with
the duration of the interventional procedure and minimizing
cardiovascular compromise or other side effects.
• Two characteristics are useful in distinguishing side effects and
pharmacokinetic behavior of neuromuscular blocking agents.
• 1- Relates to the duration of drug action:
( long-, intermediate-, or short-acting )
2- The chemical nature of the agents

8. Choice of Agent

9. Selected At-Risk Patient Populations
• With the exception of cyclobenzaprine, safety in pregnancy is
uncertain (category C).
Muscle Relaxant SPECIAL POPULATIONS
Cyclobenzaprine presumed safe in pregnancy (category B)
Carisoprodol is concentrated in breast milk and is considered
unsafe in lactation
Baclofen and tizanidine should be used cautiously in patients with renal
insufficiency.
Tizanidine and dantrolene contraindicated in the setting of liver disease
Orphenadrine and carisoprodol associated with acute porphyria and are
contraindicated in patients with porphyria.

10. Adverse Drug Interactions
• All skeletal muscle relaxants have the potential for adverse
drug interactions with other CNS depressants.
• Baclofen and levodopa administration has resulted in
hallucinations and worsening of parkinsonian symptoms.
• Chlorzoxazone metabolism is decreased with concomitant
disulfiram administration and in slow acetylators on
isoniazid.
• Oral contraceptive use has been associated with decreased
tizanidine clearance, while tizanidine use is associated with
decreased phenytoin clearance.

11. TOXICOLOGY
• Adverse Effects with chronic use and Acute intoxication

12. Botulinum toxin
 Onabotulinum toxin A ( BOTOX)
• Uses to Control of Muscle Spasms
• Its dermatological uses include treatment of hyperhidrosis of
the palms. (involves local intramuscular or intradermal injections )
• a popular cosmetic procedure for those seeking a wrinkle-
free face.
• The FDA has issued a safety alert, warning of respiratory paralysis
from unexpected spread of the toxin from the site of injection.

13. Reversal of Effects by Chelation Therapy.
• Now There is an investigational chelating agent specific for
Rocuronium and Vecuronium, Sugammadex (BRIDION).
 Dose :
• Administration of sugammadex at doses >2 mg/kg is able to reverse
neuromuscular blockade from Rocuronium within 3 minutes.
• The majority of sugammadex and its complex with Rocuronium is
eliminated in the urine.
• In patients with impaired renal function  should be avoided.
 Side effects include :
1. Dysgeusia
2. Rare self-limiting hypersensitivity.

14. Investigations
• Diagnosis of skeletal muscle relaxant poisoning is based on
History and clinical examination. Although analytic
laboratory monitoring methods exist to confirm exposure to these
agents.
• Baclofen may be detected in serum using either high-
performance liquid chromatography or gas
chromatography/mass spectrometry technology.
• Therapeutic serum concentrations range from 80 to 395 ng/mL
• Postmortem levels of 17 μg/mL have been reported 12 hours after
ingestion.

15. Investigations
• Orphenadrine therapeutic blood levels are less than 0.2
μg/mL, while moderate effects have been described at levels
of 5.1 μg/mL and severe effects at 12.3 μg/mL.
• Postmortem levels have ranged from 7 to 33 μg/mL.
• Carisoprodol therapeutic serum levels range from 4 to 7
mg/L, while coma has been reported with a serum level of
13.4 mg/L 19 hours after ingestion, and death has been reported
with a level of 36 mg/L 4.5 hours after ingestion.

16. Investigations
• No specific laboratory analyses are routinely
indicated, and clinical investigations are directed
toward identification of end-organ toxicity.
• Creatine phosphokinase, electrolytes, and urine output
should be monitored in patients with prolonged seizures
or coma.
• Serum glucose should be rapidly determined in patients
presenting with altered mental status.
• Coagulation studies and hepatic transaminase levels are
indicated in Orphenadrine intoxication

17. Investigations
• Electrocardiographic monitoring should be considered
to detect the presence of conduction abnormalities and
dysrhythmias.
• Computed Tomography of the head and
Electroencephalographic
• assessment may be indicated to evaluate altered mental
status, prolonged coma, and status epilepticus.

18. Differential Diagnosis
The differential diagnosis for
tizanidine intoxication includes :
opiates and opioids, clonidine and
imidazolines, organophosphates
and carbamates, and olanzapine.

19. MANAGEMENT
• Management of skeletal muscle relaxant toxicity is
primarily supportive, focusing on respiratory, CNS,
and cardiovascular monitoring.
• Cardiovascular toxicity predominantly presents as
hypotension, bradycardia, or tachycardia.
• Hypotension  intravenous crystalloid boluses
• Bradycardia  Atropine
• psychomotor agitation or seizures  Benzodiazepines

20. MANAGEMENT
• Activated charcoal administration may be considered
for patients presenting within 1 hour from time of
ingestion
• Whole bowel irrigation may be considered after
ingestion of sustained-release preparations.
• Hemodialysis is not beneficial in the management
of skeletal muscle relaxant toxicity.

21. Agent-Specific Management Strategies
Antidotal Muscle relaxant Indication Dose
Atropine Baclofen
tizanidine
Bradycardia and
hypotension
Adult: 0.5–1 mg IV every 5
min
(maximum dose 3 mg).
Pediatrics: 0.02 mg/kg
every 5 min
minimum 0.1 mg, maximum
dose
Physostigmine Baclofen
Cyclobenzaprine
Orphenadrine
Severe antimuscarinic
syndrome
Adult: 1–2 mg IV over 5 min
(may repeat once)
Pediatrics:
0.02 mg/kg IV
maximum dose 0.5 mg)

22. Agent-Specific Management Strategies
Antidotal Muscle relaxant Indication Dose
Flumazenil Carisoprodol
Chlorzoxazone
CNS depression Adult: 0.2 mg IV over 30 s
every 1 min
(maximum dose 5 mg)
Pediatrics: 0.01 mg/kg IV
over 30 s every 1 min
(maximum dose 1 mg
Naloxone Tizanidine CNS depression Adult: 0.4–2 mg IV
(maximum dose 10 mg)
Pediatrics ≤ 20 kg: 0.01
mg/kg, then 0.1 mg/kg
if needed
Pediatrics > 20 kg: 0.4–2
mg IV (maximum
dose 10 mg)
Cyprohepatidine baclofen Withdrawal Adult: 4–8 mg PO every 1–4
hr until therapeutic response
(maximum dose 32 mg/day)
Pediatrics: 0.25 mg/kg/day
PO divided every 6 hr
(maximum dose 12 mg/day)

23. References
• Haddad and Winchester's clinical management of poisoning and
drug overdose 4th edition.
• Goodman and Gilman the pharmacological basis of therapeutics
13th edition.

24. • Thank you