*SKELETAL MUSCLE RELAXANTS*

NEUROMUSCULAR BLOCKING AGENTS

- affects SKELETAL MUSCLE FUNCTION
- used during SURGICAL PROCEDURES in ICUs for patients requiring VENTILATOR ASSISTANCE
2 basic mechanisms for blockade of endplate fxn:
Pharmacologic block of acetylcholine by neuromuscular blocking drugs prevent access of transmitter to its receptor prevent
DEPOLARIZATION
e.g. tubocurarine
blockade by excess of depolarizing agonist such as acetylcholine
e.g.succinylcholine

BASIC PHARMACOLOGY OF NEUROMUSCULAR BLOCKING DRUGS

Structural resemblance to acetylcholine
Presence of one or two quaternary nitrogen- making them poorly lipid soluble and limits entry into the central nervous system
Highly polar and inactive orally
Administered parenterally

2 GENERAL CLASSIFICATIONS
a. DURATION OF ACTION
long: d-tubocurarine, metocurarine, pancuronium
intermediate: vecuronium, atracurium, rocuronium(rapid onset)
short acting: mivacurium
b. CHEMICAL
natural alkaloids & congeners: d-tubocurarine
ammoniosteroids: pancuronium, pipecuronium, rucoronium, vecuronium
benzylisoquinolones: atracurium, doxacurium, mivacurium

Note: Skeletal Muscle Relaxants

- Nium
- Rium
- Rine
Shortcut:
A. Duration of Action-
Short= Gamay Monay = Mivacurium
Intermediate- Okay lang si Var= vecuronium, atracurium, rocuronium(rapid onset)
Long= Dako Mong Pitoy= d-tubocurarine, metocurarine, pancuronium
B. Chemical
Natural= -ARINE= Natural paRINE
Ammoniosteriods= -NIUM= AmmoNIUM
Benzylisoquinolones= -RIUM= BRIUM

Specific Agents:
1.Tubocurarine chloridegiven as a divided dose to reduce histamine release and ganglionic blockade
- Used cautiously to aid diagnosis of Myasthenia gravisalthough rarely
2.Metocurine iodide-a derivative of tubocurarine with lower potential for CVS effects
3.Pancuronium bromide greater potency than tubocurarine; LACK histamine releasing or ganglionic blocking actions; may increase HR if
vagal tone is high
4. Atracurium besylate intermediate; MINIMAL vagolytic activity or tendency to release histamine
5.Vecuronium bromide intermediate; LACK significant ganglionic vagolytic and histamine releasing activity
6.Succinylcholine chloride only available SHORT-ACTING depolarizing neuromuscular blocking agent

THERAPEUTIC CAUSES
- The main clinical use of neuromuscular blocking agent is as an ADJUVANT in surgical anesthesia to obtain relaxation of skeletal
muscle, particularly of the abdominal wall, to facilitate operative manipulation
- Also of value in various orthopedic surgeries such as correction of dislocations and alignment of fractures
- Neuromuscular blocking agents of short duration are often used to facilitate intubation with an endotracheal tube, facilitate
laryngoscopy, bronchoscopy and esophagoscopy in combination with a general anesthetic agent
- Control of ventilation in critically ill patients having ventilator failure; muscle paralysis to reduce chest wall resistance & ineffective
spontaneous ventilation
- Treatment of convulsions- used to attenuate peripheral manifestations of seizures associated with status epilepticus

SKELETAL MUSCLE AGENTS

- drugs that reduce spasticity in neurologic conditions
Spasticity vs Muscle Spasms
Spasticity
 o exaggerated muscle stretch reflex
o abnormal reflex activity is velocity-dependent
o a rapid lengthening of muscle resulting to a strong contraction in the stretched muscle
- occurs when supraspinal inhibition is lost or inhibited because of some lesion in the spinal cord or brain
- a motor sequelae to such pathologies as cerebral vascular accident, cerebral palsy; multiple sclerosis and traumatic lesions to brain
and spinal cord
Spasm- occurs abruptly, is painful, and is usually short-lived. It may be relieved by gently stretching the muscle
Skeletal Muscle Relaxants
Used to treat conditions associated with hypertonic skeletal muscle specifically spasticity & muscles spasms
Ultimate goal: decrease in muscle hypertonicity without a profound decrease in muscle function
2 general categories:
- Centrally acting
- Direct acting

CENTRALLY ACTING AGENTS/SPASMOLYTICS

1. Baclofen (p-chlorophenyl-GABA)
- ORALLY active GABA-mimetic agent
- derivative of central inhibitory neurotransmitter (GABA) gamma-aminobutyric acid, has preferential binding and exerts its
spasmolytic effect on GABA b receptors hyperpolarization increased K+ conductance presynaptic inhibition decreased
release of excitatory transmitters in brain and spinal cord
- Less sedation than diazepam
- Less muscle strength reduction than dantrolene
- Half-life: 3-4 hrs dose of 15 mg twice daily up to 100 mg
- Adverse effects: drowsiness but develops tolerance with chronic use; increase seizure activity in epileptic patients; fatigue, nausea,
dizziness, muscle weakness and headache

2. Diazepam works by increasing the central inhibitory effects of GABA

- Acts at GABAa receptor synapses action is reducing spasticity resulting from cord lesions and sometimes with cerebral palsy
- Can be used in patients with muscle spasm associated with musculoskeletal injuries
- Dose initial 4mg/d to a maximum of 60mg/d
- Adverse effects: sedation, respiratory depression; physical dependence
3. Tizanidine is an alpha agonist; has the ability to reduce muscle spasm.
- congener of clonidine
- Reinforces both presynaptic and postsynaptic inhibition in the spinal cord
- Also inhibits nociceptive transmission in the spinal dorsal horn
- Comparable efficacy in relieving muscle spasm to diazepam, baclofen and dantrolene
- Adverse effects: drowsiness, hypotension, dry mouth, asthenia
OTHER CENTRALLY ACTING SPASMOLYTIC DRUGS
1.Gabapentin an anti seizure drug that has spasmolytic effects multiple sclerosis
2.Pregabalina new analog of gabapentin
3. Progabide GABAa and GABAb agonist reduces spasticity
4.Glycine inhibitory amino acid neurotransmitter -reduces spasticity; orally given and crosses blood brain barrier
5.Idrocilamide and riluzole newer drugs that have spasm-reducing effects through inhibition of glutamergic transmission in the CNS are
treatment for amyotrophic lateral sclerosis

DIRECT ACTING RELAXANT

1.Dantrolene sodium hydantoin derivative that exerts its effect directly on the skeletal muscle cell
- Mechofaction: interferes with the release of calcium thru the sarcoplasmic reticulum by binding to the RyR(ryanodinereceptor)
channel and block the opening
- Dose: starts at 25mg once daily up to 100mg 4x a day; half life of 8h
- Adverse effects: generalized muscle weakness, sedation, occas hepatitis
- Malignant hyperthermia tx is dantrolene iv 1mg/kg repeating as needed to a maximum dose of 10mg/kg
2.Botulinum toxin use for ophthalmic purposes and for local muscle spasm
- Local facial injections are widely used for the short term treatment of wrinkles around the eyes and mouth
- Also useful treatment for generalized spastic disorders(cerebral palsy)

DRUGS USED TO TREAT ACUTE LOCAL MUSCLE SPASM

- Are used for the relief of of acute muscle spasm caused by local tissue trauma or muscle strains
- Act primarily at the level of the brainstem
- Prototype : Cyclobenzaprine(flexeril) structurally related to TCAs and possess antimuscarinic effects
- Other drugs: carisoprodol(Soma), chlorphenesin(Maolate), metaxalone(Skelaxin), methocarbamol(Robaxin) and
orphenadrine(Norgesic)
- Adverse effects: sedation, confusion and transient visual hallucinations
- Dose of cyclobenzaprine 20-40 mg/d in divided doses

BASIC PHARMACOLOGY OF OPIOID ANALGESICS

Morphine- Alkaloid-prototype opioid agonist
- source -Opium from poppy plant(Papaver somniferum and P album)
Opioid drugs full agonists, partial agonists and antagonists
Morphine is a
FULL AGONIST
on the mu
receptor

Chemical
Mediators in
the
Nociceptive
Pathway

1.Neurotransmitters :
- Serotonin most active histamine
- Bradykinin/kallidin in injury
2.Lactic acid, ATP & ADP ischemic pain
3. Capsaicin active substance in chili peppers
- highly potent pain-producing substance selective nociceptive & temperature sensitive nerve endings

Opiate Receptors
3 major classes
1. Mu or receptors most responsible for the analgesic property of drugs
2. Kappa or k receptors- endogenous ligand for K1 receptor is dynorphinA
3. Delta or D receptors enkephalins are the endogenous ligand

Endogenous Opioid Peptides

-peptides in parts of the CNS with opioid like properties
-morphine-like compounds mimic by opioid drugs for relief of pain & inducing euphoria
3 distinct families :
1. Enkephalins
2. Endorphins
3. Dynorphins
-appear to function as neurotransmitters, modulators or neurohormones

Classification of Narcotic Analgesics & Antagonists

Naturally Occurring Alkaloids & Semisynthetic Opiates (MoCoHyNa)
- Morphine
- Codeine(methylamine)
- Hydromorphone(dilaudid)
- Nalbuphine( nubain)
Benzomorphans (phans- P2))
- Phenazocine
- Pentazocine(talwin)
Morphinan Derivatives (De Bu Le)
- Levorphanol(levo-dromoran)
- Butorphanol(stadol)
- Dextromethorpan
Meperidine& Related Phenylpiperidines (MAAPD)
- Meperidine(demerol)
- Alphaprodine(nisentic)
 - Anileridine(leritine)
- Piminodine(alvodine)
- Diphenoxylate( in lomotil)
Methadone & Related Drugs (MP)
- Methadone(dolophine)
- Propoxyphene( darvon)
Narcotic Antagonists (allyl substituted compounds) (LNN)
- Nalorphine(nalline)
- Levallorphan(lorfan)
- Naloxone(narcan)
Pharmacokinetics
a. Absorptionmost opioid analgesics are well absorbed when given SQ, IM and oral routes
- Other routes nasal insufflation, oral lozenges and transdermal
b. Distribution all opioids bind to plasma proteins with varying affinity; drug localize in high concentrations in highly perfused tissuesbrain,
lungs, liver, kidneys & spleen; muscle main reservoir; fatty tissue-accumulation
c. Metabolism opioids are converted to polar metabolites(mostly glucuronides)
-Morphine metabolite M3G(morphine-3-glucuronide)-neuroexcitatoryeffects; M6G(morphine-6-glucuronide)-analgesic potency 4-
6x>morphine
-Hydromorphone metabolized by conjugation H3G(hydromorphone-3-glucuronide)-CNS excitatory effects
-Meperidinenormeperidineaccumulation seizures
d. Excretion polar metabolites including glucuronide conjugates of opioids excreted mainly in urine.

Pharmacodynamics
Mechanism of action:
1. Receptor types 3 major classes of opioid receptors- ,,members of G protein-coupled receptors
2. Cellular actions 2 direct G protein-coupled actions on neurons
a.) close voltage gated Ca++ channels on presynaptic nerve terminals reduce transmitter release
b.) hyperpolarize and thus inhibit postsynaptic neurons by opening K+ channels
3.majority of available opioid analgesics act primarily at the receptor
Effects: Analgesia, euphoria, respiratory depression & physical dependence
4.All three major receptors are present in high concentrations in the dorsal horn of the spinal cord. Receptors are present both on spinal cord
pain transmission neurons and on the primary afferents that relay pain messages. Opioids exert a powerful analgesic effect directly on the
spinal cord
5.With frequently repeated therapeutic doses of morphine and surrogates, there is gradual loss of effectivenessTolerance; physical
dependence developswithdrawal/abstinence syndrome

Tolerance
STRIKING FEATURE: GRADUAL TOLERANCE develops to the analgesic & respiratory effect
Chronic use both patients & addicts will require progressively larger doses to obtain the same effects
2 weeks of abstinence individual can again respond to small doses
No tolerance develops to GI & pupillary effect

Pharmacologic Effects
1.CNS
a. Analgesia
b. Euphoria -pleasant floating sensation with decrease anxiety & distress
c. Sedation disrupts REM/nonREM sleep patterns;drowsiness and clouding of mentation
d. . Respiratory depression inhibition of brainstem respiratory mechanisms; dose-related; depressed response to CO2 challenge; CO2
retention is responsible for cerebral vasodilatation & increased ICP
e. cough suppression
f. mioisis
g. truncal rigidity increase tone in large trunk muscles
h. nausea & vomiting activation of brainstem chemoreceptor trigger zone; vestibular component
i. temperature receptor hyperthermia; receptor -hypothermia

2. Peripheral effects
a. Cardiovascular- reduces arterial resistance & venous tone > postural hypotension
- beneficial in reduction of ventricular work, pulmonary congestion & edema
b. GIT-constipation mediated thru the enteric nervous system no tolerance; in large intestines decreased propulsive peristalsis with increased
tone
c. Biliary tract increase intrabiliary pressure by contracting smooth muscle of biliary tract biliary colic
d. renal renal function is depressed by opioids due to decreased renal plasma flow; antidiuretic effect
e. uterus opioids prolong labor ->due to reduce uterine tone
f. neuroendocrine stimulate release of ADH, prolactin, and somatotropin but inhibits release of LH
g. pruritus therapeutic doses produce flushing and warming of skin accompanied by sweating & itching; appear more frequently when given
IV
h. miscellaneous modulate immune system by effects on lymphocyte proliferation, antibody production and chemotaxis; reduce resistance
to infection

Opioid effects with both agonist & antagonist actions

Buprenorphine
Opioid mixed agonist antagonist
High binding affinity but low intrinsic activity receptor
used as an alternative to methadone for mgt of opioid withdrawal; functions as antagonist to and receptors
Pentazocine and albuphinemixed agonist-antagonists

CLINICAL USE OF OPIOID ANALGESICS

1.Analgesia severe constant pain associated with cancer & other terminal illnesses
2. acute pulmonary edema reduced anxiety, decreased preload & afterload
3. cough suppression of cough
4. diarrhea loperamide; diphenoxylate
5. shivering meperidinemost pronounced anti-shivering properties
6. applications in anesthesia premedicant drugs before anesthesia & surgery; intraop as adjunct to anesthetic agents; regional analgesics-
epidural

Routes of administration
1. oral /intravenous
2. rectal
3. transdermal patch fentanyl chronic pain
4. intranasal butorphanol
5. buccal/transmucosal
6. PCA(patient-controlled analgesia)

Toxicity & undesired effects

1.tolerance- clinically manifests after 2-3 wks of frequent receiving therapeutic doses; cross-tolerance
2. physical dependence- accompanies devt of tolerance; withdrawal or abstinence syndrome
3. psychologic dependence- compulsive use due to euphoria, indifference to stimuli & sedation

Poisoning
Acute Morphine Poisoning
is comatose & cyanotic
respiration slow or absent
pinpoint pupils
Mgt:
antagonist of choice IV Naloxone reverses respiratory depression dramatically
very specific
Codeine or Methylmorphine
analgesic & antitussive
in therapeutic doses less sedating & analgesic
Tolerance develop more slowly
Less effect in GIT, GUT & pupils
Most frequently prescribed
-Used in oral doses for mod severe pain in combination w/ ASA & paracetamol; severe pain IQ or IV
-Excreted in urine]

Other semisynthetic Derivatives

Oxymorphone( numorphan) more potent than morphine but more side effects
Hydromorphone(dilaudid) also more potent in producing analgesia & respdepression
Heroin highly euphoriant & analgesic drug
o preferred by addicts
o not legally manufactured

Meperidine& Related Compounds

Meperidine(pethidine, demerol, dolantin)
1st introduced as an antispasmodic of the atropine type
most frequently used for parenteral impatient analgesia
produces resp depression; no antitussive activity
cause mydriasis & tachycardia
definitively addictive
IV severe hypotension
metabolized liver toxic to px with liver dse
 drug interaction severe MAO inhibitors
Pharmacokinetics
o Onset: 10 to 15 minutes
o Peak: 30 to 50 minutes
o Duration: 2 to 4 hours
Fentanyl
potent lipophilicopioid
used as an IM or IV analgesic in balanced anesthesia with nitrous oxide & oxygen
skeletal muscle rigidity, resp depression
Pharmacokinetics
o Intramuscular
Onset: 7 to 15 minutes
Duration: 1 to 2 hours
o Intravenous
Onset: minutes
Duration: 30 to 60 minutes
Precautions: Oversedation
Antagonist: Naloxone (Narcan)
Propoxyphene
widely prescribed drug
similar analgesic potency with Codeine
weak analgesic oral admin combination with ASA or acetaminophen
dextroisomer: used for analgesia
levoisomer: used as an antitussive
overdoses ----death
Mixed Agonists & Antagonists
Pentazocine(talwin)
analgesic
weak narcotic antagonist
moderate potency-short duration
SQ & IM route
Nalbuphine HCl(nubain)
equivalent to morphine in analgesic potency
as antagonist potency of nalorphine
postoperative use to relieve opioid-induced resp depression while maintaining anesthesia
Butorphanoltartrate(stadol)
5x analgesic potency of morphine & 1/40 antagonist potency of naloxone
clinical use & abuse comparable to pentazocine
available as injectable
Buprenorphine
30x more potent than morphine
analgesic effect 6-8 h
potential as an alternative to methadone for detoxification & maintenance of cocaine abuse
Antitussive Drugs [(HD) High Definition Ubo]
Hydrocodone bitartrate
more potent antitussive than codeine
addiction liability greater
available only in combination
Dextromethorpan
same antitussive potency as codeine
no analgesic or respdepression eff
widely used as cough suppressant
CNS depressant in higher doses
Narcotic Antagonists
Nallorphone(nalline)
is an N-allylnormorphine
antagonizes all effects of morphine & other opioids
action : competitive inhibition of drugs to mu receptors
use as an antidote in morphine poisoning
administered in doses of 5-10 mg by IV route not to exceed 40 mg
Naloxone HCl (narcan)
N-allylderivative of oxymorphoneHCl
important & specific narcotic antagonist
duration of action 1h
 usual dose: 0.4 mg IV repeated at 3 min interval 2-3x
reverses resp depression eff of narcotics
differs fro ther antagonist : does not cause resp depression, no pupillary constriction, no sedative effect, no analgesia
-Indication: Narcotic overdosage
o Respiratory depression
o Sedation
o Hypotension
o Hypoperfusion
-Narcotic examples reversed by naloxone
o Heroin
o Methadone
o Pentazocine
o Propoxyphene
Precautions:
Recurrence of Narcotic intoxication
o Occurs if Narcotic half life is longer than naloxone
o Infusion may be useful with longer acting Opioid
Infants born to addicted mothers
o Naloxone may precipitate acute withdrawal or Seizures
Restrain patient overdose prior to administration
o May precipitate withdrawal

Medical Conditions Generally Considered Contraindications to Use of Morphine & Related Drugs
1.Head injuries
2. Bronchial asthma & other hypoxic states
3. Acute alcohol intoxication
4. Convulsive disorders
5. Undiagnosed acute abdominal conditions
6. pregnancy
7. endocrine diseases