pharm quiz 2

• Nicotinic Acetylcholine Receptor (nAch)

  Receptor for the neurotransmitter acetylcholine that is found on skeletal muscle

  
• Skeletal Muscle Blocking Drugs block the effects of acetylcholine at the nicotinic-muscle (Nm) receptor
• Nondepolarizing blockers


  One of the two basic types of skeletal muscle blocking drugs
• Order of Muscle Paralysis

  1. 1st - small muscles of face, eyes, head, neck

  2. 2nd - muscles of limbs, then trunk

  3. 3rd - respiratory muscles (intercostals) with the diaphragm last
• Recovery from Muscle Paralysis

  Recovery is in the reverse order of paralysis
• Nondepolarizing blockers


  • Block nAch receptor sites
  • Also block prejunctional Na channel
  • Effects can be reversed by acetylcholinesterase inhibitors (e.g. neostigmine, pyridostigmine)

  
• Tubocurarine


  • Prototype nondepolarizing blocker, less used today
  • Quaternary N, charged, requires IV administration, eliminated unchanged in urine
  • Also binds to ganglionic receptors to cause ganglionic blockade, hypotension
  • Causes histamine release > bronchospasm, hypotension, increased salivary/GI secretions, hives

  
• Atracurium


  • Nondepolarizing blocker at nAch receptor sites
  • Intermediate duration, < 1 hour; minimizes muscle pain during surgery
  • Little histamine release and no cardiac effects, minimal hypotension
  • Inactivated in plasma and undergoes spontaneous decomposition, a degradation reaction
  • Breakdown to laudanosine which may cause seizures with high blood concentration, should be avoided prolonged infusion of atracurium in ICU

  
• Cisatracurium


  Stereoisomer of atracurium, forms less laudanosine, less side effects, used more clinically
• Pancuronium


  • Nondepolarizing blocker, more widely used than tubocurarine
  • Little ganglionic blockade and less histamine release compared to tubocurarine
  • Possesses antimuscarinic (anticholinergic) effect to block receptors, causes increased heart rate; also increases release of norepinephrine to increase heart rate
  • Approximately 25% is metabolized to an active metabolite 3-OH pancuronium; long-acting (2-3 hrs.)

  
• Vecuronium


  Intermediate-acting nondepolarizing blocker (1 hr.), used more than pancuronium as adjunct to general surgery
• Succinylcholine


  • Short-acting depolarizing drug, up to 15 mins
  • Induces phase I (depolarizing) and phase II (desensitizing) neuromuscular blockade
  • Used for short procedures like setting fractures, intubation, electroshock therapy
  • Rapidly metabolized by plasma or pseudocholinesterase, forms active metabolite; due to a genetic variation of an enzyme, the effect may last for hours
• Succinylcholine


  • Initial fasciculations before paralysis (this effect is suppressed with atracurium given prior to succinylcholine)
  • Myalgias (muscle pain) occurs in some patients (more pronounced in heavily muscled people)
  • May cause malignant hyperthermia
  • Increases K+ in blood in burn, head trauma, spinal cord injuries and neuromuscular disease patients; can lead to cardiac arrest
• Antidotes for Reversal of Muscle Paralysis

  Nondepolarizing drugs - acetylcholinesterase inhibitors like neostigmine, act competitively
• Malignant Hyperthermia


  • Genetic defect with Ca release from sarcoplasmic reticulum
  • Certain gas anesthetics and succinylcholine cause the massive release of Ca inside skeletal muscle
  • Causes rigor mortis type rigidity, increased body temperature, tachycardia, acidosis, and rapid death if not immediately treated
  • Antidote is dantrolene (interferes with Ca release in sarcoplasmic reticulum of skeletal muscle, more so than cardiac muscle)
• Muscle Spasticity


  • Upper motor neuron syndrome characterized by increases in tonic stretch reflexes
  • In addition to (+) signs of flexor spasm/clonus/hyperreflexia; (-) signs of fatigue, weakness, & paralysis (motor neuron damage)
  • Causes include head injury, cerebral palsy, stroke, multiple sclerosis
  • Treated with exercise/physical therapy, analgesics to reduce pain and antispastic drug treatment
• Antispastic Drugs


  • Diazepam - central action
  • Baclofen - central action
  • Dantrolene - direct action on skeletal muscle
  • Tizanidine - central action on alpha-2 receptors, agonist

  
• Dantrolene


  • Interferes with the intracellular release of Ca ions from skeletal muscle sarcoplasmic reticulum (minimal effect on cardiac SR)
  • Most effective in spasticity of cerebral origin; also used in multiple sclerosis, cerebral palsy, stroke, spinal cord injuries
  • Benefits of decreased muscle stiffness must be weighed against the disadvantage of reduction of muscle strength
  • In malignant hyperthermia, administered IV
  • Adverse reactions include muscle weakness, GI disturbances, increased liver enzymes/hepatitis/hepatotoxicity
• Baclofen


  • Chemical analog of GABA, stimulates (i.e. agonist) presynaptic GABAB receptors (found mainly in spinal cord) to open K channels (increase K out of cell to cause hyperpolarization), attenuates depolarization and is inhibitory
  • More effective in conditions that affect the spinal cord (spinal cord injuries, multiple sclerosis)
  • Adverse reactions include drowsiness, confusion, GI disturbances (nausea, diarrhea, or constipation), allergic skin reactions

  
• Tizanidine


  • Reduces excitatory neurotransmitter release (i.e., glutamate) via presynaptic and postsynaptic alpha-2 receptor stimulation in the spinal cord (inhibits intracellular Ca)
  • Reduces muscle spasticity associated with cerebral and spinal disorders
  • Adverse reactions include dry mouth, drowsiness, asthenia (muscle weakness), hypotension

  
• Benzodiazepines


  • Main sites of action: Limbic system - antianxiety effect, Reticular formation - sedation/hypnosis, Cortex - anticonvulsant effect, Spinal cord - skeletal muscle relaxation
  • Effect is through interaction with GABAA receptors which causes presynaptic inhibition via increased Cl influx

  
• Spinal cord injuries, multiple sclerosis

  Conditions that affect the spinal cord
• Adverse effects


  • Drowsiness
  • Confusion
  • GI disturbances (nausea, diarrhea, or constipation)
  • Allergic skin reactions
• Mechanism of action, clinical indication, adverse reactions

  1. Tizanidine

  2. Reduces excitatory neurotransmitter release (i.e., glutamate) via presynaptic and postsynaptic alpha-2 receptor stimulation in the spinal cord (inhibits intracellular Ca)

  3. Reduces muscle spasticity associated with cerebral and spinal disorders

  4. Adverse reactions - dry mouth, drowsiness, asthenia (muscle weakness), hypotension

  
• Benzodiazepines


  • Bind to a specific receptor, the benzodiazepine receptor that is part of the GABA-A receptor complex
  • GABA is an inhibitory transmitter that hyperpolarizes neurons by allowing the influx of negatively charged Cl ions
  • Benzos increase the inhibitory effect of GABA by increasing frequency of channel opening & greater Cl ion influx; only work if GABA is present

  
• Diazepam


  • Benzodiazepine that binds to GABA-A receptors that increase influx of Cl ions to hyperpolarize neurons which results in inhibition of neuronal activity. In the spinal cord this causes muscle relaxation
  • Used in muscle spasticity and muscle spasms
  • Also has sedative, antianxiety, and anticonvulsive/seizure effects

  
• Skeletal muscle relaxants


  • Neuromuscular blockers
  • Spasmolytics
  • Nondepolarizing
  • Depolarizing (succinylcholine)
  • Muscle action (dantrolene)
  • Short acting (mivacurium)
  • Long acting (tubocurarine)
  • Chronic use (cyclobenzaprine)
  • CNS action (baclofen, diazepam, tizanidine)
• Succinylcholine


  • Causes muscle fasciculations in the later stages of block
  • Reversibility by pyridostigmine
  • Well-sustained tension during a period of tetanic stimulation
• Nondepolarizing neuromuscular blockade


  • Block of post-tetanic potentiation
  • Effects can be reversed by cholinesterase inhibitor
  • No significant muscle fasciculations during onset of block

  
• Neostigmine does not cause skeletal muscle contractions or twitching
• Malignant hyperthermia


  Dantrolene is most effective in the management
• Prolonged neuromuscular blockade can be due to genetic variation in drug metabolism
• Tubocurarine


  • Associated with hypotension caused by histamine release
• Baclofen acts on neurons in the spinal cord to increase chloride ion conductance
• Dantrolene has little effect on calcium release in cardiac muscle
• Diazepam causes sedation at most doses required to reduce muscle spasms
• Intrathecal use of baclofen is effective in some refractory cases of muscle spasticity
• Tizanidine acts on alpha 2 adrenergic receptors to inhibit neurotransmitter release

  
• Atracurium


  • Inactivated by spontaneous breakdown
  • Laudanosine metabolites possess skeletal muscle relaxing effect
• Baclofen, dantrolene, diazepam, tizanidine


  Drugs with spasmolytic activity that could also be used in the management of seizures caused by overdose of a local anesthetic