Exam 1 Drugs: NMJ and Ganglia Blockers

Question 1

Nicotine

Answer 1

• Mech: agonist at Nn and Nm receptors (direct-acting)
• effects: activates autonomic postganglionic neurons (both parasymp and symp) and skeletal muscle neuromuscular end plates, also enters CNS and activates Nn receptors
• effects can be blocked by ganglionic nicotinic receptor antagonists
• rapid onset, half life 2 hrs with inhalation or parenterally
• mimic initial EPSP
• initially stimulate, then block b/c of persistent depolarization
• ultimate response of any one system is the summation of stim & inhibitory effects
• elicits a discharge of epinephrine from the adrenal medulla which accelerates HR and raises BP at small doses, large doses prevent release due to splanchnic nerve stim
• stimulation of emetic chemo receptor trigger zone and activates vagal and spinal afferent nerves that form sensory input of reflex
• higher brain stimulates reward centers
• increase motility in GI, increase secretion of salivary and bronchial, increase respiration
• chronic exposure causes increase in # of nicotinic receptors
• absorbed from resp, buccal membranes, and skin (can be toxic)
• intestinal absorption greater than stomach (strong base)
• elimination: N and metabolites (80-90% of N is metabolized by liver) eliminated rapidly by kidney, also in milk of lactating women
• clinical app: medical use in smoking cessation, nonmedical in smoking and insecticides
• administered in gum, patch for cessation
• adverse: besides above, high doses can cause seizures
• contra: additive w/ CNS stimulants

Question 2

Mecamylamine

Answer 2

• selectively antagonizes Nn receptors
• only ganglionic blocker currently available in the US
• effects: given as a ganglionic blocker that lowers BP while blunting sympathetic reflexes
• absorption less erratic than nicotine
• concentrates in liver and kidney, excreted unchanged by kidney
• clinical app: treat hypertension in patients w/ acute aortic dissection. also used to reduce BP during surgery to minimize hemorrhage, reduce blood loss in orthopedic procedures, facilitate surgery on blood vessels
• serious adverse: paralytic illeus, urinary retention, resp arrest, syncope
• common adverse: dyspepsia, orthostatic hypotension, diplopia, sedation

Question 3

Succinylcholine

Answer 3

• agonist @ nicotinic ACh receptors, esp NMJ
• depolarizes and may stim ganglionic nicotinic ACh and cardiac muscarinic ACh receptors
• only depolarizing agent in clinical use!!
• has flexible structure that allows free bond rotation
• effects: initial depol causes transient contractions followed by prolonged flaccid paralysis. depol then followed by repol that is also accompanied by paralysis
• rapid metabolism by plasma esterases, normal duration 5-8 mins
• to get longer relaxation, must have continuous IV
• clinical app: placement of tracheal tube, at start of anesthetic procedure (rare), also control of muscle contractions in epilepticus, use to prevent trauma in ECT
• rarely causes effects attributable to ganglionic blockade
• CV effects SOMETIMES observed with successive stim
• vagal ganglia: bradycardia
• symp ganglia: hypertension and tachy
• adverse: arrhythmias, hyperkalemia, transient increased intra-abdominal and/or intraoccular pressure, post-op muscle pain
• unless administered rapidly, causes little histamine release
• not indicated for children 8 and under unless emergency intubation or securing airway
• contra: nontraumatic rhabdomyolysis, ocular lacerations, spinal cord injuries w/ para or quadrapelegia
• using succinylcholine with certain anesthetics can cause malignant hyperthermia (treat with dantrolene)

Question 4

Tubocurarine

Answer 4

• non-depolarizing Nm blocking agent
• competitive antagonist at nACh receptors, esp at NMJ
• no longer available in US! - hepatotoxicity
• natural alkaloid, bulky, rigid, cannot cross BBB
• effects: prevents depol by ACh, causes flaccid paralysis, can cause histamine release w/ hypotention, weak block of cardiac muscarinic ACh receptors
• only need one molec of antagonist to block, need two agonists to stim
• AChEs reverse the block
• clinical app: prolonged relaxation for surgical procedures
• adverse: histamine release, hypotension, tachy, prolonged apnea
• renal excretion duration 80-120 mins (long)

Question 5

Atracurium

Answer 5

• competitive antagonist at nACh receptors, esp NMJ
• benzlisoquinoline
• intermediate duration: 30-60 mins
• elim by hoffmann and plasma esterases (not dependent on liver or kidney function)
• effects: prevents depolarization by ACh, causes flaccid paralysis, only slight histamine release (when administered rapidly), more selective –> NO antimuscarinic effects
• clinical app: prolonged relaxation for surgical procedures, relaxation of muscles to facilitate intubation, relaxation of resp to facilitate mechanical ventilation
• adverse: usually due to histamine release (flushing, itching), prolonged apnea

Question 6

Cisatracurium

Answer 6

• competitive antagonist @ nACh receptors, esp NMJ
• benzylisoquinoline
• intermediate duration: 25-45 mins
• elim by hoffmann deg and renal
• effect: prevent depol by ACh at nicotinic receptors, cause flaccid paralysis, can cause histamine release (when administered rapidly), more selective –> NO antimuscarinic effects
• clinical apps: prolonged relaxation for surgical procedures, relaxation of muscles to facilitate intubation, relaxation of muscles to facilitate mechanical ventilation
• adverse: prolonged apnea but less toxic than atracurium

Question 7

Mivacurium

Answer 7

• competitive antagonist at nACh receptors, esp NMJ
• benzylisoquinoline
• short duration of action 12-18 mins
• extremely sensitive to AChEs or other plasma esterases
• effects: inhibit ACh release, flaccid paralysis, slight histamine release (when administered rapidly), selective (NO antimuscarinic effects)
• also used to prevent trauma during ECT
• clinical apps: muscular relaxation for long surgeries, muscular relaxation for intubation, relaxation of resp for mechanical ventilation
• adverse: flush, hypotension, rash, broncospasm

Question 8

Doxacurium

Answer 8

• competitive antagonist at nACh receptors, esp NMJ
• benzylisoquinoline
• no longer available in US
• long duration: 90-120 mins
• renal elim
• effects: prevent ACh release, flaccid paralysis, low histamine release (unless administered rapidly), selective (no antimuscarinic effects)
• clinical: prolonged relaxation for surgeries, relaxation of muscles for intubation, relaxation of resp for mechanical ventilation
• adverse: flush, prolonged muscle weakness

Question 9

Pancuronium

Answer 9

• competitive antagonist at nACh, esp NMJ
• ammonio steroid
• long duration: 120-180 mins
• renal and hepatic elim
• effects: prevent ACh release, flaccid paralysis, NO histamine release, SOME antimuscarinic effects (blocking)
• manifest primarily in vagal blockade and tachy
• clinical app: prolonged relaxation for surgery, relaxation for intubation, resp relaxation for mechanical ventilation
• adverse: CV (increased arterial pressure, HR, CO), salivation, apnea
• less ganglionic blockade @ clinical doses than other neuromuscular blocking agents

Question 10

Rocuronium

Answer 10

• competitive antagonist @ nACh receptors, esp NMJ
• ammonio steriod
• intermediate duration: 30-60 mins
• elim by liver
• effect: prevent ACh release, flaccid paralysis, NO histamine release, MINIMAL antimuscarinic effects
• clinical app: prolonged relaxation for surgery, relaxation for intubation, resp relaxation for mechanical ventilation
• adverse: prolonged apnea, less toxic than pancuronium
• tachy is eliminated as adverse

Question 11

Vecuronium

Answer 11

• competitive antagonist @ nACh receptors, NMJ
• ammonio steriod
• intermediate duration: 60-90 mins
• hepatic and renal elim
• effect: prevent ACh release, flaccid paralysis, NO histamine release, MINIMAL antimuscarinic effects
• clinical app: prolonged relaxation for surgery, muscular relaxation for intubation, resp relaxation for mechanical respiration
• adverse: apnea, skeletal muscle weakness

Question 12

Baclofen

Answer 12

• centrally acting spasmolytic drug
• acts @ spinal cord or higher centers
• GABAb agonist
• facilitates spinal inhibition of motor neurons
• effects: pre- and post-synaptic inhibition of motor output
• clinical app: treats severe spasticity due to cerebral palsy, multiple sclerosis, stroke
• adverse: sedation, weakness

Question 13

Dantrolene

Answer 13

• muscle relaxant
• blocks RYR1 Ca2+ release channels in the SR of skeletal muscles
• duration IV and oral: 4-6 hrs
• effects: reduces actin-myosin interaction, weakens skeletal muscle contraction
• clinical app: IV: treats malignant hyperthermia, oral: treats spasms due to cerebral palsy, spinal cord injury, M.S.
• adverse: muscle effects
• hepatotoxicity reported with continued use

Question 14

Botulinum Toxin A

Answer 14

• muscle relaxant
• cleaves SNAP-25 in NMJ to disrupt SNARE complex and prevent ACh release
• effects: produce flaccid paralysis of skeletal muscle, diminish activity of parasymp and symp cholinergic synapses
• clinical app: many types of dystonias esp. cervical, and cosmetic procedures
• inhibition lasts weeks to months
• requires new nerve sprouting