Drugs Acting On PNS Flashcards
Competitive blockers (non depolarising blockers) as neuromuscular blockers
The competitive blockers have affinity for the nicotinic (Nm) cholinergic receptors at the muscle end plate, but have no intrinsic activity.
They exhibit fade phenomenon
Nm receptor structure
It is a protein with 5 subunits (2 α,β,ε,γ,δ) which are arranged like a rosette surrounding the Na+ channel
The two α subunits carry two ACh binding sites (negatively charged) groups which combine with the cationic head of ACh. This triggers opening of Na+ channels.
What happens at high concentrations of curare like drugs
They enter Na+ channels of Nm receptors and directly block them to produce intense noncompetitive neuromuscular block that is only partly reversed by neostigmine.
Actions of non depolarising blockers
1. Skeletal muscle: rapidly produces muscle weakness followed by flaccid paralysis. 2. Autonomic ganglia: some degree of ganglionic blockade 3. Histamine (and heparin) release: hypotension, flushing, bronchospasm and increased respiratory secretion 4. CVS effects 5. GIT
Action of non depolarising blockers in skeletal muscles occurs in the order
- Small fast response muscles (fingers, extraocular) are affected first
- Paralysis spreads to hands, feet- arm, leg, neck, face-trunk-intercostals
- Finally diaphragm, respiration stops
Recovery occurs in the reverse sequence
Effects of competitive/non depolarising blockers in autonomic ganglia
- Some degree of ganglionic blockade
* d-TC has the maximum effect while the newer drugs (vecuronium, etc.) are practically devoid of it
Non depolarising/competitive blockers and histamine
•Histamine (and heparin) release is stimulated
•Hypotension, flushing, bronchospasm and increased respiratory secretion
•Intradermal injection of d-TC produces a wheal similar to that produced by injecting histamine.
(Atracurium and mivacurium have significant histamine releasing potential)
d-Tubocurarine produces significant fall in BP.
- Ganglionic blockade
- Histamine release and
- Reduced venous return:
a result of paralysis of limb and respiratory muscles.
Cardiovascular effects of non depolarising/ competitive blockers
- Heart rate may increase due to vagal ganglionic blockade.
- d-TC produces significant decrease in BP
- Pancuronium tends to cause tachycardia and rise in BP
- atracurium may cause hypotension
- All newer nondepolarizing drugs (vecuronium, rocurorinium, cisatracurium) have negligible effects on BP and HR
Conditions in which dual mechanism of depolarising agents
- In dog, rabbit, rat, monkey
- In slow contracting soleus muscle of cat
- Under certain conditions in man when the depolarizing agents:
injected in high doses
infused continuously
Non depolarising blockers/ competitive blockers and GIT
The ganglion blocking activity of competitive blockers may enhance postoperative paralytic ileus after abdominal operations.
Why is d-Tubocurarine not used
Because of its prominent histamine releasing, ganglion blocking and cardiovascular actions as well as long duration of paralysis needing pharmacological reversal, d-TC is not used now.
Pancuronium properties
- More potent and longer acting than d-TC
- Good CVS stability
- Lower histamine release
- Primarily renal excretion
Rapid IV injection- rise in BP and tachycardia due to vagal blockade and NE release
Pancuronium uses
More potent and longer acting than d-TC and needs reversal
Restricted to prolonged operations, especially neurosurgery
Pipecuronium
- Competitive muscle relaxant with a slow onset and long duration of action
- Recommended for prolonged surgeries.
- It exerts little cardiovascular action, (though transient hypotension and bradycardia can occur)
- Elimination occurs through both kidney and liver
Vercuronium
Competitive neuromuscular blocker
1. Shorter duration of action:
•rapid distribution
•hepatic metabolism (excreted mainly in bile)
2. Spontaneous recovery (may need neostigmine reversal)
3. Cardiovascular stability (tachycardia sometimes occurs)
Most used muscle relaxant for routine
surgery and ICU
Atracurium
Competitive neuromuscular blocker
- Less potent than pancuronium and shorter acting, so that reversal is not required
- Inactivated spontaneously by Hofmann elimination (+enzymatic)
- Hence duration of action is unaltered in patients with hepatic / renal insufficiency or hypodynamic circulation
- Cisatracurium is preferred
Side effects of atracurium
- Atracurium causes dose dependent
histamine release (hypotension) - When used for long periods its
metabolites may accumulate and cause CNS toxicity.
Less toxic cisatracurium is preferred over atracurium
Cisatracurium
Competitive neuromuscular blocker More potent, slower in onset Undergoes Hofmann elimination, but unlike atracurium: 1. Not hydrolysed by cholinesterase 2. Hepatic metabolism is limited so 3. Less toxic 4. No histamine release 5. Preferred especially for liver/kidney disease patients and elderly.
Rocuronium
Competitive blocker with the most rapid onset
- Intermediate duration of action
- No CVS changes
- Doesn’t need reversal.
- Dose-dependent onset and duration of action
- Mild vagolytic action mildly increases HR
- Eliminated mainly in bile
Rocuronium uses
- Alternative to SCh for tracheal intubation (without disadvantages of depolarizing block and CVS changes)
- Used as maintenance muscle relaxant, never needing reversal.
- To facilitate mechanical ventilation in ICU
The 2 phases seen in some cases of depolarising agents
Phase 1 block: normal
•rapid onset
•persistent depolarization of muscle end plate
•has features of classical depolarization blockade
Phase 2 block: •slow in onset •desensitization of the receptor to ACh. •resembles block produced by d-TC. • fade occurs
Actions of depolarising blockers
- Skeletal muscle: produce fasciculations lasting a few seconds before flaccid paralysis
- Autonomic ganglia:
SCh may cause ganglionic stimulation by its agonist of Nn - CVS
Action of depolarising blockers on skeletal muscles
- Produce fasciculations lasting a few seconds before flaccid paralysis
- Fasciculations-not prominent when well anaesthetized
- Action of SCh is too rapid to perceive the sequence (though different)
- Apnoea generally occurs within 45-90 sec, but lasts only 2-5 min
- Rapid recovery
Cardiovascular effects of SCh
•bradycardia occurs initially (activation of vagal ganglia) followed by tachycardia
•rise in BP:
stimulation of sympathetic ganglia
(but BP occasionally falls due to muscarinic action causing vasodilatation)
Prolonged administration of SCh has cardiovascular effects like
•Prolonged administration of SCh has caused cardiac arrhythmias and even arrest in patients with:
1. burns
2. soft tissue injury
3. tetanus.
•Efflux of intracellular K occurs in these conditions worsened by prolonged depolarization of skeletal muscles.
Pharmacokinetics of neuromuscular blockers
- All neuromuscular blockers are polar quaternary compounds
- Not absorbed orally, do not cross cell membranes
- Low volumes of distribution and do not penetrate placental or BBB
- They are practically always given i.v., though i.m. administration is possible. Muscles with higher blood flow receive more drug and are affected earlier.
Neuromuscular blockers metabolised in plasma or liver
V. Vecuronium A. Atracurium C. Cisatracurium O. Ocuronium M. Mivacurium especially They have relatively shorter t1⁄2 and duration of action (20-40 min)
Neuromuscular blockers excreted by kidney
- Pancuronium
- d-Tc
- Doxacurium
- Pipecuronium
They have longer t1⁄2 and duration of action (>60 min).
Major use of succinyl choline
Most commonly used muscle relaxant for passing tracheal tube despite side effects.
Reasons:
1. Induces rapid, complete and predictable paralysis with spontaneous recovery in ~5 min
2. Relaxed jaw
3. Vocal cords apart and immobile
4. No diaphragmatic movements (Occasionally, continuous IV infusion for longer duration)
Side effects of succinyl choline
- Muscle fasciculations and soreness
- Changes in BP and HR, arrhythmias
- Histamine release
- K efflux from muscles causing hyperkalemia and its complications
Metabolism of SCh
- SCh is rapidly hydrolysed by plasma pseudocholinesterase to succinylmonocholine and then succinic acid + choline (action lasts 5- 8 min).
- Some patients have genetically determined abnormality (low affinity for SCh) or deficiency of pseudocholinesterase causing phase 2 blockade (4-6 hours)
Contraindications of SCh
- In younger children, because risk of hyperkalemia and cardiac arrhythmia is higher
- In GERD patients and in the obese, risk of regurgitation and aspiration of gastric contents is increased by SCh especially if stomach is full
