Download Non - Depolarizing Blockade

Non - Depolarizing Blockade:
Ion channel agonists. Competitively block the ACh binding sites. Actions can be reversed by an excess of ACh due to competitive
nature of blockade
Non - Depolarizing Neuromuscular Blockers
Drugs
1.Tubocurarine
(curare)
Description
Tx Application
Paralytic agent (80 – 120 mins).
No initial excitation, only blockade
resulting in paralysis.
Muscle relaxant & surgical adjuvant.
S/E
Poisoning –
treatable with
AchE inhibitors
2. Histamine release – be careful with asthmatics.
Order of paralysis eye, jaw, throat & neck,
appendages, abdominal muscles,
intercostals muscles and diaphragm.
3. Synergism with antibiotics (Streptomycin, and
Tetra’s)
a. chelates Ca ~>paralysis
b. prolonged duration of action
Have bifunctional 3 and 4 N, and a
Benzylisoquinoline group. (BenzIsoQ)
2. Cisatracurium
(1R cis 1’R cis)
Duration is 30 – 40 mins.
C/I or Precaution
1. Excreted in urine – May have extended duration of
action in patients with renal insufficiency.
Better choice for patients with
reduced renal function
I don’t know!!! But
the drug is
degraded thru non
–enzymatic
Does not require Liver or Kidney for cessation of
action.
10 possible isomers for 4 chiral centers
3. Pancuronium
Has two 4’nary
ammonium.
Duration is 120-180
mins
4. Vecuronium
Can produce active
metabolite at C3
alcohol. Has 3 and
4N
5. Rocuronium
No ester grp at C3hydroxyl grp.
Ammonio steroids: steroid backbone
provides as a spacer. Greater selectivity for
Nm over Nn r/c.
No histamine release, preferred for
asthmatics
I don’t know!! But
drug is renally
eliminated
Long acting: 120-180 mins
Same as 3
Same as 3
Don’t know!!!
Metabolized in the
liver
Intermediate acting: 60-90 mins.
Same as 3
Same as 3
Same as 4
Intermediate acting: 30-69 mins.
Drugs
Description
1.Mecamylamine
Very limited use!
Structure does not fit
SAR
Some selectivity for Nn over Nm r/c, adjust
dose to affect only Nn r/c
Control BP and bleeding during
surgery.
Competitively block the channel and ACh
binding sites.
Tested for off-label CNS
neuroprotective effects.
Non - Depolarizing Ganglionic Blockers
Axn can be reversed by an excess ACh
due to competitive nature of blockade
Tx Application
S/E
Decrease BP
C/I or Precaution
Hypotension? - I don’t know.
Depolarizing Blockade: Ion channel agonists.
Opening the ion channel causes an initial depolarization of the post-ganglionic neuron (or the adrenal medulla). Persistant
stimulation induces Phase I followed by Phase II blockade. Blockade can NOT be reversed by excess ACh (must wait for resensitization of the ion channels to occur over time.
 Phase I blockade: ion channel remains open in the presence of a depolarizing blocker and repolarization can’t occur.
 Phase II blockade: ion channels closes, repolarization of the cell occurs, but the Nn r/c is desensitized and unable to respond for further stimulation for a time ~ 5min.
Depolarizing Neuromuscular Blockers
Drugs
1.Succinylcholine
Nm r/c selective.
Each half is ACh:
bifunctional.
Rapidly hydrolyzed
by ButyrlChE and
circulating plasma
pseudocholinesterases,
thus short duration of
action.
Description
Opens the ion channel and causes and
initial depolarization of the muscle cell
leading to contraction and twitching for ~
1 min.
Tx Application
Short duration effect is useful where
short term paralysis is required:
Electroshock therapy
Setting fractures and dislocations
Endotracheal intubations.
Persistent stimulation renders the muscle
cells incapable of repolarization and
blockade ensues Phase I and Phase II
blockade.
S/E
May have muscle
pain and soreness
from initial
twitching.
Hyperkalemia
(release of K into
bloodstream).
MALIGNANT
HYPERTHERMIA
(MH) – if used in
conjunction with
inhalational
anaesthetics.
Following the contraction, a short term,
~5min, paralysis.
C/I or Precaution
There is no Chemical antidote for a depolarizing
blocker.
Duration of action may be dangerously extended
with liver disease or genetic defects resulting in low
levels of circulating cholinesterase.
Hyperkalemia is problematic for patients in
electrolyte imbalance or taking digitalis.
MH – dangerously increased body Temp.
Treatment includes cooling, heat dissipation,
Oxygen admin, control of acidosis and ……
Dantrolene, which blocks calcium release from SR
to control hypermetabolism leading to hyperthermia.
Depolarizing Ganglionic Blocker
Drugs
Description
1. Nicotine
Initial excitation
followed by persistent
blockade. Effect is
release of EPI
following excitation
of Adrenal medulla
Nn r/c
Some selectivity for Nn over Nm r/c. In
high doses, effects in Nm r/c are muscle
twitching and blockade.
2. Varenicline
Nicotinic partial agonist at
(alpha4)2(beta2)3 and full agonist at
(alpha7)5 nicotinic r/c
Tx Application
Smoking cessation patches,
analgesics. GI protective effects to
reduce inflammation in ulcerative
colitis
As a partial agonist: reduce
withdrawal symptoms without
activating dependency p/w.
S/E
Epi will Increase
HR, BP
Special effects of
nicotine: activation
followed by
depolarization of:
Nn pain afferent
r/c.
Nn r/c on
chemosensory
neurons; increase
respiration.
Nn r/c on stretch
sensory neurons:
reflex vomiting.
Irritability,
insomnia,
restlessness. Aches,
pains.
Constipation,
increased appetite,
sugar cravings.
C/I or Precaution
Addictive properties based on CNS effect; NO
antidote, induce vomiting
Ganglionic Signaling Blockade:
Ganglionic Signaling:
 Activation of Nn r/c by ACh is rapid, excitatory and REQUIRED for development of an action potential (AP) in post synaptic cell.
 Activation of other receptors or input from other neurons in the ganglia may POTENTIATE or INHIBIT the primary effect of Nn activation, but have NO EFFECT ALONE.
 Special summation in the ganglia is THE SUMMING OF ALL POTENTIATING AND INHIBITORY INPUTS modifying the Nn activated EPSP (excitatory post synaptic
potential), and determining whether a threshold is reached whereby an AP is generated down the post ganglionic neuron.
Ganglionic Blockade
 Agents that activate or inhibit Nn signaling in the ganglia (Nicotinic agonists and antagonists) BOTH ULTIMATELY PRODUCE BLOCKADE.
 Primary actions are variable depend on: PREDOMINANT TONE OF THE ORGAN, AGE, SYMPATHETIC TONE, ETC.
SITE
BLOOD VESSELS
BLADDER & GI SPHINCTERS
HEART
EYE
GI TRACT
URINARY BLADDER
SALIVARY GLANDS
PRDOMINANT TONE
SYMPA
SYMPA
PARA
PARA
PARA
PARA
PARA
PRIMARY EFFECT OF GANGLIONIC BLOCKADE
HYPOTENSION
???
TACHYCARDIA
MYDRIASIS, BLURRED VISION
DECREASED MOTILITY
URINARY RETENTION
DRY MOUTH
Neuromuscular Signaling Blockade:



Neuromuscular signaling – Nm r/c at the muscle enplate activated by ACh released from somatic nerves
Both non-depolarizing and depolarizing neuromuscular blockers exists
Some neuromuscular blockers are Nm selective because they can NOT cross into the ganglionic space.