How does neuromuscular junction transmission occur?

Action potential at prejunction nerve ending depolarizes nerve terminal

Depolarization activates adenylate cyclaseconvert ATP to cAMPCauses Ca entery to nerve
terminalRelease ACH into the synaptic cleft  ACH diffuse and attach to post synaptic nicotinic
receptors  muscular contraction occurs

ACH is then hydrolazed causing depolarization.

Give information about the post synaptic receptors ?

4 subunits : Alpha , beta , gamma , delta
2 alpha subunits poses ACH binding sites ach binds to binding sites opens ion channel (Na , K ,
Ca ) ACH hydrolized channel closed  repolarization

Binding ACh favors muscular contraction, whereas binding NMBA favors paralysis

Antagonist drugs can bind to only alpha sub unit

What are the 2 mechanisms of lingand receptor interactions?

1-Desentization
2-Channel blockade

Collapsed state : When 2 ACH molecules aren’t attached to alpha sub units  ion channel collapses

Open state : 2 ACH are bond to alpha subunits  channel opens

Desensitization state : binding happens , but change doesn’t occur Agonists, antagonists, and inhalant
anesthetics

Channel blockade : a molecule is stuck to the channelstop ion flux the entrance (Mouth) is bigger
than exit ion comes in but don’t go out
The paralysis induced by channel blockade may not be antagonized by administration of an
anticholinesterase.

Compare Depolarizing and non depolarizing drugs :

>Non depolarizing : Bind to the receptor but not activate it

> Depolarizing drugs : bind to the receptor , cause stimulation ,  notsusceptible to breakdown by
acetylcholinesterase  ion channel remains open epolarization does not occurFlaccid paralysis

Describe large dose succinylcholine effect on the block :

Block changes to phase 2 resembling non-depolarizing drugs ,
Prolonged exposure causes desensitization, channel blockade, or a combination of both.

What is the non-neuromuscular effects of NMBA?

1-Cardiovascular :
Cardiac dysrhythmia due to : agonist/antagonist action at cardiac muscarinic or nicotinic receptors
decreasing or increasing heart rate
Succinylcholine: At muscarinic receptors mimic ACH at muscarinic receptors causing bradycardia ,
junctional rhythm and sinus arrest
At sympathetic ganglia : increase heart rate and blood pressure

paralyzing dose of d-tubocurarine: blocks ACH at sympathetic ganglia  hypotention

2-Histamine : due to quaternary ammonium structurehistamine releasedvasodilation, a decrease in

blood pressure, and possibly a compensatory increase in heart rate

3-Placental Transfer: Minimum (NMBA are large , polar , hydrophilic)

4-CNS: Limited entrance , if it happened : myotonia, autonomic effects, and seizures
>Ludanosine cross blood-brain barrier in dog

What are the Non-neuromuscular Effects of Succinylcholine?

1-Hyperkalemia: it opens nicotinic receptors , don’t degrade , channels stays open K moves from fiber
to intramuscular space
2-Intraocular pressure: peak in 3 mins
3-Intragastric pressure causes muscle contractions = abdominal constriction and increases in
intraabdominal and intragastric pressure can occur, = regurgitation.
4-Intracranial pressure : caused by Muscle fasciculations
5-Muscle response : due to muscle fasciculations during the initial depolarization

When giving NMBA , what are the indications , precautions and criteria for selection?

1- Indication:
 keep patient motionless during eye surgery
typically given with hypnotic drugs to eliminate laryngeal spasm and provide rapid control of the
airway

Eliminate sudden movement

reduced resistance to controlled ventilation,
 and facilitation of surgical access during surgery

2-Precautions:
1-Respiration is paralysed : ventilation must be controlled, either by a mechanical ventilator or
manually the patient until muscle strength is restored
2-no sedative, anesthetic, or analgesic effect
3-Hard to assess level of anaesthesia
3-Selection is based on:
1-consider species
2-Reason
3-Duration
4-Health status
5-Concurrent drugs

rapid onset and brief action  rocuronium or mivacurium,

longer action without significant cardiovascular effects .  doxacurium

hepatic or renal disease  Atracurium (metabolized via Hofmann elimination)

What are the Factors Affecting Neuromuscular Blockade?

1-Impaired Metabolism and Excretion:

hepatic failure : Alter the effect due to change in volume and time of distribution ,
decreased metabolism ,
 prolong or cause residual neuromuscular blockade
 Decreased esterase activity may slow the biotransformation
 Reduced hepatic clearance of muscle relaxants

Renal failure : void the use of high doses, repeated doses, or continuous infusions of muscle relaxants
that primarily depend on renal elimination in patients with significant renal disease.

2- Anesthetic Drugs: Inhalant anesthetic agents cause a time and dose-dependent enhancement

of the intensity and duration of block , suppressing motor evoked potentials in response to spinal cord
and transcranial stimulation

diethyl ether > enflurane > isoflurane > desflurane >halothane

3- Acid-Base Disturbances:
> respiratory acidosis increases the intensity of muscle blockade,
>respiratory alkalosis decreases the effect.
>Both metabolic acidosis and alkalosis potentiate the effects .  make it more difficult to antagonize.

4-Electrolyte Disturbances:
-Decreases in extracellular K  in hyperpolarization of the end plate and resistance to ACh-induced
depolarization.

- increase in extracellular K lowers the resting membrane potential, opposing the muscle relaxant.

-Increased serum Mg  compete with ionized Ca, decreasing ACh release.

-Hypocalcemia decreases ACh release increasing the effect of the neuromuscular

block.
-hypercalcemia decreases the effect of d-tubocurarine, pancuronium,
and possibly other NMBAs= need higher dose.

5-Hypothermia: >slows drug elimination > decreases nerve conduction and muscle contraction.
Doses may need to be reduced to prevent prolonged paralysis.

6-Age: altered dose requirements due to Receptor immaturity and decreased clearance = more potent

7-Neuromuscular Disorders:

unpredictable responses to both depolarizing and nondepolarizing muscle relaxants.

Peripheral neuropathies may be classified as idiopathic, familial, metabolic, or immune mediated.

> tick paralysis and botulism impair presynaptic release of ACh.

>Patients with presynaptic neuromuscular disorders  an increased sensitivity to nondepolarizing
muscle relaxants.
> Myasthenia gravis is an autoimmune disease that

causes generalized muscle weakness BECAUSE decrease in the number of ACh receptors

. ACh is released normally, but its effect on the postsynaptic membrane is reduced. =resistant to
succinylcholine-induced paralysis, but are extremely sensitive to nondepolarizing relaxants and have an
increased sensitivity toward succinylcholineinduced phase II block.

8-Antimicrobial and Other Drug Interactions:

> polymyxin and aminoglycoside antimicrobials,

How to reverse neuromascular blockade?

Nondepolarizing Blockade:  administering an anticholinesterase

 inhibits the enzyme acetylcholinesterase, increasing the ACh concentration more ACH to
compete on binding sites

edrophonium, neostigmine, and pyridostigmine.

> phase II block from succinylcholine can be antagonized similarly to the nondepolarizing muscle
relaxants
Depolarizing Blockade:
succinylcholine hydrolysis by plasma cholinesterase= rapid recovery
. Can be delayed in patients with decreases in plasma cholinesterase levels or activity.

>anticholinesterase prolong the depolarizing block.

What is hofman elimination? a process of spontaneous molecular decomposition that appears to be pH

and temperature dependent

What are the Neuromuscular Blocking Drugs?

1-Succinylcholine: This is currently the only depolarizing NMBA used in veterinary

medicine.
Structurally two ACh molecules joined end to end.
 This drug is rapidly hydrolyzed in plasma , but not in neuromuscular junction

, so succinylcholine-induced paralysis is terminated by diffusion of the drug away from the

neuromuscular junction

2-Pancuronium: steroid nucleus.

>Onset of action 5 min and action ranging from 40-60 min in dogs.

>The action lasts longer in patients with renal insufficiency.

Acts on nicotinic receptons , can inhibit cardiac muscarinic receptors, = moderately increasing heart
rate.

3-Atracurium:
Short-acting nondepolarizing NMBA

>Onset of action of approximately 5 min,

> lasts approximately 30 min in dogs.

> half is degraded by Hofmann elimination

>>> patients with hepatic or renal insufficiency without significantly increasing its duration of action.

4-Cisatracurium:

>four times more potent, and has much less potential for histamine release.
5-Vecuronium:
>Has remarkable cardiovascular stability and does not induce tachycardia

nor release histamine.

5 min onset

duration of action 30 min.

6-Rocuronium: T
1/8th the potency of vecuronium
>. No cardiovascular effects and doesnot release histamine.

7-Doxacurium:
This is a very potent
a long duration of action.
No vagolytic properties or cause ganglion blockade.

does not cause histamine release.

What are the centrally acting vs peripherally acting muscle relaxants ?

1-Centrally Acting Muscle Relaxants

Guaifenesin >large animal species.

>disrupt nerve impulse transmission at the level of thespinal cord, brain stem, and subcortical areas of
the brain.

> skeletal muscle relaxes, Non analgetic ,

>No antagonist

At high concentrations : hemolysis, hemoglobinuria, and venous thrombosis.

Prevasculary: Tissue damage

>Systolic, diastolic, and mean arterial pressures are decreased.

2-Peripherally Acting Muscle Relaxants

Dantrolene:
interferes with excitation-contraction coupling relaxing skeletal muscle through a decrease in the
amount of calcium
>released from the sarcoplasmic reticulum.

> do not adversely affect cardiac or smooth muscle and do not depress respiration.

> treatment of malignant hyperthermia.

>Severe myocardial depression has been reported when dantrolene is administered

concurrently with verapamil or other calcium channel blockers.

Analgesics -opioids

Noxious stimulus: Harmful stimuli that cause real or potential tissue damage

Nociceptors: Nerve receptors that are sensitive to noxious stimuli

>responsible for low-intensity (painless) and high-intensity (painful) mechanical, thermal and chemical
stimulation

Nociception: The response to noxious stimulations > pain

What are types of pain?

physiological pain: Pain, which is not related to tissue or nerve lesions, as part of the defense
mechanism
Pathological pain: Pain caused by actual tissue destruction and nerve damage
Acute pain: sudden onset, and resulting from soft tissue trauma or inflammation > C , A-δ
Chronic pain: prolonged noxious stimulation. The most common form is cancer pain, osteoarthritis

What are the stages of painful stimuli ?

a) Transduction: The transformation of one energy into another energy. While nociceptors are

insensitive to a normal degree of heat, they become sensitized by an increase in temperature,

b) Transmission: The transmission of pain information perceived by nociceptors to higher

centers. In this transmission, myelinated A-δ and unmyelinated C fibers play an active role,

c) Modulation: The painful stimulus changes at the level of the spinal cord and is transmitted to

the higher centers as a result of this change,

d) Perception: passing through the spinal cord to the upper centers through the detection of pain.
What are opioids?

opioid: broadly to cover all drugs that are chemical derivatives of the compounds purified from opium
Opiates :refined
Opium: Unrefiend extract of poppy

>Mechanism of action:
Mimic opioid peptide
There are three well defined types of opioid receptors, µ (mu), δ (delta), and к (kappa)
 Opioid receptor binding, via activation of various types of G proteins, may inhibit cyclic adenosine
monophosphate activity, activate receptor-operated K+ currents, and suppress voltage-gated Ca2+
currents.

 Presynaptic : decreased Ca2+ influx will reduce release of transmitter substances  inhibiting
synaptic transmission of nociceptive input
Postsynaptic : K+ efflux causes neuronal hyperpolarization of spinal cord projection neurons and
inhibits ascending nociceptive pathways

 upregulation of supraspinal descending antinociceptive pathways in the periaqueductal gray matter

What are the side effects of opioids?

A.Central Nervous System:

1-.Arousal:

>CNS depression  in dogs, monkeys, and people

>CNS stimulation elicited in cats, horses, goats, sheep, pigs, and cows

2-Thermoregulatory Center:

>Hypothermia especially in perioperative period Mixed with CNS-depressant drugs.

>hyperthermia in cats, horses, swine, and ruminants.

3-Emetic Center:
Nausea and vomiting  direct stimulation of the chemoreceptor trigger zone for

postrema of the medulla

>Horses, rabbits, ruminants, and swine do not vomit

>Cats may vomit , dogs more

4.Cough Center:

cough center located in the medulla.

5.Pupillary Diameter mydriasis in those species that exhibit CNS excitation,
> miosis in those that become sedated after opioid administration.

Cardiovascular System:
minimal effects

>Bradycardia may be caused by opioid-induced medullary vagal stimulation

>morphine and meperidine can cause histamine release, > lead to vasodilation and hypotension.

Respiratory System:

dose-dependent depression of ventilation, primarily mediated by µ2 receptors, leading to a direct

depressant effect on brain-stem respiratory centers.
> decreased responsiveness to carbondioxide > increased resting arterial carbondioxide partial pressure.

Gastrointestinal System: mediated by µ and δ receptors located in the myenteric plexus of the
gastrointestinal tract

>stimulate dogs and, less frequently, cats to defecate.

> spasm of gastrointestinal smooth muscle predisposes patients to ileus and constipation.

>Horses and ruminants in particular may be predisposed to gastrointestinal complications associated

with opioid administration, such as colic and ruminal tympany,

Urogenital System:

>cause urinary retention suppression of detrusor contractility and decreased sensation of urge.

>Urine volume

>hormone release leading to altered renal tubular function. Elevations in circulating

plasma atrial natriuretic peptide

What are the Opioid agonists :

Morphine:
> full agonist at µ receptors, t δ and к receptors.

>relatively hydrophilic and

>crosses the blood-brain barrier more slowly
>lasts 3 to 4 h.
> Morphine's poor lipid solubility means that it can produce long-lasting analgesia

when administered into the epidural or subarachnoid space,

with effects persisting for 12 to 24

> in dogs, cats, horses, and rats.

Oxymorphone:
full agonist at µ receptors

> more lipid soluble drug than morphine and is readily absorbed after IM or SC administration

> likely to cause dogs and cats to vomit

> more sedation

>more likely to cause dogs to pant.

> It does not produce histamine release

Hydromorphone:

used in both human and veterinary medicine. > Like oxymorphone,

hydromorphone is not associated with histamine release,

Meperidine:

Meperidine can block Na channels and inhibit activity in dorsal horn neurons in a manner analogous to
local anesthetics.

> negative inotropic effects when administered alone to conscious dogs.

> to increase heart rate rather than predispose patients to bradycardia, a
> histamine release

Serotonin syndrome:

The combination of meperidine (and perhaps other opioids)

with a monoamine oxidase inhibitor

>characterized by confusion, fever, shivering,diaphoresis, ataxia, hyperreflexia, myoclonus, and diarrhea

Fentanyl:

>Highly lipid soluble, short-acting synthetic µ opioid agonist.

Peak in5 min and last approximately 30 min. Rapid

redistribution of the drug to inactive tissue sites, such as fat and skeletal muscle, leads
>cardiovascular stability is excellent with fentanyl,
> not associated with histamine release.
>Bradycardia may be significant with bolus doses.

>Clinically, fentanyl is used most frequently in dogs and cats, but is also a potentially

useful analgesic in other species, including horses, cows, sheep, goats, and pigs.

Alfentanil, Sufentanil, and Remifentanil

structural analogs of fentanyl that were developed for use in human patients in an effort to

create analgesics with a more rapid onset of action and predictable

termination of opioid effects.

>Remifentanil is > metabolized by nonspecific plasma esterases to inactive

metabolite.

Codeine

>Codeine is the result of substitution of a methyl group onto morphine,

> limit first-pass hepatic metabolism and accounts for

codeine's high oral bioavailability.

> excellent antitussive properties

>used in dogs for the management of mild pain.

Methadone/ Etorphine

>excellent absorption after oral administration,

>high potency,

> extended duration of action.

>Vomiting and histamine release are lower than morphine

>used in dogs, cats and horses in the perioperative period by IM or IV routes.

Etorphine > respiratory depression. Dart guns

What is antagonist opoid ?

Naloxone: >reverse all opioid agonist effects,

producing increased alertness, responsiveness, coordination and, potentially, increased

perception of pain.
> intravenous doses lasting between 30 and 60 min.

>excitement or anxiety may be seen after naloxone reversal of an opioid agonist. Naltrexone is a long-
acting

derivative of naloxone and is not often used in veterinary practice.

Agonist-Antagonists and Partial Agonists

They all occupy µ opioid receptors, but do not initiate a maximal clinical response.

Butorphanol: An antitussive agent in dogs and even now, is approved as an analgesic in cats and horses

Nalbuphine and Pentazocine: Nalbuphine and pentazocine are classified as agonist-antagonist opioids

and are clinically similar to butorphanol. They induce mild analgesia accompanied by minimal sedation,

respiratory depression, or adverse cardiovascular effects.

Buprenorphine

Its considered to be a partial agonist at µ opioid receptors. The drug binds avidly to,

and dissociates slowly from, µ receptors, but cannot elicit a maximal clinical response.