Nicotinic Agents Flashcards
Sites of Nicotinic Receptors
@ All Autonomic Ganglia (Nn)
@ Adrenal Medulla (Nn)
@ Neuromuscular Junction (Nm)
_Not part of ANS; Somatic.
_Part of Cholinergic System though.
Use of Drugs Acting @ Neuromuscular Junction
Therapeutically, we use drugs that Prevent the Action of ACh @ the Neuromuscular Junction (NMJ).
They are used to Cause Relaxation of Skeletal Muscle:
_Muscle relaxation during Surgery, Intubation
_Control of Ventilation (Patients on Ventilator)
_Modify Convulsions in ECT
2 Main Types of Neuromuscular Blockers:
1) Non-Depolarizing Blockers
2) Depolarizing Blockers
Non-Depolarizing Blockers
Given Parenterally (IV)
Drugs:
D-Tubocurarine
Atracurium
Rocuronium
1) Competitive Antagonists
2) Contain Quaternary Nitrogen (Ionized)
3) No CNS effects
4) Cause Flaccid Paralysis
_Small, Rapidly Moving Muscles (e.g. Eyelids):
1st Affected; Last to Recover
_Then: Larger Muscles Affected
_Diaphragm: Last Affected, 1st to Recover.
5) Cause Apnea
_Mechanical Ventilation Required!!
6) Some may have effects @ Ganglia
_Ganglionic Block results in Hypotension!!
7) Some may cause Histamine Release
_Histamine Release will also cause a Decrease in Blood Pressure
8) Diazepam:
_Increases Duration of Non-Depolarizing Blockers
_Decreases Duration of Succinylcholine
(Depolarizing Blocker)
_______________
HOW TO REVERSE EFFECTS:
1) First!! Block Muscarinic Receptors with ATROPINE
2) Second!! Increase Agonist (ACh)
by Giving Anticholinesterase, e.g. NEOSTIGMINE
(Quaternary. You give quaternary b/c don’t want it to go to the CNS b/c the Blocker isn’t in the CNS.)
(Must give Muscarinic Blocker first b/c Anticholinesterase will cause increased ACh everywhere. Excess ACh at Muscarinic receptors will cause Increased Bronchial Secretions and Bronchoconstriction, killing the patient.)
Curare
Non-Depolarizing (Competitive Antagonist) Neuromuscular (Nicotinic) Blocker
1) Quaternary Alkaloid
2) No CNS effects @ Therapeutic doses
3) Not well Absorbed after Oral administration
(which is why they were able to eat the meat of the animals they had killed with Curare)
South American Arrow Poison
Active Compound is D-Tubocurarine
D-Tubocurarine
Prototype Non-Depolarizing (Competitive Antagonist) Neuromuscular (Nicotinic) Blocker
Found in Curare
1) Quaternary Alkaloid
2) Not well absorbed with Oral administration
3) No CNS effects @ Therapeutic doses
4) Weak Ganglionic Blocker
=> Hypotension
5) Liberates Histamine
=> Hypotension
=> Bronchospasm
(These adverse effects are why we no longer use this)
Atracurium
Non-Depolarizing (Competitive Antagonist) Neuromuscular (Nicotinic) Blocker
**Broken Down by Hoffman Elimination!
=> **Temperature and pH Dependent
_Not Enzymatic breakdown
(Not patient dependent)
**Does NOT Depend on Hepatic or Renal Function for its breakdown.
_Thus, will last just as long in elderly and healthy younger person.
Also Broken Down by Ester Hydrolysis
Cisatracurium
Non-Depolarizing (Competitive Antagonist) Neuromuscular (Nicotinic) Blocker
Stereoisomer of Atracurium
Produces Less Histamine than Atracurium
(Now widely used)
Rocuronium
Non-Depolarizing (Competitive Antagonist) Neuromuscular (Nicotinic) Blocker
Has Steroid structure.
Rapid Onset
Intermediate Duration
May be used to Facilitate Intubation.
(Like, need the patient to be paralyzed briefly for just a brief procedure, like intubation)
Gantacurium
Non-Depolarizing (Competitive Antagonist) Neuromuscular (Nicotinic) Blocker
Investigational
New class (chemical structure)
Competitive Antagonist
Ultra-Short-Acting
–May be an Alternative to Succinylcholine (which is a Depolarizing blocker and the only other ultra-short-acting blocker available)
Depolarizing Neuromuscular Blockers
1) Partial Agonists
_Have Affinity and Intrinsic Activity
2) Excess Acetylcholine will act as a Depolarizing Blocker
3) Cause Fasciculations, Followed by PAIN
4) Followed by Flaccid Paralysis
Succinylcholine
Prototype Depolarizing (Partial Agonist) Neuromuscular Blockers
1) Very Brief Duration of Action (5-10 min)
2) Hydrolyzed by Plasma Pseudocholinesterase
_____________
May Get Prolonged Action:
1) Severe Malnutrition
(Not synthesizing enough Pseudocholinesterase)
2) Hepatic Disease
(Not synthesizing enough Pseudocholinesterase)
3) Drug Interactions:
_Neostigmine and other Anticholinesterases
_Ester Local Anesthetics
(Esters are Broken down by Pseudocholinesterase; thus, compete with succinylcholine for enzymatic breakdown)
4) Organophosphate Exposure
(Chronic, Sub-Clinical):
e.g. Field workers and Avid Gardeners with Chronic, Low-dose use of Insecticides
5) Succinylcholine Apnea:
Genetic difference in type of Pseudocholinesterase (less effective form)
\_\_\_\_\_\_\_\_\_\_ Diazepam: _Increases Duration of Non-Depolarizing Blockers _Decreases Duration of Succinylcholine (Depolarizing Blocker)
____________
Adverse Effects:
1) Malignant Hyperthermia:
Treat with Dantrolene*
2) Hyperkalemia
=> Results in Cardiac Depression
(More common in Burn, Trauma patients; Dangerous if on Digoxin)
3) Histamine Release
4) Ganglionic Block:
=> Hypotension!
5) Bradycardia: (Muscarinic)
_Cardiac Arrest may result
6) Increased Bronchial Secretions (Muscarinic)
(Both Succinylcholine and Acetylcholine are derived from Choline. So, may act @ Muscarinic receptors too.)
7) Fasciculations of Abdominal Muscles:
Causing Increased IntraGastric Pressure:
=> Increased Risk for Reflux
(Most likely in patients with Delayed Gastric Emptying, e.g. Diabetics, Morbid Obesity
8) Increased IntraOcular Pressure:
- -Transient (Peaks @ 2-4 min)
9) Post-Operative Muscle Pain
__________________
HOW TO REVERSE EFFECTS:
_Give Plasma!!
Need Normal Pseudocholinesterase!!!
_Cannot give Neostigmine b/c will only exacerbate.
_Don’t give Atropine because Atropine is a Muscarinic Blocker.
Factors Influencing Action of Neuromuscular Blockers
1) Blood Flow: _High Blood flow, _Quicker Onset, _Shorter Duration (Faster drug gets to target tissue; faster it gets out)
2) Age:
_Prolonged Action in Elderly
3) Diazepam:
_Increases Duration of Non-Depolarizing Blockers
_Decreases Duration of Succinylcholine
(Depolarizing Blocker)
4) **Aminoglycosides:
_Large Doses can cause muscle block.
_When given with a Muscle Blocker, will Increase the Intensity and Duration of the Block. (Synergy)
(With Competitive or Depolarizing Blockers)
5) Ester Local Anesthetics: (Esters are Broken down by pseudocholinesterases; thus, compete with succinylcholine for enzymatic breakdown)
6) Low Pseudocholinesterase: _If Low, Increases Duration of Blockers: (i) Succinylcholine Apnea (Genetic) (ii) Liver Disease (iii) Severe Malnutrition
7) Cholinesterase Inhibitors:
e.g. Echothiophate (irreversible)
_Neostigmine and other Anticholinesterases
_ Organophosphate Exposure
(Chronic, Sub-Clinical):
e.g. Field workers and Avid Gardeners with Chronic, Low-dose use of Insecticides
8) Myasthenia Gravis:
_Increased Sensitivity to Competitive Blockers
(Non-Depolarizers)
Ganglion Blockers
Trimethaphan
Mecamylamine
No longer available in USA
Uses:
_Anti-Hypertensive (Short-term, for Hypertensive Crisis)
Adverse Effects:
_Many; Depend on the predominant tone at the time of the block
_Usually see Decreased Muscarinic Effects:
1) Mydriasis (Dilated Pupils) (Iris)
2) Cycloplegia, Blurred Vision (Ciliary muscle) (Accommodation)
3) Dry Mouth (Xerostomia),
4) Anhidrosis (Sweat Glands)
(Sympathetic)
5) Tachycardia
6) Constipation
7) Urinary Retention
Note:
1) Predominant Tone in Vasculature is Sympathetic.
_Ganglionic Block results in Vasodilation, Hypotension.
(Sweat Glands Sympathetic too)
2) Predominant Tone everywhere else is Parasympathetic.
_Ganglionic Block results in Anti-Muscarinic effects.
Botulinum Toxin
Inhibits Release of Acetylcholine
- Uses (Diluted form):
1) Local Muscle Spasms
2) Excessive Sweating
3) Cosmetic (Reduce Wrinkles)
4) Migraines
Extremely Toxic! High Mortality.
Recovery: Weeks to Months
Food Poisoning
=> Progressive Parasympathetic Block
=> Motor Paralysis
1) Dry Mouth,
2) Blurred Vision
3) Difficulty Swallowing
4) Progressive Respiratory Paralysis => Death!
Anti-toxin is used to treat the poison.
