7) Cholinoreceptor Blockers Flashcards
The muscarinic blockers can also be subdivided based on their
- Primary clinical target organs (CNS, eye, bronchi, or GI and genitourinary tracts)
Drugs used for their effects on the CNS or the eye must be
- Sufficiently lipid-soluble to cross lipid barriers
Charged (quaternary) amine group in the drug are
- Polar
- NOT lipophilic
- Cannot be used for CNS
Competitive antagonists and their blocking effects can be overcome by
- Increased muscarinic concentrations
Anticholinergic symptoms
- Urinary retention
- Sedation, dizziness, confusion, hallucinations
- Dry throat/mouth, constipation
- Feeling hot, decreased swetting
- Blurred vision, dry eyes
- Tachycardia
Non selective anti-muscarinic drugs
- Scopolamine
- Dicyclomine
- Oxybutinin
- Atropine
- Homoatropine
- Cyclopentolate
- Tropicamide
Selective anti-muscarinic drugs
- Darifenacin
- Fesoterodine
- Solifenacin
- Tolterodine
Scopolamine
- Motion sickness
- Targets CNS
- DOA = 2-6 hours
- Brand = TransdermScop
Dicyclomine
- Intestinal cramping
- Targets GI
- DOA = 1 hour
Oxybutinin
- Reduce bladder urgency
- Targets bladder
- DOA = 6-10 hours
- Brand = Oxytrol
Atropine
- Dilates pupils (mydriasis), cramping, hypermotility in diarrhea
- Targets eye and gut
- DOA = 2-4 hours (except > 72 hours in eye)
Characteristic of atropine
- Competitive antagonist of all Ms
- Antidote for cholinesterase inhibitors of toxicity
Homoatropine
- Dilates pupils (mydriasis)
- Targets eye
- DOA > 24 hours
Cyclopentolate
- Dilates pupils (mydriasis)
- Targets eye
- DOA = 2-12 hours
Tropicamide
- Dilates pupils (mydriasis)
- Targets eye
- DOA = 0.5-4 hours
Darifenacin, fesoterodine, solifenacin, and tolterodine usage
- Urinary urgency/incontinence
- Overactive bladder
- Selective for M3 receptors
- Oral administration
- DOA = 12-24 hours
- Excessive parasympatholytic effects
Ipratorium (Atrovent HFA)
- Short acting muscarinic antagonist (SAMA) in the lungs
Ipratorium (Atrovent HFA) selectivity
- Non-selective antagonist of M1, M2, and M3 muscarinic racetylcholine receptors (mAChRs)
Ipratorium (Atrovent HFA) effects
- Allows bronchodilation in asthma/COPD
- OOA = 10 min
- Peak = 2 hours
- DOA = 6 hours
Ipratorium (Atrovent HFA) administration route
- Nebulizer form
Ipratorium (Atrovent HFA) metabolism
- Partially metabolized to inactive ester hydrolysis products
- Excreted in urine
Long acting muscarinic antagonists (LAMA) in lungs
- Aclidinium
- Glycopyrrolate
- Tiotropium
- Umeclidinium
- MOA for all = reversible antagonists
Aclidinium selectivity
- Non-selective M receptors
- Similar affinity to all Ms
- Dissociation half life from subtype M3 = 30 hours
LAMA dosage form
- Oral inhalation
- Causes bronchodilation in asthma/COPD
Aclidinium brand
- Tudorza
- Pressair
Aclidinium peak and DOA
- Peak = 10 min
- DOA = 12 hours
Aclidinium metabolism
- Rapid and extensive hydrolysis via plasma esterases
- Become inactive metabolites
- Excreted in urine
Glycopyrrolate selectivity
- Non-selective, but acts mainly on M3
Glycopyrrolate brand
- Seebri
- Neohaler
Glycopyrrolate peak and DOA
- Peak = 5 min
- DOA = > 24 hours
Glycopyrrolate metabolism
- Hepatic (minimal) then bile excreted
Tiotropium selectivity
- Non-selective, but acts mainly on M3
- Has short M2 activity
Tiotropium brand
- Spiriva
- Handihaler/Respimat
Tiotropium peak and DOA
- Peak = 10 min
- DOA = 24 hours
Tiotropium metabolism
- Hepatic (minimal)
- Urine excreted
Umeclidinium selectivity
- M3 inhibitor
Umeclidinium brand
- Incruse Ellipta
Umeclidinium peak and DOA
- Peak = 10 min
- DOA = 24 hours
Umeclidinium metabolsim
- Hepatic via CYP2D6
- Excreted in feces
Nicotinic antagonists
- Ganglionic blockers
- Neuromuscular blockers
Ganglionic blockers
- Competitive antagonists
- Drugs are discontinued because of severe side effects
Neuromuscular blockers
- Block transmission at muscle end plate
- Muscle relaxation (required for surgical relaxation, tracheal intubation, and control of ventilation)
Neuromuscular blockers structure
- Quaternary amines structurally related to acetylcholine (ACh)
Most NMB are
- Antagonists (nondepolarizing type)
- Prototype = tubocurarine
Succinylcholine (a neuromuscular blocker)
- Agonist at the nicotinic end plate receptor
- Depolarizing type
Neuromuscular blocking drugs are quaternary amines thus they do not enter
- CNS
- No effect on cognition, memory, or sensory input, including perception of pain
NMB mechanism of action
- ACh (normal agonist) opens the sodium channel
- Non-depolarizing and depolarizing blockers
Non-depolarizing blockers
- Bind to the receptor to prevent opening of the channel
Depolarization blockers (Succinylcholine)
- Initial depolarization accompanied by twitching and fasciculations
- Then persistent depolarization (followed by repolarization) of the channel
- Leads to muscle relaxation and paralysis
All non-depolarizing NMBs are administered
- Parenterally
- Highly polar drugs that can’t cross BBB
Rocuronium (non-depolarizing NMB)
- Eliminated in bile
- DOA = 10-20 min
- Most rapid onset time (60-120 seconds)
Metocurine, pancuronium, pipecuronium, and tubocurarine (non-depolarizing NMBs)
- Eliminated via kidney
- Usually have durations of action of 35–60 min
Atracurium (non-depolarizing NMB)
- Hepatic metabolism
- Clearance forms laudanosine (can cause seizures)
- Rarely used
Cisatracurium (non-depolarizing NMB)
- Stereoisomer of atracurium
- Inactivated spontaneously but forms less laudanosine
- One of the most commonly used muscle relaxants in clinical practice
Non-depolarizing drugs prevent the action of
- ACh at the skeletal muscle end plate
- Can be overcome by increasing the amount of agonist [ACh] in the synaptic cleft
Succinylcholine (depolarizing NMB)
- Duration of action of only a few minutes if given as a single dose
Succinylcholine effects
- Stimulates autonomic ganglia
- Stimulates cardiac muscarinic receptors
Depolarizing NMB (Succinylcholine) toxicity
- Muscle pain and muscle damage may occur
- Hyperkalemia, especially in patients with burns or spinal cord injury, peripheral nerve dysfunction, or muscular dystrophy
- Increases in intragastric pressure caused by fasciculations
List of non-depolarizing NMBs
- Atracurium
- Cisatracurium
- Rocuronium
- Pancuronium
- Tubocuranine
- Vecuronium
- Doxacurium
- Pipecurium
Pancuronium effects
- Moderate block of cardiac muscarinic receptors
Tubocuranine effects
- Moderate ability to release histamine
Non-depolarizing NMBs toxicity
- Respiratory paralysis
Cholinesterase generators
- Pralidoxime (2PAM)
Pralidoxime (2PAM) use
- Treat exposure to organophosphate AChE inhibitor insecticides (such as parathion) or to nerve gas
Pralidoxime (2PAM) structure/MOA
- Oxime that binds to organophosphate inactivated by acetylcholinesterase
