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Autonomic drug, G-protein-linked second messenger, Autonomic drugs, Beers…
Autonomic drug
G-protein-linked second messenger
β₃
Gs
↑lipolysis, ↑thermogenesis in skeletal muscle, ↑bladder relaxation
D₁
Gs
relax renal vascular smooth muscle, active direct pathway of striatum
M₂
Gi
↓heart rate and contractility of atria
α₁
Gq
↑smooth muscle contraction, ↑pupillary dilator muscle contraction, ↑intestinal and bladder sphincter muscle contraction
β₁
Gs
↑heart rate, ↑contractility, ↑renin release, ↑lipolysis
β₂
Gs
vasolidation, bronchodilation, ↑lipolysis, ↑insulin release, ↑glycogenolysis, ↓uterine tone, ↑aqueous humor production, ↑cellular K⁺ uptake
M₁
Gq
higher cognitive function, stimulate enteric nervous system
α₂
Gi
↓sympathetic outflow, ↓insulin release, ↓lipolysis, ↑platelet aggregation, ↓aqueous humor production
M₃
Gq
↑exocrine gland secretion, ↑gut peristalsis(蠕動), ↑bladder contraction, bronchoconstriction, ↑pupillary sphincter muscle contraction, ciliary muscle contraction, ↑insulin release
H₁
Gq
↑nasal and bronchial mucus production, ↑vascular permeability, bronchoconstriction, pruritus, pain
V₂
Gs
↑H₂O permeability and reabsorption via upregulating aquaporin-2 in collecting tubule of kidney
D₂
Gi
modulates transmitter release, indirect pathway of striatum
H₂
Gs
↑gastric acid secretion
V₁
Gq
↑vascular smooth muscle contraction
cascade
(Gq→phospholipaseC→)PIP₂→DAG→Proteinkinase C
PIP₂→IP₃→Ca²⁺ →smooth muscle contraction
(Gs,Gi→Adenylyl cyclase→)ATP→cAMP→proteinkinase A
Autonomic drugs
muscarinic antagonist
atropine, homatropine, tropicamide: eye
benztropine, triphenidyl: CNS
glycopyrrolate: GI, respiratory
hyoscyamine, dicyclomine: GI
ipratropium, tiotropium: respiratory
oxybutynin, solifenacin, tolterodine: genitourinary(泌尿器)
scopolamine: CNS
atropine
airway: bronchodilation, ↓secretion
stomach: ↓acid secretion
eye: ↑popildilation, cycloplegia
gut:↓motility
used to bradycardia, ophthalmic application
bladder: ↓urgency in cystitis
adverse effect: ↑temperature, dry mouth, skin, flushed skin, cycloplegia, constipation, disorientation, urinary retention,etc
sympathomimetics
direct
fenoldpam: D₁: hypertention, vasodilator
isoproterenol: β₁=β₂: electrophysiologic evaluation of tachyarrhythmias
epinephrine: β>α: anaphylaxis, asthma, open-angle glaucoma
midodrine: α₁: autonomic insufficiency and postural hypotention(起立性低血圧)
dopamine: D₁=D₂>β>α: bradycardia, HF, shock
mirabegron: β₃: urinary urge incontinence or overactive bladder(過活動膀胱)
dobutamine: β₁>β₂,α: HF, cardiogenic shock
norepinephrine: α₁>α₂>β₁: hypotension, septic shock
albuterol, salmeterol, terbutaline: β₂>β₁: for acute asthma or COPD (albuterol), for long-term asthma or COPD (salmeterol), for acute bronchospasm in asthma and tocolysis(子宮収縮抑制) (terbutaline)
phenylephrine: α₁>α₂: hypotension, ocular procedure, rhinitis(鼻炎), ischemic priapism(持続勃起)
indirect
amphetamine: for narcolepsy, obesity, ADHD
cocaine: vasoconstriction and local anesthesia
ephedrine: for nasal decongestion(うっ血), urinary incontinence, hypotension
norepinephrine vs isoproterenol
NE
↑systolic and diastolic pressure (α₁ vasoconstriction)→↑mean arterial pressure→reflex bradycardia
isoproterenol
β₂mediated vasodilation→↓mean arterial rate, ↑heart rate through β₁activity and reflex
α₂ agonist
hypertension in pregnancy
relief of spasticity(けいれん)
clonidine, guanfacine: for hypertensive urgency, ADHD, Tourette syndrome
α blocker
effect of α-blocker on BP response to epinephrine and phenylephrine
epinephrine: reversal of mean arterial pressure
phenylephrine: not reversed
α₁ selective
prazosin, tarazosin, doxazosin, tamsulosin: for urinary symptom of BPH(前立腺肥大症); PTSD, hypertension
nonselective
phenoxybenzamine: for pheochromocytoma(褐色細胞腫) to prevent catecholamine crisis
phentolamine
α₂ selective
mirtazapine: depression
β-blocker
for angina pectoris, glaucoma, heart failure, hypertension, hyperthyroidism, hypertrophic cardiomyopathy, myocardial infarction, supraventricular tachycardia(発作性上室頻拍), variceal bleeding(静脈瘤出血)
adverse: erectile dysfunction, cardiovascular, CNS, dyslipidemia, asthma, COPD
acebutolol, atenolol, betaxolol, bisoprolol, carvedilol, esmolol, labetalol, metoprolol, nadolol, nebivolol, pindolol, propranolol, timolol
β₁-selective: acebutolol, atenolol, betaxolol, bisoprolol, esmolol, metoprolol
non selective: nadolol, pindolol, propranolol, timolol
nonselective α and β: carvedilol, labetalol
nebivolol: cardiac selective β₁ blockade, stimulation of β₃
cholinesterase inhibitor poisoning
due to organophosphate, such as parathion, that irreversively inhibit AChE
diarrhea, urination, miosis, bronchospasm, bradycardia, emesis, emesis(嘔吐), lacrimation, sweating, salivation
may lead to respiratory failure
antidote: atropine+pralidoxime
cholinomimetic agent
direct agonist
carbachol: carbon copy of acetylcholine
methacholine: stimulate muscarinic receptor in airway when inhaled
bethanechol: activate bowel and bladder smooth muscle, no nicotinic activity
pilocarpine: contract ciliary muscle, pupillary sphincter, can cross BBB
indirect agonist
donepezil, rivastigmine, galantamine: ↑ACh: Alzheimer disease
edrophonium: ↑ACh
neostigmine: ↑ACh
physostigmine: ↑ACh
pyridostigmine: ↑ACh; ↑muscle strength
release of norepinephrine from a sympathetic nerve ending is modulated by NE, acting on presynaptic α₂-autoreceptor→negative feedback
amphetamine use NET to enter the presynaptic terminal, utilize vesicular monoamine transporter to enter neurosecretory vesicle, displace NE from vesicle→concentration threshold, release
Beers criteria
benzodiazepine (delirium, sedation, fall)
PPIs(C.difficile infection)
NSAIDs (GI bleeding)
should be avoided in elderly
α-blocker: hypotension
anticholinergic, antidepressant, antihistamine, opioid (delirium(せん妄), sedation, fall, constipation, urinary retention)
central and peripheral nervous system
somatic
voluntary motor nerve
ACh-Nm
skeletal muscle
parasympathetic
pre(long)
ACh-Nn
post(short)
ACh-M
smooth muscle, gland cell, nerve terminal, cardiac muscle
sympathetic
pre(short)
ACh-Nn
post(long)
NE-α₁,α₂,β₁
smooth muscle, gland cell, nerve terminal, cardiac muscle
pre(short)
ACh-Nn
post(long)
D-D₁
renal vasculature smooth muscle
pre(short)
ACh-Nn
post(long)
ACh-M
sweat gland
pre
ACh-Nn (adrenal gland)
blood
NE-α₁,α₂,β₁
cardiac muscle, vessel
Epi-α₁,α₂,β₁,β₂
parasympathetic nerve
pelvic splanchnic nerve(骨盤内臓神経) and CNsⅢ,Ⅶ,Ⅸ,Ⅹ
adrenal medulla is directly innervated by preganglionic sympathetic fiber
ingested seafood toxin
histamine (scombroid poisonig)
histidine to histamine
mimics anaphylaxis
spoiled dark-meat fish
treat with antihistamine, albuterol, epinephrine
ciguatoxin
reef fish
open Na channel, causing polarization
tetrodotoxin
bind voltage-gated Na channel, preventing depolarization
pufferfish(ふぐ)
ACh receptor
Nicotinic ACh
ligand-gated Na/K channels
Nn and Nm
Muscarinic ACh receptor
M1~5 types
G-protein coupled receptor