Lec 34 Drugs acting on the ANS Flashcards
What is the 1 synapse vs 2 synapse organization of our nervous system?
somatic uses 1 synapse
autonomic system uses 2 synapses = have preganglionic and postganglionic fiber
What are the 3 branches of the ANS?
- parasympathetic
- sympathetic
- enteric
What is the action of enteric nervous system?
- complex network of neruons in gut wall
mostly independent of CNS
does extensive intrinsic gut activity including peristalsis
Where are preganglion cell bodies located for sympathetic vs parasympathetic?
SNS: thoracic and lumbar levels of spinal cord
PNS: medulla, sacral levels of spinal cord
Which nerves cary preganglionic axons for SNS vs PNS
SNS: thoracolumbar = thoracic + lumbar
PSN: craniosacral = cranial and sacral
Where are ganglia located for SNS vs PNS?
SNS: near spinal cord in paravertebral or prevertebral ganglia
PNS: near or in wall of innervated organ
In what tissues do the SNS and PNS exert complementary/similar effects?
male sex organs
uterus during labor
What tissues are only innervated by one branch [PNS or SNS]?
vasculature = only SNS
liver = only SNS
sweat glands = only SNS
generally when something is innervated by only one branch its going to be sympathetic!
What types of ANS synapses release ACh?
- all preganglionic neurons
- all postganglionic PNS neurons
- a few post-G SNS neurons = sweat glands
What types of ANS synapses release NE?
most sympathetic postganglionic neurons
What types of ANS synapses release dopamine?
sympathetic fibers that innervate the renal vasculature and some other vessel beds
What types of ANS synapses realease epinephrine?
not synaptic! its a hormone released by adrenal medulla
How can you tell wich is the predominant tone of a titssue?
usually its the branch of ANS that makes the organ or tissue contract/movie
ex. PNS increases GI motility so is dominant tone
exception: hearts predominant tone is PNS but PNS slows HR
How is ACh action terminated at synapse?
- acetylcholinesterase [AChE] on postsynaptic membrane hydrolyzes
What is action of physotstigmine?
inhibits AChE –> more ACh around –> more PNS
How is action of catecholamines [NE, Epi, Dopamine] terminated at synapse?
mainly by reuptake of transmitter
What type of receptor is cholinergic nicotinic receptor? cholinergic muscarinic receptor?
nicotinic = ionotropic = voltage gated muscarinic = GPCR
How does nAChR of ANS ganglia differ from one at NMJ?
Nn = ganglionic type
Nm = NMJ type
different morphologies –> drugs can be selective for one type or the other
What are the different types of muscarinic ACh receptors? What G proteins are they coupled to?
M1/M3/M5 = couple to Gq
- activate phospholipase C, increase Ca, stimulate protein kinase C; mostly M3 in ANS
M2/M4 = couple to Gi and Go
- inhibit adenylyl cyclase and hyperpolarize membrane via GIRKs [inward rectifying K channels]; mainly M2 in ANS; activate G
What type of receptors are a receptors vs B receptors
a = GPCRs B = GPCRs
What are action of a1 vs a2 receptors? what G proteins?
a1 = expressed on possynaptic effector cells
- couple to Gq –> IP3 and DAG –> elevate intracellular Ca and stimulate protein kinase C
- contract smooth muscle in arterioles/viscera/pupils
a2 = inhibitory autoreceptors
- couple to Gi/Go –> reduce cAMP –> hyperpolarize membrane through activation of GIRK channels
What are actions of B1/B2/B3 receptors? what G proteins?
all couple to Gs and increase cAMP
B1/B2 widely distributed
B3 expressed on fat cells and contribute to lypolysis
Where are some tissues where B1 > B2 and some where B2 > B1?
B1> B2 in : heart, juxtaglomerular cels
B2 > B1 in: skeletal and coronary arterioles; bronchial smooth muscle;
What are the 2 types of dopamine receptors in ANS? What G proteins?
D1 = couple to Gs –> mediate vasodilation; prominent in renal vasculature
D2 = couple to Gi –> negative feedback
What is mech of action epinephrine? What does it do to HR, TPR, DBP, SBP, MAP at low dose?
non selective a and B receptor agonist
HR: increase TPR: decrease slightly--> b/c more potent activity for B2 DBP: decrease SBP: increase MAP: increase slightly
What is mech of action norepinephrine? What does it do to HR, TPR, DBP, SBP, MAP at low dose?
selective a and B1 receptor agonist [no B2]
HR: decrease [b/c of baroreceptor reflex] TPR: increase = b/c no B2 vasodilation DBP: increase SBP: increase MAP: increase
What is mech of action isoproterenol? What does it do to HR, TPR, DBP, SBP, MAP at low dose?
selective B receptor agonist
HR: increase a lot TPR: decrease a lot = vasodilator DBP: decrease a lot SBP: decrease or slightly increase MAP: decrease
What are homeostatic mech on scale of sec? on scale of min to hr?
sec: autoreceptors sense recent history of transmiter release from terminal, inhibit more release
min/hrs: during periods of little synaptic activity, adiditonal receptors synthesized + placed in postsynaptic membrane [= denervation sensitization]; reverse occurs during period of high activity
What is baroreceptor reflex?
- decrease in BP sensed by baroreceptors
- decrease baroreceptor activity conveyed to medulla
- increased SNS and decreased PNS activity in medullary centers –> vasoconstriction and increase CO
- homeostatic increase in BP
What type of sympathetic receptors expressed in vasulature?
- a1 receptors widely in vasculature
- B2 among vascular beds [in coronary + skeletal muscle arterioles]
What is action of sympathetic acivity on vasculature?
- net increase in TPR and decrease in venous capacitance
blood flow redistributed to vessels with lots of B2 and away from vessels where mostly a
renal blood flow preserved by activation of D1 receptors on afferent and efferent arterioles
What is effect of sympathetic on the heart?
B1 receptors in ventricles; B2 in atria/ SA node
- increase contractility via B1 [inotropy]
- increase HR at SA node [chronotropy]
What is role of GIRK current in SA node?
contributes to negative resting Vm
drives Vm toward Vk
How is mechanism of sympathetic positive chronotropic effect?
- stimulation B receptors increase intracellular cAMP
- cAMP binds HCN [funny current] channels and increases their conductance
- large If drives membrane voltage to AP spike threshold sooner
- also acts to increase conudction velocity through AV node by increasing cAMP –> activates protein kinase A –> phsophorylate L type Ca channels and increases their conductance –> faster propagation
What is mech of action of sympathetic on contractility/relaxation [positive inotropy/lusitropy]?
- SERCA pump inhibited by phospholamban
- cAMP activated PKA phosphorylated phospholamban –> high SERCA activity –> more Ca into SR –> more contractile strength
- rate of relaxation following AP depends on how quickly SERCA can sequester Ca in the SR
What are sympathomimemetic vs sympatholytic drugs?
sympathomimetic = direct agonists or uptake/degradation inhibitors or release; mimic effect of SNS NT release
sympatholytic = block normal sympathetic transmission = antagonists
What is use of B-blockers?
have wide use in HTN, angina, arrhythmias, heart failure
use primarily in HTN due to excessive sympathetic activity; reduce mortality in CHF
What is parasympathetic effect on vasculature?
few vessels PNS innervated so does not afect vascular tone
BUT there are muscarinic receptors on vascular endotehlium –> when activated release NO –> increase cGMP –> vasodilation
What are parasympathetic effects on heart? mech?
- mostly on atria
- at SA node –> negative chronotropy
stimulate muscarinic receptors –> increase current through GIRK channels mediated by Gby –> membrane more negative between APs –> takes longer to reach spike threshold
at AV node –> negative dromotropy –> longer PR; AV block if too much
activates Gi–> reduce cAMP phosphorylation of Ca channels –> slow upstroke of AP
in atrial muscle –> decreased contractility and shorter AP duration by same mech
What are PNS effects on airway?
- bronchoconstriction
- increase secretions
What are PNS effects on bladder?
- contract bladder wall
- relax sphincter
What are PNS effects on eye?
- miosis
- near vision
What are the types of cholinesterase inhibitors?
- competitive inhibitors
- carbamates
- organophosphates
What is SLUDGE signs of PNS overdose?
- salivation
- lacrimation
- urination
- defecation
- GI pain
- emesis
What is killer B’s of PNS overdose?
- bronchorrhea
- bronchospasm
- bradycardia
What is DUMBELS of PNS overdose?
- defecation
- urination
- miosis
- bronchorrhea/bronchospasm/bradycardia
- emesis
- lacrimation
- salivation
What is use of carbamate and organophosphate type AChE inhibitors?
use as insecticides and nerve gases = sarin
What is use of ganglion blockers?
- antagonist of neuronal nicotinic receptors –> denervate autonomic targets = effect oppostie to predominant tone
–> HR increase; BP decrease
ANS reflexes absent when ganglia blocked
What happens if you abruptly stop Beta blockers?
- abrupt withdrawal can lead to exacerbation of angina and possible MI
- need to taper off B blockers
Who should you avoid giving beta blockers?
diabetes: give with precaution; can induce hypoglycemia and mask symptoms of hypoglycemia; also linked to increased risk of insulin resistance
avoid in pts with asthma b/c risk of bronchoconstriction
What are adverse effects of beta blockers?
- bradycardia
- bronchoconstriction
- fatigue
- CNS effects
- vasospasm –> worsening of raynaud’s phenomenon
- erectile dysfunction
