Autonomic Pharmacology Flashcards
location of baroreceptors (3)
and
location of central autonomic centers
- walls of carotid sinus
- aortic arch
- heart wall
- hypothalamus
- limib system
- medulla oblongata
Somatic system: origin, neurotransmitter, receptor and location
various levels of spinal cord, ACh, nicotinic receptors (Nm), skeletal striated muscle
Autonomic system- Parasympathetic: origin, neurotransmitter, receptor and location
cranial and spinal, Ach, nicotinic receptors in ganglion ;;;; Ach, muscarinig receptors in smooth muscle, cardiac tissue, and secretory glands
Autonomic system - Sympathetic: origin, neurotransmitter, receptor and location
see figure
Muscarinic M2 and M4 receptors
(what are these antagonists of?)
Gi –> inhibit adenylyl cyclase and cAMP signaling
(antagonists of agents like beta receptors that strictly work through activating adenylyl cyclase)
Muscarinic M1, M3, and M5 receptors
signal through Gq –> activate phospholipase C and IP3-DAG signaling —> Calcium binds calmodulin –> activates myosin light chain kinase –> phosphorylation of myosin globular heads, allowing interaction with actin –> **smooth muscle contraction **
How are nicotinic receptors different that muscarinic?
- ionotropic (muscarinic are metabotropic/secondary signaling)
- receptor has instrinsic chanel activity within it
- agonist/ligand binds to receptor, opens channel and get ion passing through
- much faster, since channel is part of the receptor itself (muscarinig have to go through signalling through other proteins)
*
Adrenergic receptors
a type of muscarinic GPCR
2 classes: alpha and beta
NE is released and interacts with receptors
Glaucoma
defect/deficit in outflow of the aqeuous humor fluid. It is constantly being made and drained through the trabecula network. If this drainage gets messed up, you have an elevated intraocular pressure and can destroy the optic nerve.
List the 5 drugs used for glaucoma
- cholinomimetics (cholinergic agonists)
- alpha agonists (non-selective or alpha2-selective
- beta blockers
- carbonic anyhdrase inhibitors
- prostaglandins
For each drug used for glaucoma, describe the effect:
cholinomimetics
ciliary muscle contraction (lens round for close vision), opening of trabecular meshwork, increased outflow
For each drug used for glaucoma, describe the effect: alpha agonists
increased outflow and decreased aqeuous production
For each drug used for glaucoma, describe the effect: beta blockers
decreased aqeuous production
For each drug used for glaucoma, describe the effect: Carbonic anhydrase inhibitors
decreased aqueous production
For each drug used for glaucoma, describe the effect: Prostaglandins
increased outflow
Cholinoceptor agonists
indirectly-acting cholinoceptor agonists
- mimic actions of ACh
- vary in chemical structure and selectivity
- indirectty acting: cholinesterase inhibitors: inhibit the hydrolysis of ACh
atropine
muscarinic antagonist- tertiary amines, can be used in treating intoxication from cholinoceptor agonists
drug action for tx of myasthenia gravis
cholinomimetic -cholinesterase inhibitors, work on nicotinic receptors found at the neuromuscular junction, nonselective for muscarinic receptors
ex. neostigmine
What is the purpose of making derivatives of ACh?
can adjust the molecule to a) increase resistance** to degradation by acetylcholinesterase or b) change thespecificity** to make it more selective for certain receptors (muscarinic vs nicotinic)
ex. choline esters (change methyl group for NH2)
For each m uscarinic receptor subtype, list the primary location and dominant effector system:
M1, M2, M3 (most abundant)
M1: nerves, IP3 DAG,
M2: heart, nerves, smooth muscle, cAMP, K+ channel current
M3: glands, smooth muscle, ednothelium, IP3 DAG
- Note: M1 and M3 use Gq*
- M2 and M4 use Gi*
explain the differential effect of ACh on blood vessels with and without endothelial layer. What is the m echanism? (Ach acts on which receptor, whats the secondary signaling etc)
- “unrubbed” / endothelial layer in tact = blood vessel relaxation
- “rubbed off” / endothelial layer gone = blood vessel contraction
endothelial cells contain endothelial derived relaxation factor (EDRF) = nitric oxide = relaxation
3 structural types of indirect-acting cholinomimetics (AChE inhibitors)
- simple alcohols (edrophonium)
- carbamic esters of alcohols (neostigmine)
- organophsophates (nerve gases: sarin, soman, tabun)
all bind to active site of AChE enzyme
all consirered reversible (slow degradation by AChE) EXCEPT organophosphates)
important of amount of nitrogen groups for AChE inhibitors
different nitrogen groups affects solubility and thus whether it crosses the BBB
quaternary and charged CANT cross, stay in periphery (Neostigmine, good for MG since stays in periphery)
tertiary can cross
Reactivation of organophsophate-inhibited AChE
2-PAM (pralidoxime)
-interacts directly with the organophosphate by recognizing its side chains, sitting on serine group on active site of AChE and knocks organophsophate off
Symptoms of nerve gase poisoning
Basically asking: what happens when you add esterase ACHE inhibitors?
-youre going to elevate ACh levels everywhere, and ACh interacts with nicotinic and muscarinic
SLUDGEM “rest and digest”
- salivation
- lacrimation (tears)
- urination
- defecation
- GI upset
- emesis (vomiting)
- miosis (pupil constriction)
drug management of nerve gase poisoning
- atropine
- pralidoxime (2-pam)
- diazepam for convulsions (benzodiazepine, via GABA)
CLinical use of AchE inhibitors for postoperative ileus
-often following surgery, you have paralysis of these organs, so you can use AChE to “jump start” them again
Atropine
-usage for eye exams?
muscarinic antagonist (AcH antagonist)
-hangs around for a long time pharmacokinetically, so wouldn’t be good for eye exams since you’d want it to wear off so pt can drive hom
Antimuscarinic or Atropine-like effects (5)
think of inhibiting “rest and digest”
- blurred vision
- dry mouth
- constipation
- urinary retention
- mental confusion
organ system effects of muscarinic antagonists (atropine)
CNS
Eye
GI system
Genitourinary
CNS:
- tremor relief in parkinson’s
- vestibular disturbance relief
Eye
- mydriasis (pupil dilation)
- cycloplegia (loss of accomodation)
- dry eye (decreased lacrimal secretion)
GI
- inhibits motility and secretion in the gut
- inhibits salivary secretion
Genitourinary
- relaxes smooth muscle of uterus and bladder wall ==> inhibits motility ==> SLOWS DOWN going to the bathroom
- thus anticholinergics treat urinary incontinence (unable to prevent urine from leaking out)
Explain mechanism of muscarinic antagonists for Parkinson’s
Normal: you need dopamine to block pathways that cause movement inhibition and bradycardia ==> dopamine allows for movement
Parkinson’s: degeneration of dopamine, get more ACh release, more bradycardia movement inhibition ===> less dopamine, can’t move
muscarinic antagonists try to overcome the increased ACh (end up being more effective for tremor)
alpha 1: tissue and actions
most vascular smooth muscle –> contraction
pupillary dilator muscle –> contraction of muscle, pupil dilation
heart –> increased force of contraction
prostate –> contraction
pilomotor smooth muscle –> erects hair
alpha 2: tissue and actions
post synaptic CNS adrenoceptors –> multiple actions
platelets –> aggregation
adrenergic and cholinergic nerve terminals –> inhibits transmitter release
some vascular smooth muscle –> contraction
fat cells –> inhibits lypolysis
beta 1: tissue and action
heart –> increases force and rate of contraction
juxtaglomerular cells –> increases renin release (RAAS –> increases BP)
beta 2: tissue and actions
respiratory, uterine, and vascular smooth muscle –> smooth muscle relaxation
skeletal muscle –> potassium uptake
beta 3: tissue and actions
fat cells –> lipolysis
D1 and D2: tissue and actions
D1: smooth muscle –> dilates renal blood vessels
D2: nerve endings –> modulates transmitter release
which receptor does NE have very little effect on?
B2
(epi is non selective for all the alpha and beta)
While direct sympathomimetics act directly on adrenoreceptors, expalin the two ways indirect sympathomimetics acts
- displace stored catecholamines
- decrease clearance of released NE
- inhibit NE reuptake
- inhibit degradation by inhibiting MAO or COMT enzymes
phenylephrine
isoproterenol
adrenergic agonists:
phenylephrine - a1 selective
isoproterenol- ß1 ß2 non-selective
(as a result, you relax smooth muscle in bronchioles but you also get tachycardia)
phentolamine
propranolol
adrenergic receptor antagonists:
phentolamine: non-selective alpha receptor antagonist
propranolol: non-selective beta receptor antagonist
two factors controlling BP: which one predominates?
BP = CO x PVR
peripheral vascular resistance predominates because you have a HUGE vascular bed
Action of phenylephrine
- a1 selective agonist
- vascular smooth muscle contraction
- increase in BP
Action of Epinephrine
- mixed- agonist for alpha and betas
- a1 predominates in blood vessels - contraction
- get increase in BP (not as sustained, because you have the baroreflex, and epi also acts on B2 receptors in blood vessels that promote relaxation
- increase in HR (beta 1 receptor in heart)
Action of isoproterenol
beta selective agonist
- B1: increase force of contraction and HR
- B2: relaxation in blood vessels
- peripheral trumps cardiac, so overall you get relaxation
effect of phentolamine
- non-selective alpha antagonist
- small decrease in BP
effect if you add epinephrine before phentolamine
vs
effect if you add phentolamine before epi
epi before phentolamine (nonselective alpha antagonist)
- contraction via a1
- increase BP
phentolamine before epi
- BP comes down
- effect of epi gets reversed - phentolamine blocks all the alpha receptors on blood vessels, so epi will react with B2 receptors, which promote relaxation
- synergistic effect
describe what happens to cardiac contractil force, arterial pressure, and HR when adding:
- epinephrine
- Propranolol then epinephrine
epinephrine:
- increase in all three
propranolol (beta blocker) then epi
- decreases force of contraction and HR (B1)
- no real change in BP - most of blood vessels are a1, which arent affected by propranolol (a little inhibition of B2 which inhibits smooth muscle relaxation, so you might see a little increase but not much)
therapeutic uses of sympathomimetic drugs:
orthostatic hypotension
alpha agonist –increase PVR (midodrine)
therapeutic uses of sympathomimetic drugs: inducing local vasoconstriction
epi and cocaine–reduce mucous membrane congestion
therapeutic uses of sympathomimetic drugs: pulmonary/asthma
beta2 selectives: albuteral, metaproterenol, terbutaline (bronchodilators)
therapeutic uses of sympathomimetic drugs: anaphylaxis
epinephrine
therapeutic uses of sympathomimetic drugs: opthalmic: mydriasis for retinal exams, glaucom
PHENYLEPHRINE for mydriasis (agonists a1>a2>>>>>>B)
alpha 2 agonists for glaucoma
therapeutic uses of sympathomimetic drugs: genitourinary: relax pregnant utereus, suppress premature labor
beta 2 agonists - relax pregnant uterus and suppress premature labor
