Exam 2 Flashcards
main mechanism for ACh termination
degradation by AChE
main mechanism for catecholamine termination
re-uptake by transporters
beta 1 adrenergic receptor
sympathetic
increase HR at SA node, conduction at AV node, conduction/contraction at ventricles
M2 receptor
parasympathetic
decrease HR at SA node, decreased conduction velocity; AV blocks at AV node
bronchoconstriction, bronchial gland secretion
alpha 1 receptor
sympathetic
constriction of arteries
mydriasis in eye
beta 2 receptor
sympathetic
dilation of arteries in skeletal m.
bronchodilation in bronchial smooth m.
increase aqueous humor in eye
M3 receptor
Parasympathetic
increase NO in arterial endothelium –> dilation
bronchoconstriction, bronchial gland secretion
In the GI, what do M3 and M2 receptors do
increase GI motility & secretions
relax sphincters, salivation
In the bladder what do M3 receptors do
detrusor contraction
trigone & sphincter relaxation
In the eye what do M3 and M2 receptors do
miosis of pupil (constriction)
lacrimal gland secretion
alpha 2 receptor
sympathetic
decrease NE release at ANS nerves (presynaptic)
CNS inhibition
anticholinergic
muscarinic antagonist
Cholinergic/parasympathomimetic
NT that affects muscarinic receptors only (aka parasymp)
SLUDGE
Signs suggesting excessive cholinergic (parasymp) stimulation
Salivation, Lacrimation, Urination, Defication, GI symptoms, Emesis
Acetycholine
- endogenous cholinergic
- acts on both musc and nico receptors –> widespread unpredictable response
- short half life
- not used much clinically, except opthalmic
Bethanechol (direct cholinergic agonist)
w/ selectivity for M3
GI secretions/motility, bladder contraction, slight decrease HR
Used to treat non-obstructive urinary retention
Pilocarpine (direct cholinergic agonist)
induces miosis, decreases intraocular pressure for glaucoma
sometimes to induce salivation
Indirect acting cholinergic agnoists
inhibit AChE to decrease ACh degradation
act on both muscarinic and nicotinic, less selective
inotropic
modifying force or speed on contraction
cAMP activates what? Stimulated by what?
PKA
Receptors M2, M4, alpha 2 cause decrease in cAMP
Beta 1, 2, 3 increase cAMP
DAG, IP3 activate what? Stimulated by what?
PKC
Receptors M1, 3, 5, alpha1 cause increase in DAG, IP3
Non-covalent AChE inhibitors
reversible competitive antagonists of AChE
Physostigmine, Neostigmine
Physostigmine
counters CNS signs of anticholinergic intoxication
can cross BBB, Neostigmine can’t
Cholinergic antagonist (anticholinergic, parasymptholytiv)
Blocks ACh at muscarinic (parasymp) receptors
Signs of anticholinergic toxicity
tachycardia, bronchodilation, dry mouth, decreased urination, decreased lacrimation, mydriasis, accomodation
aka anti-SLUDGE
Atropine (competitive anticholinergic)
- non-discriminant, so affects multiple organ systems
- enters CNS
- used as adjunct during general anesthesia (decrease salivation, airway secretions, increases HR)
Glycopyrrolate (synthetic competitive anticholinergic)
- similar to atropine
- quaternary, so can’t affect CNS
- used as adjunct during general anesthesia (decrease salivation, airway secretions, increases HR)
Ipratropium (anticholinergic)
- Bronchodilation, decrease airway secretion
- used for lung disorders (asthma, RAO, chronic bronchitis)
Propantheline (anticholinergic)
- promotes urine retention (reduces detrusor contraction, increases trigone contraction)
- treats incontinence due to detrusor instability
Ganglionic blocker
overstim nicotinic receptors –> inactive
widespread effects, no longer used
hypotension
Uses of NMJ blockers
tracheal intubation
orthopedic manipulations
balanced anesthesia (but hard to monitor)
skeletal muscle paralysis
What’s special about the NMJ
Spare receptors - not all need ACh stim for contraction to occur
May need to give more drug to fully block all receptors
May have absence/reversal of clinical blockade but still lots of circulating drug - lapse in and out of drug state
Non-depolarizing (aka competitive) NMJ blockers
- no motor endplate depolarization (no m. contraction)
- see initial muscle weakness –> flaccid paralysis
- Pancuroniu, Atracurium, Mivacurium
Pancuronium (non-depolarizing NMJ)
long lasting (2-3 hrs)
eliminated by kidneys
Also blocks muscarinic receptors –> tachycardia
no histamine release
Atracurium (non-depolarizing NMJ)
Intermediate duration (.5 - 1 hr) degradation is temp, pH dependent (cold, acidosis = longer lasting) does promote histamine release (decrease BP)
Mivacurium (non-depolarizing NMJ)
short acting (15 min) rapidly altered by plasma esterases does promote histamine release (decrease BP)
How would you reverse a non-depolarizing NMJ?
AChE inhibitor - Physostigmine, neostigmine
Outcompetes NMJ blocker, ACh accum’s and takes back over
Depolarizing (non-competitive) NMJ blockers
- Cause prolonged motor endplate depolarization
- see initial fasciculations –> muscle relaxation –> spontaneous flaccid paralysis with continued exposure
- Succinycholine
Succinylcholine (depolarizing NMJ blocker)
- Mimics ACh at nicotinic receptors at NMJ but resistant to AChE
- not pharmacologically reversible (b/c receptors in state of constant depolarization)
- rapid onset, short acting, so good for tracheal intubation
- causes some histamine release
- can cause hyperkalemia
NMJ block toxicity
- respiratory paralysis, ganglionic blockade
- histamine release - bronchospasm, hypotension (pre-treat with antihistamine)
- can progress to apnea, cardiovascular collapse (b/c of histamine)
- malignant hyperthermia b/c excess calcium = excessive contracture, heat production
adrenergic agonist (sympathomimetic)
Mimic effect of catecholamines (NE, Epi, Dopamine) to alter symp activity
cardiac excitation, catabolic states, CNS stim, minimize alpha 2 receptor action
PPA (phenylpropanolamine)
mixed-acting adrenergic antagonist
- affects both alpha and beta receptors to promote NE release
- increases urethral tone, manage urinary incontinence
- opposite acting of Phentolamine, Phenoxybenzamine
Do you have better selectivity at higher or lower doses?
Lower doses
Epinephrine (direct-acting adrenergic agonist)
- Increases CO (beta1) - contractility, HR, oxygen consump
- Get combo of peripheral vasoconstriction (alpha 1), & vasodilation to increase skeletal m. blood flow (beta 2)
- powerful bronchodilation (esp. if pre-constricted)
Low dose of Epi
Beta 2 dominance –> decreased BP due to vasodilation
High dose of Epi
alpha 1 dominance –> increased BP, CO due to vasoconstriction
Therapeutic uses of Epi
hypersensitivity, restoring cardiac rhythm, control superficial bleeding, adjunct to keep local anesthetics local
Epi toxicity
Cardiac arrhythmia, hypertensive crisis, cerebral hemorrhage
How does NE potency differ from Epi?
Beta 1 = potency same
Beta 2 = EPI, NE basically no-existant
Alpha 1 = Epi better than NE
Norepinephrine (direct-acting adrenergic agonist)
- Increases CO (beta1) - contractility, HR, oxygen consump
- Get combo of peripheral vasoconstriction (alpha 1), & vasodilation to increase skeletal m. blood flow (beta 2)
- no effect on bronchodilation
NE toxicity
intense vasoconstriction, robust in BP causing baroreceptor vagal response
Therapeutic use of NE
Help maintain BP during shock but also may inadvertently decrease perfusion so of limited use
Low dose Dopamine
Vasodilation (D1), Positive inotropy (beta 1 receptors)
good for hypovolemia following trauma
Good for short term fix for CHF w/ compromised renal fx
High dose dopamine
Vasoconstriction (alpha 1)
Dobutamine (Non-selective beta adrenergic agonist)
Increases contractility, but only minimally changes HR/BP
Positive inotrope for heart failure
toxicity - tachycardia
Selective beta2 adrenergic agonist
- Bronchodilators
- Albuterol, Clenbuterol
- Chronic administration can lead to down regulation of receptors, loss of efficacy
- Can be used to increase muscle mass
Mierbegron (selective beta3 adrenergic agonist)
relaxes detrusor m. to improve bladder capacity
fixes incontinence in humans, but toxic to dogs
Selective alpha 1 adrenergic agonist
vasoconstriction –> increased BP
Phenylephrine - decongestant, vasopressor (constrictor), toxicity = hypertension
Selective alpha 2 adrenergic agonist
CNS inhibition, decreased symp outflow, decreased NE release (alpha 2 receptors)
Dexmedetomadine, Xylazine - sedation/anesthesia, decrease BP, very safe (opposite of Atipamezole)
Adrenergic antagonist (Sympatholytic)
Block NE, Epi, Dopamine catecholamine effect
direct-acting sympatholytic
- reversibly block NT’s from stimulating alpha and beta receptors
- get decreased BP b/c decreased vasoconstriction
Phentolamine (non-selective alpha adrenergic antagonist)
- reversibly blocks both alpha 1 & 2 receptors
- opposite effect of PPA, used to manage urethral blockage (reduces sphincter tone)
Prazosin (selective alpha 1 adrenergic antagonist)
- vasodilation, decreased cO, decreased preload
- antihypertensive, treat CHF
Atipamezole (selective alpha 2 adrenergic antagonist)
- rapid reversal for Dexmedetomadine with minimal risk of relapse (b/c longer half life)
- relieves CNS, pre-synaptic inhibition
- increased NE release, less sedation, etc
Atenolol (selective beta 1 adrenergic antagonist)
- Blocks NE, Epi –> decreased CO, bp, cardiac arrhythmia
- safer for patients with bronchospastic dz
- Potential use for slowing feline hypertrophic cardiomyopathy
Selective beta 2 adrenergic antagonist
would block Epi, increase bronchoconstriction
No scenario to need this, no drugs for it
Propanolol (non-selective beta adrenergic antagonist)
decreased Co (beta1 blockade), antiarrhythmic, bronchoconstriction (beta 2) not much use when you have Beta1 selective drugs
Timolol (non-selective beta adrenergic antagonist)
decreases aqueous humor production with glaucoma
Carvedilol (non-selective beta adrenergic antagonist)
Blocks beta 1, beta 2 AND alpha 1 so REALLY good at lowering work of heart (decreased CO, vasodilation)
Used for congestive heart failure, vavlular dz
Phenoxybenzamine (direct acting non-competitive adrenergic antagonist)
Irreversibly blocks alpha1 & 2 receptors
Effect lasts until new receptors are synthesized
Reduced urethral sphincter tone, used to manage urethral blockage (opposite PPA)
Strategy to treat primarily vascular shock or a mix
promote vasoconstriction
high dose dopamine –> vasoconstrict, some increased CO
Maybe NE - max vasoconstriction
Mix - moderate dopamine
How to treat primarily myocardial shock
increase CO (beta one) Dobutamine - increase contractility, minimal change to vasculature, HR
Treat anaphylactic shock
Epi + antihistamine
beta 2 (bronchodilate, inhibit mast cell degranulation)
alpha 1, beta 1 cardio support
Which part of the heart is the pacemaker
SA node
Differences about pacemaker action potential
Technically no true resting membrane potential, just a slow depolarization of phase 4/0
No plateau phase (phase 2)
funny current
funny current
Slowly depolarizing inward current activated by hyperpolarization causing phase 4 in pacemaker cells
Class 1 antiarrhythmics
Sodium channel blockers
3 subgroups
Class 2 antiarrhythmics
beta blockers
Slow av node conduction
Atrial fibrillation
Sotalol - non selective beta antagonist, most common antiarrhythmic, blocks K channels too
Class 3 antiarrhythmics
K channel blocking
Prolong AP
Sotalol, Amiodarone (blue skin)
Class 4 antiarrhythmics
Ca channel blocking to slow AV node conduction
Vascular (dihydropyridines) or non-vascular specific - inhibit both cardiac myocytes AND nodal cells (Diltiazam, Verapamil)
Class 1 antiarrhythmics subgrp IA
moderate conduction slowing, prolongs AP duration
Procainamide blocks repolarizing K channels
Used for Supraventricular tachycardia
Class 1 antiarrhythmics subgrp IB
little conduction slowing if healthy cells, shortens AP duration
Lidocaine or Mexiletine blocks keeps inactivated Na channels inactivated
Class 1 antiarrhythmics subgrp IC
profound conduction slowing, little change to AP duration
Flecainide used for life-threatening tachycardia etc b/c cure worse than dz
Digoxin
decreases AV node conduction similar to Ca channel blocks b/c inhibits Na/K ATPase pump to decrease Ca efflux
very arrhythmogenic, very narrow therapeutic window, hypokalemia can = toxicity
How do you treat CHF
reduce work of heart (beta blockers, diuretics, vasodilators)
increase heart performance (contractility)
3 ways to increase cardiac performance
- increase beta 1 stim - but careful of ceiling effect - Dopamine, dobutamine
- Increase intracellular Ca in myocytes - beta 1, PDE-3 inhibitors (Milrinone, esp. if beta blockers on board)
2b. Decrease Ca efflux - inhibit na/ca pump, Digoxin - Enhance contraction - Pimobendan increases sensitization to Ca, vasodilator
How do vasodilators work?
disrupt excitation-contraction coupling in vascular smooth m. either by blocking receptors or limiting Ca in some way
Inhibitors of Renin-Angiotensin Aldosterone system
Aliskiren - renin antaognist, no conversion to Ang I
Enalapril - ACE antagonist, no conversion to Ang II
Lsoartan/Telmisartan - AT1 antagonist, no ADH or vasoconstriction (aldosterone)
See vasodilation, less water/na retention
How do you disrupt the baroreceptor reflex?
Block alpha 1 –> vasodilation
Prazosin or alpha antagonist
See immediate drop in BP, then increase, but vasodilation remains
Ca channel antagonists and vasodilation
decreased Ca = decreased contraction = dilation
Dihydropyradines - act in vasculature only, don’t affect AV node conduction
Non-vascular specific - Diltiazem, verapamil antiarrhythmics
NO
NO –> cGMP –> PKG –> PROFOUND vasodilation
Nitroglycerin (venous dilation only)
Sodium nitropursside (arterial and venous dilation)
PDE-5
inhibition = prolonged cGMP –> increased PKG –> vasodilation
Lung smooth m, the pene
Sildenafil
K channel activators and NO
prolonged open K channels = vasodilation, decreased TPR/BP
Minoxidil - rarely used
In the kidney, what’s typically secreted, what’s reabsorbed?
Secreted - H+, K+
Reabsorbed - Nacl, bicarb (HCo3), Ca
Most Na & water reabsorption occurs where in the kidney?
proximal tubule»_space;> loop of henle > distal nephron
Reasons to use diuretics
reduce ECF vol
Oliguric renal failure
Hypertension (e.g. EIPH)
Osmotic diuretics
Thin descending limb
MOA: amount filtered excess tubular transport changes osmolarity of filtrate
e.g. diabetes (glu in filtrate = water stays in urine)
Mannitol - freely filtered, for oliguric renal failure, cerebral edema
Carbonic anhydrase inhibitors
-proximal tubule & acidification in collecting duct
- MOA: Na, bicarb loss = water loss
Acetazolamide - may cause hypokalemia
Glaucoma, altitude sickness
Loop diuretics
- thick ascending limb of loop of henle
- inhibit Nacl reabsorption via na/k/cl pump –> increased Na excretion
- Furosemide, may cause hypokalemia
- treats EIPH, CHF, oliguric renal failure (causes vasodilation)
Thiazide diuretics
- distal tubule
- blocks Na, Cl reabsoprtion by blocking co-transporter
- Chlorothiazide
- hypertension
K+ sparing diuretic
Collecting duct
1. Blocks aldosterone = no na/K atpase acitivty, Na secretion
Spironolactone - competitive antagonist, may cause hyperkalemia
2. Blocks Na channels
Amiloride - use w/ loop diuretic
Aquaretics
increase water clearance with little effect on ion secretion
Demeclocycline
