week 1 vasoconstrictors Flashcards
Parasympathetic receptor/ transmitter pathway
pre-ganglionic neuron releases acetylcholine > nicotinic receptor causing post-ganglionic neurons to release acetylcholine > muscarinic receptor
sympathetic receptor/ transmitter pathway
pre-ganglionic neuron releases acetylcholine > nicotinic receptor causing post-ganglionic receptor release norepi which binds to adrenergic receptor
Sympathetic nervous system nerve location
- thoracolumbar origin (T1-L2)
- preganglia near spinal cord
- postganglia secrete norepi
what converts dopamine to NE
dopamine beta hydroxylase
how NE is formed
- dopamine enters the synaptic vessel
- dopamine beta hydroxylase converts dopamine to NE
- an action potential releases NE from the synaptic vessel
what happens to NE when the signal is terminated
- reuptake
- dilution by diffusion
- metabolism
what metabolizes NE and catecholamines
- monamine oxidase (MAO)
- catechol-o-methyltransferase (COMT)
receptors and their location of effect
- alpha 1: peripheral
- alpha 2: cnetral
- beta 1: heart
- beta 2: smooth muscle (lungs)
binding pathway from NE
NE binds to B1 and B2 extracellularly causing Gs proteins (2nd messenger) to release adenylyl cyclase which uses ATP to release cAMP to cause contraction
effects from activation of Alpha-1 postsynaptic receptor
- increases in intracellular Ca
- smooth muscle contraction
- peripheral vasoconstriction
- bronchoconstriction
- inhibits insulin secretion (increases glucose for energy)
- stimulates glycogenolysis and gluconeogenesis
- mydriasis
- GI relaxation
activation of presynaptic alpha 2 receptors (PNS)
- decreases Ca into the cell
- limits the release of NE
activation of alpha-2 in postsynaptic (CNS)
- sedation
- decreased sympathetic outflow
- decreased BP
- platelet aggregation
beta 1 postsynaptic activation
- increases HR
- increases conduction velocity
- increases myocardial contractility
activation of postsynaptic beta-2 receptors
- smooth muscle relaxation
- peripheral vasodilation
- decreased BP
- bronchodilation
- increases insulin secretion
- increases glycogenolysis and gluconeogenesis
- decreases GI mobility
- many more beta 2 in lungs which overrides alpha 1 constriction
parasympathetic nervous system location
- craniosacral origin (III, VII, IX, X)
- preganglia near organs of innervation
- postganglia secrete acetylcholine to cholinergic fibers
effects of acetylcholine
- activates both arms of the autonomic nervous system
- choline + acetyl CoA = acetylcholine - choline acetyltransferase
- calcium mediated action potential
what deactivates acetylcholine
- acetylcholinesterase
- breaks it down to choline and acetate
cholinergic receptors
- nicotinic
- muscarinic
down regulation
- extended exposure to agonists reduces the number but not their response = tachyphylaxis
- movement of receptors from the cell surface to intracellular compartments, but then destroyed
- prolonged process
up regulation
- chronic depletion of catecholamines or agonists increases the number of receptors but not their sensitivity
- may account for withdraw syndrome with beta blockers
receptor uncoupling
- occurs rapidly
- inability of the receptor to bind to G protein (alter the function of the receptor)
- desensitization
sequestration
- occurs more slowly (desensitization)
- movement of the receptors from the cell surface to intracellular compartments
tone
- residual basal activity of the autonomic nervous system
what are catecholamines and where do they act
- both neurotransmitters and hormones
- act on adrenergic receptors
what are sympathomimetics
- compounds that resemble catecholamines except hydroxyl groups are not present in the 3 and 4 positions of the benzene ring
- classified according to their selectivity for receptors (alpha or beta)
- all catecholamines are sympathomimetic but not all sympathomimetics are catecholamines
what are indirect-acting sympathomimetics and what do they do
- synthetic non-catecholamines
- release endogenous NE from postganglionic sympathetic nerve endings
what are direct acting sympathomimetics
- catecholamines and synthetic non-catecholamines
sympathomimetics are derived from
B phenylethylamine
composition of catecholamines
- presence of hydroxyl groups in the 3rd and 4th position of the benzene ring of hte B phenylethylamine creates a catachol
inhibition of the reuptake of catecholamines
- inhibition of the reuptake mechanism produces a greater potentiation of effects of epinephrine that inhibition of either enzyme
metabolism of synthetic non-catecholamines
- lack a 3-hydroxyl group
- not metabolized by COMT
- dependent on MAO for metabolism
- metabolism often slower than catechols
- pts on MAO inhibitors manifest exaggerated responses
sulfoconjugation reactions
- participate in the metabolism of catecholamines and phenylephrine
- SULT1A3/ SULT1A4 polymorphisms primarily effect phenylephrine metabolism
vasoconstrictors effects on the body
- increase arterial resistance and afterload & increase venous return
- reflex changes: decreased HR, conduction, contractility
time frame for end-organ damage with decreased MAP
MAP < 65 mmHg for 13-28 min
MAP < 50 mmHg for 1 min
natural catecholamines
- dopamine
- NE
- epi
epinephrine receptors
- stimulates Alpha-1, Beta-1, Beta-2
- most potent for Alpha-1
indirect effects of epinephrine
- increases lipolysis, glycogenolysis, inhibits insulin
- decreases renal BF even in the absence of changes in BP
- stimulates the release of renin indirectly
low dose effects of epi (1-2 mcg / min)
- stimulates beta-2
- net effect is decreased SVR
intermediate dose effect of epinephrine (4 mcg/min)
- stimulate beta-1
- increased HR, contractility, and CO
- increased automaticity (dysrrhythmias)
high dose epi effects (>10 mcg/ min)
- stimulates alpha-1
- potent vasoconstrictor (no effect on cerebral arteries)
- used to maintain myocardial and cerebral perfusion
- reflex bradycardia can occur
racemic epi
- mixture of levo- dextrorotatory isomers that constrict edematous mucosa
- lasts 30-60 min
side effects of epi
- hyperglycemia, mydriasis, platelet aggregation, sweating, headache, tremor, nausea, arrhythmias
norepinephrine effects on body
- increases BP by adjusting SVR
- increases systolic, diastolic, MAP
- vasoconstricts renal, mesenteric, cutaneous vascular beds
- may decrease renal blood flow (oliguria)
- mesenteric infarct
norepi receptors
- primarily alpha-1
- beta-1 is overshadowed by by alpha-1
CO and norepi
- CO increases at low doses
- CO may decrease at high doses due to increased afterload and baroreceptor mediated reflex bradycardia
dopamine effects at different doses
- low dose causes NE to be released
- high doses effects alpha receptors
ephedrine receptors
- synthetic catecholamine
- works on alpha-1 and beta
- tachyphylaxis can occur
ephedrine effects to body
- principle action increased myocardial contractility
- venoconstriction > arteriolar = increased preload w/ increased HR, and increased myocardial contractility = increased CO, increasing BP
ephedrine effects in in other parts of the body
- increases uterine blood flow
- bronchial smooth muscle relaxant
phenylephrine effects
- synthetic non-catecholamine
- alpha-1
- increases preload > afterload
- increases pressure without changing CO
- ok in pregnant pts
side effects of phenylephrine
- reflex brady
- decreases renal and splanchnic blood flow
- increases pulmonary artery resistance and pressure
- no dysrrhythmias as a direct effect
vasopressin primary use
- preserve cardiocirculatory homeostasis in patients with advanced vasodilatory shock
- pts who failed conventional vasopressor therapy
- pts with adverse effects of vasopressors
- unlike catecholamines, effects of vasopressin are preserved during hypoxia and severe acidosis
V1 receptors
- arterial constriction
- increases sensitivity of baroreceptor in aortic arch = increased HR = increased BP
- angiotensin is the primary working molecule
V2 receptors
- in renal collecting ducts
- increases the permeability of cell membranes resulting in reabsorption of water
- AQP2 pulls the fluid back into circulation
advantages of vasopressin over epi
- epi increases myocardial O2 consumption (risk of MI and arrythmias)
- vasopressin has not direct effect on HR reducing myocardial O2 consumption
- vasopressin works in an acidic environment
oxytocin effects and uses
- increases Ca++ in the myometrium, increasing strength of contraction
- oxytocin receptors increase during pregnancy
- used to increase uterine contractions and reduce postpartum hemorrhage
oxytocin effects on mother
- HTN
- N/V
- bleeding
- pelvic hematoma
- arrythmias, PVC’s
- uterine rupture in high doses
***severe water intoxication + seizures and coma with 24 hour infusion - possible death
oxytocin effects on baby
- bradycardia, PVC, arrythmias
- permanent brain damage
- death
- seizures
- low apgar at 5 min
- jaundice
- retinal hemorrhage
drug interactions with vasoconstrictors
tricyclic antidepressants and MAO inhibitors
- cause increased endogenous NE
- worse in the first 14-21 days and then down regulation occurs
- okay to use these drugs pre-op (use decreased dose of pressor)
cocaine and vasoconstrictors
- interferes with re-uptake of catecholamines (enhanced effects)
- cocaine produces vasoconstriction and tachycardia
- acute toxicity may be managed with lebatolol (has both alpha and beta effects)
what to give for extravasation
- phentolamine (alpha 1 and 2 antagonist)
- peripheral vasodilator
- 5-10 mg around the site of extravasation
