Lecture 10: Sympathetic NS Flashcards
How does NE effect the CV system?
- overall vasoconstriction (increase in TPR)
- increased strength of vasoconstriction (ionotropy)
- initially HR goes up (chronotropy) but drops back down due to baroreceptor reflex
What would be used to delay premature contractions?
epinephrine: decreases smooth muscle tone so it can’t contract as well
salbutamol: B2 agonist that relaxes uterine smooth muscle
Phenylephrine (PE), an a1 Ag are used in cold remedies because?
- during colds, there is vasodilation causing fluids to lead causing congestion
- a1 agonist causes vasoconstriction in upper respiratory mucosa to stop congestion
Phenylepherine (half life and potency)
- selective a1 agonist
- longer t1/2 than NE because not broken down by COMT, but less potent than NE
- can activate B2 R at high doses
Phenylepherine clinical use
selective a1 agonist
CV: increases BP
- causes reflex bradycardia, so used to treat atrial bradycardia
- in hypotensive states (people who are hypertensive should not use this)
decongestant and anti-allergy
- causes constriction
- but desensitization with repeated dosing
dilation (myadratic)
clonidine use
selective a2 R agonist (mainly on N terminals)
treats hypertension
- decreases BP, bradycardia, and CO due to blocking NE release from nerve terminals
- centrally blocks excitatory outflow
- peripherally presynaptic inhibition
clonidine ADR
adverse effects
- decreased TPR with chronic admin
- rebound hypertensive crisis with sudden withdrawal
- dry mouth and constipation (targets a2 on parasympaethic terminals too), bradycardia,
and sedation
Apraclonidine
more seletive than clonidine
use as adjust glaucoma treatment because it is very local (reduces production of aqueous humour and decreasing IOP)
Isoproterenol
non-selective B agonist
- no therapeutic use
- most potent B agonist with longer t1/2
- severe cardiac side effects: peripheral vasodilation, tachycardia, myocardial stimulation
Dobutamine
selective B1 agonist
- synthetic DA derivative
- positive ionotropic effect greater than chronotropic effect
- increases SV at low dose and no change in HR –> increases CO
- used short term treatment of HF, acute MI, and heart surgery (long term would cause death)
What are selective B2 R agonists used to treat?
primarily asthma without stimulating B1
Salbutamol (albuterol)
selective B2 R agonist
bronchodilation
- B2 on bronchiole sm
- skeletal muscle vasodilation to decrease TPR
- high dose could stimulate CV effects
delay premature labour
- relaxes uterus sm so there are no contractions
duration and t1/2 can be extended with newer agents
Salmeterol
selective B2 agonist
- anchors to R for extended action
Terbutaline
selective B2 agonist
used to delay premature labour
Mirabegron
selective B3 agonist
- treats overactive bladder
Indirect acting sympathomimetics can act by
- increase synthesis
- stimulate release
- inhibit presynaptic transporter for reuptake to increase NT in cleft –> cocaine (DAT), desimimpramine/amytriptyline (NET), amphetamine
- inhibit degredation by enzymes –> MAO-A I: clorgyline, MAO-B I: selegiline
Why should we be cautious when eating foods with tyramine (cheese)?
- VMAT substrate with no direct effect
- when used with MAOIs –> this prevents degrdation and increases NE displacement causing a sudden increase in BP
- can lead to hypertensive crisis
Ephedrine
mixed action sympathomimetic
- both NE release and direct a1, B1, B2 R binding
- orally effective prolonged action stimulant
- increases heart rate, bronchodilation and skeletal muscle tone
- less potent vasopressor than EPI
Pseudoephedrine
mixed action sympathomimetic
- isomer of ephedrine
- a1, b2 R agonist
- decongestant, stimulant
- however can be used to make methamphetamine
Phenoxybenzamine
non selective a R ANT (at a2 will block synaptic feedback –> increase NT release)
- irreversible (dose response curve shifts right)
- decreasing but persistant block 3 days after exposure
results
CV: decreases TPR, DR, and causes tachycardia (baroreceptores aren’t active so NE release into the heart increases HR)
- hypotensive response greater in HT patients
- used to treat pheochromocytoma
metabolic
- insulin secretion (unmasking B2 effects and no alpha inhibition of insulin release –> hypoglycemia), lipolysis
Phentolamine
non selective alpha R ANT
- reversible and competitive inhibition
- slightly higher affinity for a1 –> increases SP but also triggers baro reflex and blocks a2 autoreceptors
- cv effects same as phenoxybenzamine but transient
use
- short term HT treatment
- pheochromocytoma
- tyramine rich diets in pateinst atking MAOI
Prazosin
selective a1 R ANT
used for mild-moderate HT, CHF
- decrease in TPR, DP, VR, pre and after load, pulmonary congestion
- increase in CO
- tachycardia via baroR can occur –> decrease in TPR increases symp. outflow to heart but is not due to autoinhibition via a2 (bc this is a1 selective)
- first dose phenomenon - orthostatic hypotension
Tamsulosin
selective alpha 1 R ANT
used to treat
- mild/moderate HT and benign prostatic hyperplasia (BPH - a1A overexpression)
- high affinity for a1A and a1D subtypes (70% alpha R are a1A in prostate and sphincter of bladder)
Yohimbine
selective a2 ANT
(not used because it inhibits autoreceptors)
low dose: reversible competitive a2 ANT
- stimulates NE release
- increases BP, HR, tremor, excitation, ADH release
- blocks clonidine peripheral CV/motor effects
high doses: blocks a1 R
- causes transient decrease in BP and binds to 5HT R
used to be for treating male sexual dysfunction but rplaced by PDE inhibitors
Nadolol
non selective B R ANT
- longest acting: t1/2 = 14-24 hours
- slow absorption
- used as prophylaxis for angina
Pindolol
non selective B R ANT
- acts as partial agonist –> in the absence of catecholamines it maintains signalling but in excess it will block beta R
- can be used in bradycardia or low cardiac reserve
Timolol
non selective beta R antagonist
- similar t1/2 as propranolol (4 hours) but less potent
- clinical use in glaucoma to decrease IOP
Propranolol
non selecting beta R antagonist
absorbed from GI, t1/2 =4 hours
CV therapeutic effects
- negative chronotropic effects = bradycardia (HT or normotesnive during exercise)
- negative ionotropic effect, decreased CO, decreased O2 use, decreased ACE
- unbalanced vagal tone: slowed pacemaker activity, decreased AV conduction
- increased TPR via alpha R activation but overall hypotension with chronic use
Propranolol effects in a normotensive individual
- efficacy depends on sympathetic tone –> won’t do anything to a normal person btut will have an effect on someone who is hypernsive since they have a lot of NE
Propranolol unwanted effects
bronchiolar smooth muscle
- bronchospasm and airway resistance increased due to block of B2
- not ideal for asthma
metabolic effects
- inhibit insulin secretion via B2 block
- block hyperglycemic response to EPI
–> alpha2 activity increases blood glucose –> can induce hypoglycemia after exercise or insulin admin if there are no glucagon stores
- can mask hypoglycemic symptoms such as increase in HR so people don’t know they’re hypoglycemic
- need to be used with caution in diabetics
predictable, widespread, and diffuse effects
- severe bradycardia, CHF, bronchoconstriction
- hypoglycemia
- aggravation of peripheral artery disease (PAD) due to unopposed alpha R activation
CV effects
- with abrupt withdrawal
Metoprolol/Atenolol
selective B1 R ANT (cardioselective)
- similar activity as propranolol at B1 but less at B2
- prophylaxis of angina, HT, heart failure
Esmolol
selective B1 R Antagonist
short acting - rapidly hydrolyzed by esterases in blood cells
Betaxolol
used to treat glaucoma
- opthalmic prep alone or with muscarinic (pilocarpine) to decrease IOP
Labetolol
mixed action beta ANT (3rd gen)
ANT at B1 and a1 (3:1 ratio of antagonist)
partial AG at B2 - won’t block diastolic pressure drop so won’t cause reflexive tachycardia
decrease in BP without reflex tachycardia and increase in CO
Carvedilol
mixed action beta antagonist
ANT at a1 and B with 10x higher affinity for B
- reduce TPR and improve LV ejection fraction
Cimetidine interaction with beta blockers
CIMETIDINE (antihistamine) inhibits CYP associated with metabolism of PROPRANOLOL, METOPROLOL, LABETALOL
- increases their bioavailability and plasma concentration
What is the effect of Beta Adr R ANT on insulin effects?
insulin hypoglycemic effects enhanced/prolonged
can mask hypoglycemia
Beta blocker paradoxical pharmacology in CHF and asthma
- congestive heart failure
Beta R agonist
- acute: beneficial (increases contractility)
- chronic: detrimental
Beta R antagonist
- acute: detrimental (decreases contractility_
- chronic: beneficial (increases contractility and decreases mortality) - asthma
Beta R AG
- acute: beneficial (bronchodilation)
- chronic: detrimental
Beta R ANT
- acute: detrimental (bronchoconstriction)
- chronic: ALSO DETRIMENTAL
Reserpine MOA
indierect ADR ANT
binds to VMAT –> blocks transport of NE/DA into vesicles –> NE leaks into cytoplasm and is degraded by MAO –> decreases abilty to store NE so there is no NT release when an action potential happens
chronic treatment - R upregulation
- increases sensitivity to catecholamines –> sympathomimemtic effects
- abolishes response to indirect acting sympathomimetics
used for Ht with hydrocholothiazide
Reserpine clinical CV effects and ADR
CV effects
- decreased NE in peripheral synaptic terminals –> decreases stimulation of a1 R –> decreased S tone and PS is dominant tone
- decreased HR, BP, CO
- effects additive with hypertensive agents
Adverse effects
PS tone dominant
- bradycardia, postural hypotension
- NA and fluid retention
- increased GI tone and decreased –> increased motility and diarrhea
- increased nasal congestion and respiratory issues
CNS
- Parkinsonism, lethargy,s edation, depression
- increse breast gancer, galatorrhea
effects of reserpine on tyramine and amphetamine
reduces their effects
- tyramine: precursor to catecholamines –> res leads to their degredation
- amphetamine: increased DA/NE in synapse –> res prevents them from being released into the synapse
Guanethidine
indirectly acting ADR ANT
- competes for NAT with NE –> transported into peripheral nerve endings and accumulated in vesicles
- gradual depletion of NR from vesicle stores
- chronic use leads to supersensitivity and potebtiates exogenous NE and sensitizes effector cells to catecholamines
- effects of indirect sympathomimetics are reduced
- blocks amine uptake and vesicle NE release after MOA degredation
false transmitter –> cocaine, TCAs interefere competitively with uptake of guanethidine
alpha-methyldopa/alpha-methyl NE
indirectly acting ADR ANT
- false transmitter
- substrate for dopa decarboxylase in vesicles
- released upon nerve stimulation
alpha-methyltyrosine
indirectly acting ADR ANT
- inhibits biosynthesis of catecholamines centrally, periphearally, and in adrenal medulla
- competitive inhibitor of tyrosine hydroxylase
clinical CV effects
- decreased HR and BP
- greater response in hyperstention: decreased TPR and CO
- reduced SYMP tone
Clonidine’s indirect ADR ANT action
- both sympathomimemtic and sympatholytic
- binds to a2 autoreceptor and inhibits NE release
- in medulla oblongata: blunts sympathetic tone
- peripherally: decreases NE release form axon terminal
use
- prophylactic for migraine
- alleviate alcohol and opioid withdrawal
ADR
- dry mouth, constipatoin, sedation, bradycardia
- rebound HT with sudden withdrawal
- TCA, desmethylimipramine, phenothiziane interfers with CV anti hypertensive effects
