Lecture 10: ANS: Sympathetic Flashcards
Sympathomimetics: based on dopamine’s structure, substitution at the alpha carbon acts to…?
increase the half life, monoamine oxidase can’t degrade it anymore
Sympathomimetics: based on dopamine’s structure, substitution at the beta carbon acts to…?
decrease CNS activity, less lipophilic can’t cross BBB
increased alpha and beta receptor activity
Sympathomimetics: based on dopamine’s structure, substitution of the amino group acts to…?
increase beta adr receptor activity, especially beta 2R (IPE)
Sympathomimetics: based on dopamine’s structure, substitution at C3/C5 acts to…?
increase beta 2 adrenergic receptor activity
Sympathomimetics: based on dopamine’s structure, loss of C3/C4 hydroxyl groups acts to…?
decrease potency at adrenergic receptors, increase oral absorption, increase half life (COMT and MAOs can’t break it down as well)
Short acting beta2 agonists (3)
often used as?
- albuterol
- salbutamol
- terbutaline
rescue medication
long acting beta 2 agonists (2)
- formeterol
- salmeterol
Once daily long acting beta2 agonists
Indacaterol
Overall CV effects of Adrenergics (5)
- transient tachycardia via positive chronotropic effect of beta 1 receptors (makes APs quicker at SA node but then baroreceptor reflex kicks in and blocks this)
- shortening of AV node refractory period
- increased overall blood pressure (both SP and DP), which would trigger baroreceptor reflex
- positive inotropic effect (increased SV, CO, and O2 use) which decreases cardiac efficiency
- coronary vessels dilate via beta 2 and DP goes down
How do beta1 receptors make the heart beat
- faster
- stronger
faster - increases in cAMP increase PKA activity. PKA phosphorylates funny channels and t-type calcium channels to increase cation influx for faster depolarization
stronger - PKA phosphorylates L-type calcium channels (VGCaCh), induces calcium release from SR, phosphorylates myosin, puts more calcium back into SR so it replenishes stores for next release
Adrenergic effects on the genitourinary tract
- NE will increase frequency of contraction on pregnant uterus smooth muscle contraction
- Epi will reduce uterine smooth muscle tone and contraction in last month of pregnancy and at parturition (Beta 2 agonists used to prevent premature labour)
- there are alpha 1 adr receptors at the urethral sphincter and prostrate
- beta 3 adr receptors on the detrusor muscle
Adrenergic effects on the GI tract
- alpha 2 presynpatic inhibition of cholinergic neurons which causes relaxation and reduced peristalsis
- beta 2 inactivates MLCK (through increased cAMP) which decreases contraction
Adrenergic effects on Respiratory system
- beta 2 activation causes relaxation of bronchiole smooth muscle which decreases airway resistance - epi given during asthma attack
- alpha1 R mediated vasoconstriction of upper mucosa (dilation of this causes congestion so alpha 1 agonists fix this)
Adrenergic effects on the eye
- alpha1 adr R mediate dilation of the pupil (on the radial muscles or spokes of the eye) but this does not increase intraocular pressure
Adrenergic effects on skeletal muscle
- epi and beta1 agonists increase ACh release at NMJ
- inhibition of alpha 2 increases ACh release at NMJ
- beta 2 induced muscle tremor
why is ephedrine/amphetamine used to treat myasthenia gravis?
Myasthenia gravis is autoimmune condition that affects the NMJ
- ephedrine and amphetamine are sympathomimetics thus increase catecholamines and indirectly increase ACh release
Adrenergic effects on metabolic function
think about it, all to help you get away in a stitch so more breakdown of fat and glycogen stores, creating glucose
- increased lipolysis and thermogenesis via beta3
- increased glycogenolysis via beta 2 to increase serum glucose
- increased gluconeogenesis
- increased oxygen consumption via beta 2
Adrenergic effects on endocrine function
- beta 2 increases insulin release to mobilize glucose and increase uptake to cells
- alpha 2 decreases insulin release to increase serum glucose conc and alpha 1 decreases GLUT4 transporters to increase serum glucose conc
beta effects increase glucose utilization and cause hypoglycemia but then alpha effects cause hyperglycemia and they counteract each other.
Adrenal medulla releases what ratio of epi to NE
80% epi and 20% NE
also a little bit of DA (negligible)
Vasculature in response to NE
overall vasoconstriction via alpha1 activation
- increase in TPR and BP both SP and DP
at low doses it is positive inotropic and chronotropic but the BaroR reflex blows chronotropy
Vasculature in response to IPE
overall vasodilation
- IPE is a non-selective beta agonist and poorly activates alpha receptors
- vasodilation of vascular smooth muscle via beta 2 and therefore decreased TPR and lower DP
- increases CO via beta 1 mediated positive inotropic and chronotropic effect
Vasculature in response to Epi
both vasodilation and vasoconstriction
- alpha1 receptors will respond and constrict VSM in skin, renal, and GI blood vessels
- beta 2 receptors will also respond and vasodilate skeletal muscle vasculature
- a very high dose of Epi will look similar to NE
Why do cold meds contain alpha1 adr R agonists?
Vasoconstriction of upper mucosal blood vessels
- reduces congestion
phenylephrine
selective alpha 1 agonist
- not COMT inactivation so increased half life
- used clinically for hypotensive states, as decongestant, and for pupil dilation
clonidine
selective alpha 2 agonist
- trials as decongestant but caused hypotension, sedation, and bradycardia
- blockage of NE release at nerve terminals so we see a decrease in CO, BP, and HR.
- tricyclic antidepressants will interfere with this (they increase NE in the synapse)
adverse effects
- dry mouth and constipation (reduced release from cholinergic fibres). low heart rate and sedation
- will get decreased TPR with chronic use and sudden withdrawal can cause rebound hypertension
apraclonidine
more selective clonidine (alpha 2 agonist) used to treat open angle glaucoma (reduces cAMP and thus reduces production of aqueous humour, therefore decreasing IOP)
isopreterenol
most potent beta 1 and beta 2 agonist
- causes peripheral vasodilation and tachycardia
- severe cardiac side FX and O2 insufficiency
(beta 2 activation increases o2 consumption and vasodilation, beta 1 activation increases heart rate)
dobutamine
selective beta1 R agonist
- use for short term heart failure, low dose increases CO
- greater positive inotropic than chronotropic effects
salbutamol
selective beta2 agonist
- causes bronchodilation (for asthma)
- used to delay premature labour
salmeterol
selective beta 2 agonist
- longer acting
Drugs used to delay premature labour
salbutamol and terbutaline both short acting beta 2 adr agonists
Indirect sympathomimetics include agents that:
- increase synthesis
- stimulate release
- inhibit re-uptake
- inhibit degradation
of catecholamines - so basically cocaine, antidepressants like MAOA-inhibs, amphetamine, tyramine
how can tyramine and MAOIs cause a hypertensive crisis? give one MAOI
tyramine displaces NE from vesicles as it is a substrate of VMAT2. Tyramine is also broken down by MAOIs so prevention of tyramine breakdown means it displaces NE. more NE ends up released in the synapse.
think about all the effects of NE - vasoconstriction, increased TPR and BP.
clorgyline
What adrenergic drugs are mixed action i.e. bind multiple adrenergic Rs?
ephedrine - binds alpha 1, beta1, beta2
pseudoephedrine - isomer of ^. is decongestant. binds alpa1 and beta 2 Rs.
phenoxybenzamine
non-selective alpha adrenergic antagonist
- irreversible
- decreasing but persistent block for 3 days post exposure
- dirty drug (binds other things) but mainly enhances NE release by blocking action of alpha2 autoreceptors
CV effects: increased heart rate because more NE being released in heart and no baroreceptorR because decreased TPR, decreased venous return.
Metabolic: also causes insulin secretion and lipolysis (alpha receptors cause insulin decrease so blocking them means increase)
treats pheochromocytoma (tumour in adrenal glands)
phentolamine
reversible and compet inhibitors of alpha adrenergic receptors
- similar effects, similar indications
prazosin
selective alpha 1 antagonist
- decreased TPR, DP, VR, pulmonary congestion
- increased CO
- clinically used for mild to moderate HT, CHF.
- tachycardia via BaroR may occur (decreased TPR results in increased sympathetic flow to the heart). this is NOT a result of lack of autoinhibition by alpha 2 R
Which drug is associated with first dose phenomenon
Prazosin - may see extreme orthostatic hypertension
related: clonidine may cause rebound hypertension is removed quickly
Tamsulosin
treats mild HT and also symptoms of BPH
- over 70% of alpha1A adrenergic Rs are in prostate and sphincter of bladder
Yohimbine
reversible competitive alpha 2 antagonist
- not used - inhibits autoreceptors so stimulates NE release
- increased HR, BP, excitation, tremor
at high doses blocks alpha 1 adr receptors for transient decrease in BP
propranolol:
- some points about the drug
- therapeutic
- unwanted effects
- adverse effects and toxicity
non-selective beta adr R ant
- equal affinity for beta1and beta2
- efficacy of the block depends on the sympathetic tone
- extensive first pass metabolism , F <30%
- half life of around 4 hours
therapeutic effects
- bradycardia
- negative inotropic effect, decreased CO and O2 use
- unbalanced vagal tone results in decreased AV conduction
- initial elevation in TPR via unopposed alpha adr Rs but then hypotension with chronic use
unwanted effects
- potentiates bronchospasm (no Beta 2 bronchodilation)
- inhibits lipolysis
- inhibits insulin secretion by beta 2 activation
- blocks hyperglycemic response to epi
adverse effects and toxicity
- severe bradycardia, CHF, bronchoconstriction, hypoglycemia (nogluconeogenesis), aggravation of peripheral artery disease (unopposed alpha adr activity)
- CV effects with abrupt withdrawal (weaned over 1-2 weeks)
Will a beta blocker affect a nomotensive person?
A normal person wont really experience effects on a beta blocker. circulating NE is higher in hypertensive individuals
How do beta blockers block hyperglycemic response to epi
- alpha adrenergic activity will be unopposed - insulin levels will drop and blood glucose will increase
- may induce hypoglycemia following exercise or insulin admin because no release from glycogen stores
- can mask hypoglycemic symptoms
nadolol
long acting non selective beta antagonist
- half life of 14-24 hours
pindolol
non-selective partial beta receptor agonist in absence
timolol
non-selective beta adr R antagonist
- similar half life as propranolol (4 hours ish) but it’s less potent
- clinically used for glaucoma to decrease IOP
non-selective beta adr R antagonists
propranolol
nadolol
timolol
pindolol (partial agonist so could block with excess catecholeamine signalling)
Selective beta 1 antagonists
metoprolol and atenolol
(for angina HT and heart failure)
esmolol - short acting
betaxolol - for glaucoma
third generation beta blockers
labetalol
- antagonist at alpha1 and beta 1, partial agonist at beta2
- decreased BP without causing reflex tachycardia and decreased cardiac output (seen with alpha adr R blockers)
carvedilol
- antagonist at alpha 1 and beta with 10x higher affinity for beta. will reduce TPR
Cimetidine and first pass metabolism of some beta blockers
Cimetidine inhibits CYP associated with first pass metabolism of propranolol, metoprolol, and labetalol so will increase bioavailability and therefore plasma conc.
(one from each category: nonselective, beta 1 selective, and third gen)
reserpine and antihypertensive agents are
additive
- reserpine depletes catecholamines
- antihypertensives act against catecholamine action
reserpine
it depletes catecholamines
PS tone will be more pronounced
clinical CV effects - decreased HR, CO, and BP
adverse effects
- bradycardia, flushed skin, hypotension, Na+ and fluid retention, nasal congestion, increased GI tone and secretions.
- super-sensitized adrenergic receptors
CNS issues
- Parkinsonism, lethargy, depression
abolishes response to any indirect acting sympathomimetics like cocaine, TCAs, clorygline (bc there are no catecholamines for them to act on)
guanethidine
competes with NE for NET - NET takes it into the cell instead of NE, thus there is a gradual depletion of NE
- effects of indirect sympathomimetics are reduced
alpha-methyldopa and alpha-methyltyrosine
both reduce heart rate and BP
- affect the enzymes producing catecholamines
- methyldopa inhibits AADC (enzyme turning LDOPA to DA)
- methyltyrosine inhibits TH
