Week 3: Adrenergics III Flashcards
What are the functions and mechanisms of aminophylline (theophylline), and sildenafil? What do they treat?
“ATS”
Aminophylline & theophylline (non-selective), as well as sildenafil (PDE-5) are all phosphodiesterase (PDE) inhibitors.
Aminophylline & theophylline increase cAMP and cGMP in cells, which relax bronchial smooth muscle BUT increase HR.
Sildenafil (Viagra) is a PDE-5 inhibitor, which increases cGMP. This is usually stimulated by NO release by non-adrenergic, non-cholinergic (NANC) nerves. Sildenafil was originally used as a vasodilator in the lungs, but was later found to assist with relaxation of penile vascular smooth muscle, allowing erection to occur.
What is “epinephrine reversal,” and how was it discovered?
Experiment was done to assess how epinephrine affected BP.
Phentolamine (a1 antagonist) was found to lower BP on it’s own
Epinephrine delivered before phentolamine was found to increase BP.
Epinephrine delivered after phentolamine was found to decrease BP.
Conclusion: there were multiple epinephrine receptors, one of which raised BP (alpha) and one of which lowered BP (b2)
What subtypes of adrenergic receptors are found in arterioles, bronchi, heart, brain, and kidneys, and what are their functions in each location?
Arterioles: a1 and a2 receptors mediate arteriolar contraction
Lungs: b2 receptors mediate bronchodilation
Heart: b1 receptors mediate increased HR, increased contractility/conductivity and coronary artery vasodilation
Brain: D1 receptors mediate cerebral arteriolar dilation
Kidney: D1 receptors mediate renal/mesenteric vasodilation
What is the function of b3 receptors? Where are they located? Where are b2 receptors located?
b3 receptors are found in the small intestine, adipose tissue, and vascular endothelium, and are involved in lipolysis, glucose uptake, cardioinhibition, and relaxation of the colon, esophagus and bladder (no excretion/movement).
b2 receptors are found in the lungs, skeletal muscle, and liver (relaxation), and in the heart (contraction). They are stimulated ONLY by EPI.
What happens to peripheral resistance, blood pressure (systolic AND diastolic) and pulse rate with the administration of a bolus of norepinephrine?
TPR: increases (stim. alpha receptors in arterioles)
BP:
systolic - increases due to alpha receptors in the heart being stimulated
diastolic - increases for same reason as TPR increase
Pulse: decreases (baroreceptor reflex to compensate for higher BP)
What happens to peripheral resistance, blood pressure (systolic AND diastolic) and pulse rate with the administration of a bolus of epinephrine?
TPR: decreases (stim. b2 receptors in arterioles, vasodilation)
BP:
systolic - increases due to beta receptors in the heart being stimulated
diastolic - decreases for same reason as TPR decreases
Pulse: increases (heart alpha and beta receptor stimulation)
What happens to peripheral resistance, blood pressure (systolic AND diastolic) and pulse rate with the administration of a bolus of isoproterenol?
Isoproterenol has the same effects as epinephrine (because it is a synthetic derivative of epinephrine)
TPR: decreases (stim. b2 receptors in arterioles)
BP:
systolic - increases due to beta receptors in cardiac muscle being stimulated
diastolic - decreases for same reason as TPR increase
Pulse: increases (heart beta receptor stimulation only, and decreased TPR tone leads to increased SNS activation by baroreceptor reflex)
What are the catecholamine drugs and/or NTs?
“DINED”
Dopamine
Isoproterenol
NE
EPI
Dobutamine
Why does isoproterenol have a greater effect than epinephrine on pulse rate and TPR?
There is no alpha receptor stimulation to offset the TPR decrease, so stimulation of beta receptors increases HR while decreasing TPR significantly. This has a twofold effect on HR, because the baroreceptor reflex interprets this TPR drop, and increases SNS tone, increasing HR even more.
Of the adrenergic drugs, which is the only one that does not affect cardiac output?
Out of NE, EPI and isoproterenol, only NE does not affect cardiac output (CO). This is because it decreases heart rate to compensate for increased sys/diastolic BP and increased mean/TPR, so the overall cardiac output stays the same
What is NE mainly used for as a treatment?
NE is usually used as a hypotension treatment when overall CO does not need to increase. Its principal use is in cases of septic shock.
What is the main function of dopamine as it relates to the kidneys?
Dopamine infusion improves renal and mesenteric blood flow
What is the function and mechanism of dobutamine? What is it used to treat? What issues exist with its use?
Dobutamine is a b1 agonist and an a1 partial agonist (stimulates increased HR, contractility, and CO), and is used to treat heart failure. It has a very short half life (2 min) and must be given by continuous infusion.
Issues include decreased response if the patient is treated chronically due to receptor desensitization and down-regulation
What are the b2 selective agonists and what are they used for?
“Breathe for ART”
Albuterol, terbutaline and ritodrine are all b2-selective agonists. They are used to treat asthma,and arepreferred over isoproterenol because they are b2-specific instead of generic to all adrenergic/cholinergic receptors. During asthma attacks, isoproterenol could also increase HR, decreasing O2 delivery efficiency.
What are the alpha agonists, and which receptors are they preferential to?
“PCB”
Phenylephrine = a1 agonist (nasal decongestant, can cause rebound hyperemia)
Clonidine = a2a agonist (decrease SNS tone, anti-hypertensive)
Briminodine = a2b agonist, (glaucoma treatment)
What happens to blood pressure, SNS activity, vagus nerve activity and HR when phenylephrine is delivered? What about histamine?
Phenylephrine is an a1 agonist, so it increases BP by inducing arteriolar vasoconstriction. Consequently, there are other reactions as a result of the baroreceptive reflex, including…
SNS: Decrease
Vagus nerve: Increase
HR: Decrease
All to try to normalize overall blood/O2 delivery. Histamine, a potent vasodilator, has the opposite effect.
Why can beta blockers be used to treat chronic heart failure?
Blockage of b1 and b2 receptors (esp. b2, for example by metoprolol) prevents sudden death due to arrhythmias. This is mainly due to decreased catecholamine stimulation of the heart.
The mechanisms involved are possible decreased remodeling of myocardium (thus efficient pumping is upheld) and preservation of heart muscle cells (don’t have to work as hard, less cardiac hypertrophy).
What is the cycle of heart failure, and how do beta blockers help prevent it?
With prolonged catecholamine stimulation of a failing heart (less capacity to respond), continued forced contractility causes enlarged heart, thickening of muscle, and worsened CO. This can lead to cardiomyocyte toxicity, hemodynamic stress, and myocardial injury/infarction.
Beta blockers can attenuate continuous beta receptor stimulation, allowing for more efficient heart pumping and decreasing the likelihood of heart failure.
What is going on at nerve endings during supersensitivity or desensitization? What are other terms for these issues?
Supersensitivity or denervation supersensitivity is caused by decreased stimulation of receptors, so more receptors are generated in order to be “more sensitive” to even a small release of NT
Desensitization or overactivity involves chronic overstimulation by NT, so receptor count decreases in order to attenuate the response of the nerve
If someone taking a beta blocker goes on a trip and forgets their medication, why can that cause a serious issue?
Beta blockers act to create supersensitization in nerves due to decreased activation of nerve endings. This increases receptor numbers transiently, so when she forgets the beta blocker, even a small amount of adrenergic (NE/EPI) stimulation will highly activate the receptors, causing a drastic increase in HR and overall activity related to beta receptors.
