Adrenergic Pharmacology Flashcards
How do indirect sympathomimetic drugs function?
- promote release of endogenous catecholamines
- displace stored catecholamines
- inhibit reuptake of catecholamines
Describe the selectivity for NE/Epi, distribution, associated intracellular cascade, and primary effect of a1 adrenergic receptors.
- a1 are found in the peripheral vasculature
- they have no selectivity with regards to NE v. Epi
- activation results PLC activation, calcium mobilization, and PKC activation
- in doing so, they stimulate contraction of smooth muscle and have a pressor effect (increasing BP)
Describe the selectivity for NE/Epi, distribution, associated intracellular cascade, and primary effect of a2 adrenergic receptors.
- they are found on the adrenergic and non-adrenergic presynaptic cells
- they have no selectivity with regards to NE v. Epi
- they inhibit AC activity thereby decreasing cAMP levels and preventing a calcium influx
- they inhibit further NT release by the presynaptic cell
Describe the selectivity for NE/Epi, distribution, and associated intracellular cascade of B-adrenergic receptors.
- they are found in vasculature, lung, eye, and most other end-organs
- B1 has equal affinity for the two agonists but B2 has higher affinity for Epi than NE
- both activate AC, increasing cAMP levels in the post-synaptic cell
Through what intracellular cascade do a1, a2, B1, and B2 adrenergic receptors function?
- a1 activate PLC
- a2 inhibit AC
- B1 activate AC
- B2 activate AC
How do D1-type receptors compare to D2-type ones?
- D1 stimulate AC
- D2 inhibit AC
What is phenylethylamine?
- the parent compound for catecholamines
- a benzene ring with an ethyl amine side chain
What is the effect of sympathomimetic drugs on blood vessels?
- alpha receptors increase arterial resistance in the periphery, particularly in the skin and splanchnic vessels, raising blood pressure
- beta2 receptors relax vascular smooth muscle in skeletal muscles, increasing capacitance and O2 delivery to skeletal muscle
- the net result is a shift in blood flow
What is the effect of sympathomimetic drugs on the heart?
- B1 receptor activity dominates in the heart
- activation results in increased calcium influx in cardiac cells, increasing positive inotrophy and chronotrophy
- AV conduction velocity is increased and the refractory period is decreased
- but keep in mind that with normal reflexes, heart rate is dominated by vagal tone and pulse will slow
What is the effect of sympathomimetic drugs in the eye?
- alpha agonists contract the radial muscle, producing mydriasis, and slightly increase drainage of aqueous humor
- beta agonists increase aqueous humor secretion
What is the effect of sympathomimetic drugs on the respiratory tract?
- B2 receptors relax bronchial smooth muscle
- a1 receptors in blood vessels of the upper respiratory mucosa contract, producing decongestion
What is the effect of sympathomimetic drugs on the GI tract?
- the primary GI effect is that alpha2 receptors decrease PNS drive on the enteric system
- secondary to that, beta receptors have a direct relaxation effect on smooth muscle of the GI tract
What is the effect of sympathomimetic drugs on the GU tract?
- alpha1 receptors contract the bladder base and urethral sphincter, promoting retention
- beta2 receptors relax smooth muscle of the vessel wall, promoting retention
What is the effect of sympathomimetic drugs on exocrine glands?
alpha1 receptors on apocrine (stress) glands increase sweating on the palms of the hands, brow, and upper lip
What are the metabolic effects of sympathomimetic drugs?
shifts activity toward energy liberation and usage
- beta receptors increase lipolysis, enhance glycogenolysis, increase glucose release, and increase insulin secretion (so released glucose can move into skeletal muscle)
- alpha2 receptors decrease insulin release
a1 agonists have what effects?
- increase arterial resistance in the periphery, particularly the skin and splanchnic vessels
- inhibit renin release
- contract radial muscle of the eye, producing mydriasis
- constrict blood vessels of the upper respiratory mucosa, producing decongestion
- contract bladder base and urethral sphincter to promote urine retention
- activate apocrine sweat glands, producing sweating on the palms, brow, and upper lip
a2 agonists have what effects?
- inhibit or diminish PNS tone on the enteric system, reducing GI motility
- decrease insulin release
B1 agonists have what effects?
- stimulate renin release
- have a positive inotrophic and chronotrophic effect in the heart
- increase aqueous humor secretion
- relax GI smooth muscle
- increase lipolysis, glycogenolysis, glucose release, insulin secretion
B2 agonists have what effects?
- relax vascular smooth muscle in skeletal muscle, increasing capacitance
- increase aqueous humor secretion
- relax bronchial smooth muscle
- relax GI smooth muscle
- relax the detrusor muscle, promoting urinary retention
- increase lipolysis, glycogenolysis, glucose release, insulin secretion
Which adrenergic receptors does epinephrine activate? Norepinephrine?
- epinephrine: all adrenergic receptors
- norepinephrine: a1, a2, B1 > B2
Which is a more potent pressor, epinephrine or norepinephrine?
norepinephrine because it doesn’t activate B2 receptors very well and therefore, the vasodilation of vessels within skeletal muscle is limited
What is the effect of NE on heart rate?
- at low dose, the vagal reflex overcomes NE’s chronotrophic effect
- at high dose, it produces a tachycardia that overcomes the vagal reflex
What class of drug is isoproterenol? What are it’s effects?
- it is a nonselective B-adrenergic receptor agonist
- it has positive chronotropic and inotropic effects, which increases cardiac output
- it also dilates certain vessels, decreasing both diastolic and mean arterial pressures
What class of drug is dobutamine? What are it’s effects?
- a sympathomimetic drug with B1 and a1 activity
- it therefore stimulates the heart (positive chronotropic and inotropic effects) while raising TPR
- the effect is an increase in CO and MAP
Explain the effects of NE on peripheral resistance, blood pressure, and pulse.
- stimulation of a1 receptors increase TPR
- B1 activation has a positive inotropic effect
- overall, then diastolic, systolic, and MAP all rise
- it induces a bradycardia, however, because the vagal response overcomes the positive chronotropic effect of B1 stimulation
- summary: TPR, MAP, diastolic BP, systolic BP all increase while HR decreases
Explain the effects of epinephrine on peripheral resistance, blood pressure, and pulse.
- stimulation of a1 and B2 receptors results in a slight decrease in TPR
- B1 activation has a positive inotropic effect
- diastolic BP drops, systolic BP increases, and the MAP rises only slightly
- the slight change in MAP isn’t enough to activate the vagal reflex, so B1 stimulation of the heart has a chronotropic effect and induces a tachycardia
Explain the effects of isoproterenol (B-receptor agonist) on peripheral resistance, blood pressure, and pulse.
- stimulation of B2 receptors induces vasodilation within skeletal muscle, and TPR drops significantly
- B1 activation has a positive inotropic effect
- diastolic BP drops, systolic BP increases, MAP drops
- the drop in MAP activates the sympathetic reflex, which releases NE on the heart, contributing to a tachycardia as does the isoproterenol stimulation of B1 receptors, so the increase is significant
What class of drug is phenylephrine? Describe it’s half life. What are it’s effects and uses?
- the prototypic a1 agonist
- not inactivated by COMT because it isn’t a catechol derivative, therefore it has a longer duration of action than catecholamines
- it causes mydriasis, decongestion, and can raise BP
What is methoxamine?
an alpha1 receptor agonist
What is ephedrine?
the first orally active sympathomimetic drug
What is pseudoephedrine?
- a sympathomimetic
- a widely available OTC decongestant
- has direct and indirect effect of releasing endogenous NE
Oxymetazoline
a direct a1 agonist used as a topical decongestant
Xylometazoline
a direct a1 agonist used as a topical decongestant
List the important alpha2-selective agonists and their uses. What is their primary side effect?
- clonidine, methyldopa, guanfacine, guanabenz
- they diminish SNS outflow and are therefore used as antihypertensives
- may cause orthostatic hypotension
What is dobutamine?
a sympathomimetic drug that serves as a B1, and to a lesser extent a1, agonist
What is prenalterol?
a partial B1 agonist
What is the clinical benefit of a B1 agonist?
it increases CO with less reflex tachycardia because it doesn’t induce B2-stimulated venous dilation
List four important B2 agonists and their two most important clinical uses.
- albuterol, salmeterol, terbutaline, and ritodrine
- used to treat asthma and for uterine relaxation in premature labor
List the a1 selective agonists.
- phenylephrine
- methoxamine
- oxymetazoline
List the a2 selective agonists.
- clonidine
- methydopa
- guanfacine
- guanabenz
List the B1 selective agonists.
- dobutamine
- prenalterol
List the B2 selective agonists.
- albuterol
- salmeterol
- terbutaline
List the indirect sympathomimetics.
- ephedrine/pseudoephedrine
- cocaine
- tyramine
- amphetamine
- methamphetamine
- methylphenidate
Describe the action and effects of amphetamine. Compare it to methamphetamine.
- it is an indirect sympathomimetic
- stimulatant effects on mood and alertness but depressant effect on appetite
- works by displacing stored catecholamines
- methamphetamine is similar but with a higher ratio of central to peripheral actions
What is methylphenidate? What is it used for?
- a variant of amphetamine
- used in ADHD
How does cocaine have it’s effects?
it is a sympathomimetic that blocks the activity of uptake 1
Where is tyramine found? How does it function? What are it’s effects and side effects? What can be used to potentiate it’s effects?
- found in fermented foods such as cheese
- it has a high affinity for VMAT and blocks packaging of NE until it builds up and simply diffuses out
- its effects can be potentiated by MAOIs
- may produce a hypertensive crisis
List the important clinical applications of sympathomimetic drugs.
- hypotension, hypovolemic or cariogenic shock, cardiac insufficiency
- hemostasis in surgery, reducing diffusion of local anesthetics
- dobutamine can be used in heart failure
- bronchial asthma or anaphylaxis
- premature labor
- narcolepsy
- ADHD
Describe sympathomimetic toxicity.
- related to the extent of pharmacologic effects in the CV and CNS
- include hypertension and tachycardia
- as well as restlessness, tremor, insomnia, anxiety, and paranoia
How does phentolamine compare to phenoxybenzamine?
- they are both alpha-receptor antagonists
- phentolamine is a competitive inhibitor while phenoxybenzamine has a long duration of action thanks to it’s irreversible inhibition of alpha receptors
How do alpha receptor antagonists affect the CV system?
- antagonism of a1 receptors in the periphery lead to vasodilation, a drop in TPR, and a lower MAP
- also reduce ability to respond to postural changes so may cause orthostatic hypotension
- vagal reflex is likely to initiate tachycardia
How can an alpha antagonist be used in conjunction with epinephrine?
- epinephrine is an a1/B2 agonist
- adding an a1 antagonist can reverse the pressor effects associated with epinephrine
- the result is essentially a B2 agonist
Phentolamine
- the prototypic alpha antagonist (non-selective)
- works via competitive inhibition of receptors
- reduces TPR and MAP, initiating a reflex tachycardia
Tolazoline
an alpha antagonist very similar to the prototype phentolamine
Phenoxybenzamine
- an irreversible alpha receptor antagonist
- moderate a1 selectivity (less than prazosin)
- used in the treatment of pheochromocytoma
- SEs include postural hypotension and tachycardia which limit it’s use
Prazosin
a selective alpha1 receptor antagonist
Doxazosin
- a selective alpha1 receptor antagonist with long half-life
- used in the treatment of hypertension and BPH
Tamsulosin
- a competitive alpha1 inhibitor
- slightly structural differences from other drugs provide it with good efficacy in BPH (perhaps more selective for a subtype of a1 receptors in prostate)
Alfuzosin
- a competitive alpha1 inhibitor
- slightly structural differences from other drugs provide it with good efficacy in BPH (perhaps more selective for a subtype of a1 receptors in prostate)
Yohimbine
- a selective alpha2 antagonist
- no clinical role
Reserpine
- adrenergic antagonist
- irreversibly blocks VMAT, inhibiting storage of all catecholamines, left unprotected they are metabolized by MAO and COMT in the cytoplasm
- depletion on DA may lead to a drug-induced Parkinson’s
- no clinical use, but helpful in establishing catecholaminergic models in the lab
How are alpha receptor antagonists used int he treatment of hypertensive emergencies?
- limited use
- direct vasodilators like nitrates are preferred
How are alpha receptor antagonists used clinically?
- useful for pheochromocytoma
- limited used in hypertensive crisis
- effective against chronic hypertension but may not prevent heart failure and are likely to come with orthostatic hypertension
- used in the treatment of urinary obstruction due to BPH
Esmolol
a beta receptor antagonist with an exceptionally short half life compared to the rest of the group due to it’s ester linkage, which is readily hydrolyzed by esterase in RBCs
Propanolol
- non-selective beta-receptor antagonist
- extremely low bioavailability due to extensive first-pass effect
What is the effect of beta blockers on the CV system?
- affect the heart, vasculature, and renin-angiotensin system
- lower BP in those with hypertension but don’t often cause hypotension in normal subjects
- have negative inotropic and chronotropic effects on the heart, reducing O2 demand of the myocardium; the result is that they are cardio protective and offer significant post-MI benefit
- see slowed AV conduction and increased PR interval
What is the effect of beta blockers in the respiratory tract?
- B2 blockade increases airway resistance
- therefore they should be avoided in those with asthma (use selective B1 antagonists instead)
What is the clinical used of beta blockers in the eye?
reduce intraocular pressure by reducing aqueous humor production
What are the endocrine and metabolic effects of beta blockers? What cautions must be taken?
- inhibit SNS stimulation of lipolysis and glycogenolysis
- use with caution in insulin-dependent diabetics
- chronic use may increase plasma VLDL or decrease HDL (unknown mechanism)
Why are beta blockers with partial beta agonist activity clinically important?
- may help limit the antagonism, thereby avoiding some of the side effects associated with pure antagonists
- not as effective or cardioprotective post-MI
Metoprolol
a selective B1 antagonist
Atenolol
a selective B1 antagonist
Nadolol
a beta antagonist with very long duration of action
Timolol
a beta antagonist with very long duration of action
Pindolol
a beta antagonist with partial agonist activity
Labetalol
- a reversible a1 antagonist with nonselective beta-adrenoceptor antagonist activity
- produces hypotension with less tachycardia than alpha-blockers
Butoxamine
a selective B2 antagonist with no clinical application
What are the primary clinical uses of beta blockers?
- effective and well-tolerated in those with hypertension
- helpful in those with ischemic heart disease (reduce frequency of angina, improve exercise tolerance, decrease cardiac work, reduce myocardial O2 demand, prolong survival)
- effective against supra ventricular and ventricular arrhythmias (increase AV node refractory period, slow ventricular response rates in atrial fibrillation, and reduce ventricular ectopic beats)
- topical administration for glaucoma (particularly open-angle glaucoma)
- useful in those with hyperthyroidism because it reduces distal tremor and tachycardia
Beta Blocker toxicity
- usually well tolerated
- minor toxicity: rash, fever, sedation, depression
- major toxicity: worsening of asthma, cardiac decompensation, supersensitivty with abrupt discontinuation after chronic use (gradual tapering necessary to prevent hypertensive crisis)
- may exacerbate hypoglycemic episodes in diabetics
