topic 21 Flashcards
What are nine examples of directly acting sympathomimetic agents (agonists)? What receptors do they work at?
α1, α 2, β1, β2, - epinephrine
α1,α2, β1 - norepinephrine
α1 - phenylephrine
α2 - clonidine
β1, β2 - isoproterenol
β1 - dobutamine
β2 - terbutaline; albuterol; metaproterenol
How do you differentiate between direct acting sympathomimetic agents, mixed acting, and indirect acting? What are examples of mixed acting and indirect acting? How do they work?
Direct acting agents action is not reduce by pretreatment with reserpine or guanthidine (deplete NE). In fact, it may be increased b/c reserpine could cause superselectivity (upregulation of receptors).
Indirect acting agents aciton is depleteed by pretreatment with reserpine or guanthidine b/c they simply cause NE to be released so they can’t work if there is no NE (Amphetamine and tyramine)
Mixed acting agents action is reduced by pretreatment with reserpine and guanthidine b/c they act directly and indirectly by releasing NE (ephedrine)
Where is the A1 receptor throughout the body? What effect does it have in general and at each location? What are some directly acting agonists of it?
In general, it leads to contraction or stimulation
Phenylephrine (A1 specific), NE, E
Arteries-contraction
Arterioles-contraction
Veins–contraction
Eye-contraction of dilator m.
Heart-increase force of -contraction
Uterus-contraction-Stimulation
Salivary Glands-Stimulation
Sweat Glands-Stimulation
Exocrine Pancreas-Stimulation
Growth Hormone-Stimulation
GI sphincters-contraction
Urinary bladder (trigone)-contraction
Spleen-contraction
Pilomotor SM-Erects hair
Where is the A2 receptor throughout the body? What effect does it have in general and at each location? What are some directly acting agonists for it?
Mainly inhibition in general.
Clonidine (A2 selective), NE
All Organs Receiving Adrenergic Innervation-inhibition of NE release
Pancreas ( Beta cells)-Inhibition
Some vascular smooth muscle (arteries; arterioles)-Contraction
Fat cell-inhibition of lipolysis
Platlets-aggregation
sympathetic ganglia-Inhibition of ganglionic release
Where is the B1 receptor throughout the body? What effect does it have in general and at each location? What are some directly acting agonists for it?
Stimulation in general
E, NE, Isoproterenol (Beta selective), Dobutamine (B1 selective)
Heart: Increased rate, force, conduction velocity, ventricular excitability, glycogenolysis
JG Cells: Increase renin release
Where is the B2 receptor throughout the body? What effect does it have in general and at each location? What are some directly acting agonists for it?
Relaxation/Inhibition ingeneral
E, Isoprorterenol, Terbutaline (B2 selective)
Arteries-releaxation
Arterioles-relaxation
Veins-relaxation
Ciliary muscle-relaxation
Bronchi; Bronchioles-relaxation
GI Tract-relaxation of smooth muscle
Urinary bladder (detursor)–relaxation
Secretions-Inhibition
Uterus-relaxation
Pancreas ( beta cells)-stimulation of insuli release
Growth Hormone-inhibition
Mast Cells-Inhibition of histamine release
Skeletal Muscle-promotes potassium uptake
Liver-activates glycogenolysis
Where is B3 receptor? What effect does it have there?
Fat cells-Activated lipolysis
What effect does epinephrine have metabolically? How does it bring that about? Which receptors does it use? Which receptor does it mainly use? What pathways are used?
EPI leads to increase FA, Lactic acid, and glucose in the blood.
It binds to beta receptors, mainly beta 2.
LIver: Upon binding, Adenylate cyclase converts ATP to cAMP—>cascade of phosphorylations—>active phosphorylase breaks down glycogen into glucose which is converted to glucose and put into bloodstream.
Muscle: Same thing but glucose-6P can’t be broken down into glucose, so lactic acid is forme and released.
Fat cells: Same thing, but a lipase is activated which converts TGs into FA which are released.
How are SM cells contracted and relaxed? What can be said of the affect of cAMP on SM cells?
Contracted: Ca channels lead to increase calcium which binds with calmodulin and then activates MLCK (myosin light chain kinase) which activates MLC allowing actin to bind—>contraction
Relaxed: Adenylate cyclase is activated, leading to more cAMP which activates a kinase which inactivates MLCK—>relaxation
cAMP in SM cells will always lead to relaxation.
What is the general structure of an agonist catecholamine? What kinds of changes happen to the general structure? What results in better beta activity? better alpha activity, exceptions? better CNS activity? Antagonists? Prolonged activity?
2 carbons connected to an amine group. the beta carbon connected to a benzene ring usually with OH groups on 3,4 carbons on benzene ring
Beta activity is increased by substitutions to amine and more hydroxyl groups.
Less substitutions to amine results in increased alpha activity (Epi and phenylepi have one methyl group there but still activate alpha)
Removal of 4 carbon OH results in prolonged activity (COMT)
Substitution at alpha carbon leads to prolonged activity (MAO)
Less hydroxyls—>more CNS activity
More than just alpha and beta carbons—>antagonist
What happens with baroreflex control of arterial blood pressure? What are 3 exceptions to these rules?
There are baroreceptors in the aortic arch and internal carotid arteries which send signals through the aortic and carotid sinus nerves which end up in the vagus and glossopharyngeal nerves respectively. These afferent signals become more frequent with increase in bp and less frequent with decrease in bp. These afferent signals meet up in the NTS (CNS) with efferent sympathetic and parasympathetic neurons. The parasympathetic neurons which travel in the vagus nerve are increased when the afferent signals increase and decrease when afferent signals decrease. Therefore, when bp is high, the parasymp will cause heart rate to decrease through the action of ACh on the M2 nerve at SA node. The opposite happens when bp is low. The sympathetic neurons are inhibited by afferent signals. There are two branches from these sympathetic neurons, the cardiac nerve and the vasoconstrictor nerve. When bp increases, afferent signals increase, symp. signals decrease and the heart rate is slowed, contractility decreases, and vasocontstriction decreases. The opposite happens when bp decreases. This is all short term, within minutes.
Exceptions: Isometric exercise (diastolic bp and hr increase), diving reflex (decrease in art. pressure and hr), defense reaction (increase in art. pressure and hr).
What is the effect of epi and norepi on the heart, bp, peripheral circulation, and metabolic effects?
Cardiac
heart rate-y:n,0 stroke volume-yyyy:yy Card output-yyy:0,n arrhythmias-yyyy:yyyy coronary flow-yy:yyy
BP
systolic arterial-yyy:yyy
mean arterial-y:yy
Diastolic arterial-y,0,n:yy
Peripheral
total peripheral resistance-n:yy cerebral blood flow-y:0 Muscle blood flow-yy:0,n Cut blood flow-nn:y,0,n renal blood flow-nnn:n Splanchnic blood flow-yy,0,n:0,y
Metabolic effects
02 consumption-yy:0,y
Blood sugar-yyy:0,y
Blood lactic acid-yyy:0,y
What are 2 non-specific alpha/beta andrenergic receptor agonists
epi and norepi
What receptors does epinephrine work at? What are its physiological effects? What are its therapeutic uses? How is it administered? How is it broken down? What are its untoward effects?
Potent agonist at A1, A2, B1, B2
Increase in heart rate, bp, card. output, contractility. Slight decrease in PVR. Vasoconstriction. Vasodilation at skel. muscle. Increase in blood glucose, lactic acid, FAs.
It is a substrate for COMT and MAO so it is quickly broken down
Administered parentally (IM, IV, SC, etc.)
Used in anaphylaxis, cardiac stimulant, glaucoma, with local anesthetics
Untoward effects: palpitation, cardiac arrythmias, cerebral hemorrhage, headache, tremor, restlessness
What receptors does norepinephrine work at? What are its physiological effects? What are its therapeutic uses? How is it administered? How is it broken down? What are its untoward effects?
Potent A1, A2, B1 agonist
It is a substrate for COMT and MAO so it is quickly broken down
Increase in syst. and diast. bp. Increase in PVR. Direct increase in HR, but indirect decrease in HR. Vasoconstriction.
Administered parentally (IM, IV, SC, etc.)
Used as a pressor, usually post cardiac surgery.
Untoward effects similar to EPI (palpitations, arrythmias, cerebral hemorrhage, headache, tremors, restlessness) + Hypertension.
What receptors does phenylephrine work at? What is its prominent physiological action? What are its therapeutic uses? How is it administered? How is it broken down? What are its untoward effects?
Potent A1 agonist
It is a substrate for MAO
Causes vasoconstriction
Administered parentally (IM, IV, SC, etc.), orally, locally
Used as a pressor, nasal decongestant, mydriasis w/o cycloplegia, glaucoma
Untoward: Hypertension, reflex bradycardia, dry mouth, sedation, rebound hypertension upon abrupt withdrawal
What receptors does clonidine work at? How does it reduce hypertension? What other physiological action does it have? What are its therapeutic uses? What is the therapeutic use of one of its derivatives? How is it administered? What are some adverse effects?
selective A2 agonist
An A2 receptor in the CV control center in the brainstem inhibits pacemaker cells and therefore decreases sympathetic tone–>decreased HR, contractility, decr. renin release, decr. vasoconstriction—>decreased bp and PVR. It works in the CNS. Also decreases production of aqueous humor.
Administered parentally (IM, IV, SC, etc.), orally, transdermal
Used for hypertension, opiate withdrawal (combat symp. increase), glaucoma (apraclonidine), ADHD
Sedation, Na+/H20 retention, dry mouth, withdrawal syndrome (upregulation of sympathetic receptors)
What receptors does isoproteranol work at? What are its effects? are its therapeutic uses? How is it administered? How is it broken down? Untoward effects?
non selective beta receptor agonist
REsults in bronchodilation, stimulated cardiac output, tachyarrhythmias, decrease in PVR.
Metabolized by conjugation rxns/comt
Administered parentally, locally (inhaled)
Used for asthma, COPD, cardiostimulant (shock or cardiac arrest)
Untoward: palpitations, tachycardia, headache, flushed skin, cardiach ischemia in patients with cardiac disease
What receptors do metaproteranol, albuterol, and terbutaline work at? What are its effects? are its therapeutic uses? How is it administered? How is it broken down? What is a use of terbutaline? Untoward effects?
Beta 2
Bronchodilation, only effects cardiac output at high doses. Relaxation of uterine SM. Activation of other B2 receptors after systemic admin.
Not metabolized by COMT/MAO
administered orally, parentally, locally (inhaled)
Used for asthma, COPD
Controversially, terbutaline used as a tocolytic (prevent premature labor)
Skel. muscle tremor, tachycardia and other cardiac effects.
What receptors does dobutamine work at? What are its effects? are its therapeutic uses? How is it administered? How is it broken down? What is its halflife? untoward effectgs?
B1
positive inotropic (contractility) effect on heart, with little cronotropic effect, increase in AV conduction
metabolized by COMT and conjugation, not MAO
Parentally
short half life (2 minutes)
Used for acute heart failure, shock (especially cardiogenic), get the heart working after bypass surgery.
Increase in bp and hr.
What is another drug that works at B1? What other receptor will it stimulate when given at high doses? What kind of adrenergic drug is it? What are its effects? How is it used? Why is it particularly good at treating shock? Untoward effects?
Dopamine
A1 at high doses
Effects: increase in hr and contractility. Increase in systolic bp.
It is a mixed acting adrenergic drug. meaning it causes NE to be released and is a B1 agonist
It is good for treating shock (particularly cardiogenic) because there are dopamine receptors in renal and mesenteric vascular beds which lead to vasodilation. Therefore, dopamine can cause increase cardiac output while increasing peripheral resistance while also helping blood to get into essential tissues.
High doses lead to vasoconstriction
What kind of adrenergic drug is ephedrine? What receptors does it work at? What are its effects? How is it used clinically? How is it administered? Untoward effects?
A1 ,A2, B1, B2
Mixed acting
Similar effects as epi but longer lasting. Also, causes CNS Stimulation
Used sparingly now (side effects) but is a bronchodilator for rx of asthma and a nasal decongestant and used to treat hypotension and shock
administered oral, iv, local
Untoward: REstlessness, tremor, insomnia, anxiety, tachycard, hypertension
What kind of adrenergic drug is amphetamine? What are its effects? How is it used clinically? How is it administered? What are its untoward effects?
Indirect acting-causes NE to be released, and thus has both alpha and beta activity (increase in bp, myocardial stimulation) as well as potent CNS stimulation
It is used to treat ADHD, Narcolepsy…controversially used to treat obesity
Leads to severe tolerance, physio/psych dependence. Restlessness, tremor, insomnia, anxiety, tachy, hypertension, cardiac arrythmias. paranoid schizophrenia, hemorrhagic stroke.
Administered oral/IV
What are the catecholamines? What are their characteristics? How do the non-catecholamines differ?
Epi, NE, Dopamine, isoproterenol, dobutamine.
They are fast acting, short duration, they don’t cross BBB, they can’t be taken orally
Non-catechols have a longer duration and can be taken orally. Might cross CNS
What are two non selective alpha adrenoreceptor antagonists? What is the a1 adrenoreceptor antagonist that we need to know?
non selective: phenoxybenzomine, phentolamine
A1: Prazosin,
What receptor does phenoxybenzamine work at? How does it work? What happens if its given at a slightly higher dose? What are its pharm actions? What is it used to treat? What are its untoward effects? How is it administered?
A1 and A2.
It binds covalently to the receptor and therefore acts more like a non-competitive antagonist
At slightly higher doses, blocks ACh, histamine, and serotonin receptors
It causes a decrease in PVR and BP. Venodilation.
Used to treat catechol. excess in pheochromocytoma. Used in hypertensive crisis.
Untoward: Postural hypotension, failure of ejaculation, Reflex tachycardia. nasal stuffiness.
Oral.
What receptor does Phentolamine work at? How does it work? What happens if its given at a slightly higher dose? What are its pharm actions? What is it used to treat? What are its untoward effects? How is it administered?
A1 and A2
Competitive antagonist.
At slightly higher doses, blocks ACh, histamine, and serotonin receptors
It causes a decrease in PVR and BP. Venodilation.
Used to diagnose pheochromocytoma. Used in hypertensive crisis.
Untoward: postural hypotension, failure of ejaculation, Block of presynaptic A2 receptors may result in even stronger reflex tachycardia. nasal stuffiness.
Parenteral
What receptors does prazosin work at? What are its effects? What is it used for? What are its untoward effects? Admin?
A1 Antagonist
Decrease in PVR and BP. Relax SM in neck of urinary bladder and in prostate
Primary hypertension, increase urine flow in BPH
Untoward: Postural hypotension, failure of ejaculation, Reflex tachycardia. nasal stuffiness.
Oral
What are 4 1st generation non selective beta antagonists? What is one 2nd generation B1 antagonist? What are 2 3rd generation non selective beta antagonists?
non selective first generation: Nadolol, pindolol, propranolol, timolol
2nd gen. B1 antagonist: Metoprolol
3rd gen: Carvedilol, labetalol
What makes each of the beta blockers unique? What is their selectivity? Are they membrane stabilizing? Are they intrinsic sympathomimetics? What do those things mean? Do they have additional actions?
Propranolol is the oldest most used drug. It is membrane stabilizing (antiarrhythmic).
Nadolol is unique b/c it doesn’t cross BBB
Timolol is used for glaucoma
Pindolol is membrane stabilizing and intrinsic sympathomimetic (it is a partial agonist)
Metoprolol is beta 1 selective so it doesn’t block vasodilation in lung and can be used in people with asthma, COPD, allergic disorders, hypoglycemic patients, peripheral vascular disease
Labetalol is membrane stabilizing, intrinsic sympathomimetic, and it is and alpha 1 adrenoreceptor antagonist (vasodilation)
Carvedilol is membrane stabilizing, it is an alpha 1 adrenoreceptor antagonist, it is an anti-oxidant, and it blocks calcium entry
What are the side effects of beta blockers in general? What are the contraindications?
bradycardia, hypotension, AV block, sedation, masks symptoms of hypoglycemia (don’t know you need to eat), withdrawal syndrome, vivid dreams/nightmares, fatigue, lethargy, Vomiting/nausea/diarrhea/flatulence
Contraindicated in Asthma/COPD,
What are some effects of beta blockers?
Negative inotropic and cronotropic effects. Slow aV conduction. Lower BP.
Vasoconstriction
Reduce intraocular pressure
Inhibit SNS stimulation of lypolysis and glycogenolysis in liver
Antagonize release of renin
Anti-arrhythmic
What are some therapeutic uses for beta blockers? How do some of them work?
Angina pectoris
Hypertension
arrhythmias (if due to catecholamines)
idiopathic hypertrophic subaortic stenosis
congestive heart failure
pheochromocytoma (only with alpha blockers too)-for arrhythmias
Glaucoma-Wide angle
Hyperthyroidism-excess of thyroid–>upregulation of beta receptors
Stage fright
Withdrawal therapy
non parkinsonian tremors
migraine prophylaxis
Why can’t you go off beta blockers quickly?
Upregulation of Beta receptors while using beta blockers.
What is angina pectoris? What makes it worse? better? What are 3 types? Which are beta blockers used for?
Produces sensation of squeezing in the heart. Inadequate coronary blood flow that fails to meet oxygen demands of heart–>acute myocardial ischemia–>muscle death. Often worsened by exercise and alleviated by rest.
Chronic stable angina-Fixed coronary stenosis. Precipitated by exercise or stress. Relieved by rest and Nitroglycerin. beta blockers used
Unstable Angina-At rest or with physical activity, either. Crescendo pattern. Medical emergency. Causes platelet aggregation (aspirin used to combat it). Beta blockers used prophylactically.
Variant Angina-At rest, caused by coronary spasm. Beta blockers not used.
What are 9 possible mechanisms by which beta blockers relieve hypertension?
Reduction of Cardiac output (b1 receptors)
CNS effect
Inhibition of Renin release
Blockade of prejunctional beta receptors
Reduction in venous return and plasma volume
reduction in PVR
Improvement in vascular compliance
Resetting of baroreceptor levels
attenuation of pressor response to catechol with exercise and stress.
What are 3 adrenergic neuronal blocking agents?
Guanethidine, Reserpine, Metatyrosine
What is the mechanism of action of guanethidine? How is it taken? How is it metabolized and excreted? What are its clinical uses? What are its side effects?
Oral
Hepatic metabolism to inactive metabolites which are excreted in urine.
Displaces NE in vesicles. Prevents release of NE from synaptic terminal. Only works in PNS
Used to treat hypertension
Side effects: Ortho. hypotension, parasymp dominance (GI motiliity, diarrhea, nausea, miosis, bradycardia), inhibition of ejaculation.
What is the mechanism of action of reserpine? How is it taken? How is it metabolized and excreted? What are its clinical uses? What are its side effects?
Oral
Hepatic metabolism to inactive metabolites which are excreted in urine and feces
Blocks uptake of NE, dopamine and serotonin into vesicles. Results in depletion of those 3 from CNS and PNS
Used to treat mild to moderate hypertension
Side effects: parasymp dominance (GI motiliity, diarrhea, nausea, miosis, bradycardia), sedation, parkinson like syndrome, severe depression and suicide
What is the mechanism of action of metatyrosine? How is it taken? How is it metabolized and excreted? What are its clinical uses? What are its side effects?
Oral
Majority excreted unchanged
Inhibits Tyrosine hydroxylase–>interferes with DA/NE synth
Used to treat pheochromocytoma that can’t be removed surgically
Side effects: crystalluria, anxiety, diarrhea, sedation
What is the mechanism of action of methyldopa? What receptors does it work at? What is it used to treat? How is it administered? What are its side effects?
It is prodrug that uses cellular enzymes to be converted to methylnorepinephrine which basically functions as NE.
It targets A2 receptors in the CNS and thus decreases symp outflow.
Oral, parenteral
Used to treat hypertension
Side effects: Sedation, lethargy, GI disturbances, parasymp. excess, depressed liver function, impotence.
