Adrenergic Agonists And Sympathomimetics

Front 1

What is the difference between direct and indirect sympathomimetics?

Back 1

direct: agents that bind directly to and activate the adrenergic receptors

indirect: agents that depend on the release of endogenous catecholamine

Front 2

What are the 3 major groups of adrenergic receptors?

Back 2

-all are seven transmembrane domain G-protein coupled receptors
1. A1 adrenergic receptors
2. A2 adrenergic receptors
3. B adrenergic receptors

Front 3

Alpha - 1 adrenergic receptors

Back 3

-a1A, a1B, a1D
-through G-protein Gq stimulate phospholipase C which produces IP3 and DAG
-IP3 stims the release of IC Ca++--> activation of many kinases and muscle contraction

Front 4

Alpha - 2 adrenergic receptors

Back 4

-a2A,a2B,a2C
-coupled to a decrease in adenylyl cyclase act through the Gi regulatory G-Protein
-decrease act results in a reduction of cAMP production

Front 5

B adrenergic receptors

Back 5

B1,B2,B3
-act of all 3 leads to increase in the activty of adenylyl cyclase and a rise in IC cAMP levels
-mediated by Gs regulatory G-Protein

Front 6

Dopamine receptors

Back 6

-in the ANS include D1 and D2 receptors
-D1 is coupled to increased adenylyl cyclase act and increased cAMP
-D2 have the opposite effect, they reduce cAMP levels

Front 7

alpha agonists:
phenylephrine and methoxamine

Back 7

a1>a2>>>>>B

Front 8

alpha agonist

Clonidine

Back 8

a2>a1>>>>>B

Front 9

Mixed agonists

NE
EPI

Back 9

a1=a2; B1>>B2

a1 = a2; B1=B2

Front 10

B agonists

Dobutamine

Back 10

B1>B2>>>>>a

Front 11

B agonists

Isoproterenol

Back 11

B1=B2>>>>>a

Front 12

B agonists

Terbutaline
metaproterenol
albuterol
ritodrine

Back 12

B2>>B1>>>>>a

Front 13

Dopamine agonists

Dopamine

Back 13

D1=D2>>B>>a

Front 14

Domamine agonists

Fenoldopam

Back 14

D1>>D2

Front 15

What is the parent compound in which all catecholamines and sympathomimetic drugs are derived?

Back 15

Phenylethylamine

Front 16

What confer selectivities of the agents for a and B receptors?

Back 16

-substitutions to either the a and B carbons on the ethylamine, the terminal amino group or the benzene ring

Front 17

Catecholamines

Back 17

-some are endogenous ligands (except isoproterenol) that bind to and act adrenergic receptors
-contain -OH groups on carbons 3 & 4 of the benzene ring of phenylethylamine
-dopamine is the base compound

Front 18

Substitutions on the amino group

Back 18

-tends to increase B-receptor activity

Front 19

Substitutions on the benzene ring

Back 19

-drugs having -OH groups at 3 and 4 have max activity of a and B receptors
-removal of 1 or both reduces potency

Front 20

Catecholamines are sensitive to metabolism by?

Back 20

-catechol-O-methyltransferase (COMT)
-removal of -OH groups reduces the activity of the enzyme and increases the bioavailability and duration of action of the drug
-also into the CNS

Front 21

Example of no benzene hydroxyl groups

Back 21

ephedrine and amphetamine
-both have high bioavailability, long duration of action and pronounced effects in the CNS

Front 22

Substitutions on the alpha carbon

Back 22

-block oxidation by monamine oxidase (MAO) and prolong the action, particularly of non catecholamines

Front 23

Substitutions on the beta carbon

Back 23

-direct acting agonists (NE)

Front 24

Effects of adrenergic activation on BVs

Back 24

-vasc SM tone is regulated by adrenergic recptors
-a-adrenergic increase arterial resistance in skin and splanchnic
-B2 promote SM relax and vasodil in skeletal m
-D1 receptors act by DA promote vasodil of renal, splancnic, coronary and cerebral arteries

Front 25

Effects of adrenergic activation on Heart

Back 25

-most by B1, (B2,B3, and a are there)
-Ca++ influx to cardiac cells
-inc rate of contract (+ chrono) SA node, inc act in Purkinje fibers, conduction V in AV node increases and refract period decreases, contractility increases (+ inotropic)

Front 26

Effects of adrenergic activation on BP

Back 26

-pure a-agonist like phenylephrine will inc vasc resistance and decrease venous capacity--> leads to reflex increase in vagal tone-->decrease HR

Front 27

Why might a decrease in HR not necessarily result in a decreased CO?

Back 27

-since increased venous return may increase stroke volume and stim of a-receptors on the heart increases contractility
-hypotensive states the reflex response will be diminished since rise in BP doesn't exceed normal

Front 28

Response to a beta selective agonist like isoproterenol

Back 28

-stim of B receptors in heart leads to increased CO (stim of rate and force of contraction)
-act of periph B2s leads to a decrease in peripheral resistance

Front 29

Effects of adrenergic activation on the Eye

Back 29

-mydriasis, by the radial pup dilator a1
-alpha agonists decrease prod of Aq humor (a2)
-B agonists can increase aqueous outflow
-EPI (a and B) can lower IOP thru inc outflow and dec production

Front 30

Effects of adrenergic activation on Resp tract

Back 30

-bronchial SM has B2 receptors--> relaxation, bronchodilation
-act of a-receptors in BVs of URT mucosas results in a useful decongestant effect

Front 31

Effects of adrenergic activation on GI

Back 31

-minor effects, but act of a and B receptors causes relax of GI SM
-intest tone and the stomach are usually relaxed
-pyloric and ileocecal sphincters are contracted (a1)

Front 32

Effects of adrenergic activation on GU

Back 32

-in pregos a1 act leads to contract of uterus and B2 --> relaxation
-urinary continence is med by a1
-act of B2 in bladder wall--> relaxation
-ejac depends on norm a-recep fxn in the ductus def, seminal vesicles, and prostrate

Front 33

Effects of adrenergic activation on exocrine glands

Back 33

-apocrine sweat glands secrete in response to stress not temperature and are activated by adrenergic stim (a1)

Front 34

Effects of adrenergic activation on metabolic effects

Back 34

-B3--> lipolysis
-sympathomimetics inc glycogenolysis and gluconeogenesis in liver
-K+ uptake into cells is inc
-Panc a2 recept stim decrease in insulin sec, B2 stims insulin secretion (inhib predom w/ EPI)

Front 35

Effects of adrenergic activation on Endocrine fxn and leukocytosis

Back 35

-in kidney renin secretions by B1 and inhib by a2

Front 36

Effects of adrenergic activation on CNS

Back 36

-depends on ability to cross BBB
-no catecholamines unless high rates of infusion-->nervousness/unease
-amphetamine or methylphenidate readily enter CNS and have range of effects
-a2 in brain stem-->dec symp flow

Front 37

Range of effects caused by amphetamine or methylphenidate in the CNS

Back 37

-low= mild altering and improved attention
-med= elevation of mode, insomnia, euphoria, anorexia
-high= psychotic behavior
*effects likely due to inc DA activity

Front 38

EPI

Back 38

-potent vasocontrictor and cardiac stim which has variable physiologic consequences depending on the method of administration and dose

Front 39

Rapid IV infusion of EPI

Back 39

-BP rapidly rises to peak proportional to dose (systolic > diastolic)
-act of B1 receptors--> increasing rate and force of contraction
-periph resistance is inc due to a1 inducing arterial constriction in skin and viscera

Front 40

Small doses of EPI

Back 40

-decrease diastolic BP due to vasodilator actions of B2 in skeletal m
-B2 rec more sens to EPI than a
-mean BP may actually fall below normal due to the unmasking of the B2 effect

Front 41

Slow IV infusion of EPI (or subcutaneous injection)

Back 41

-absorp is reduced due to local vaso constrict--> mod inc in systolic due to direct action on the heart (+ ino and chrono)
-reduction in diastolic due to vasodil of B2
-Mean BP does not change sign b/c minimal baroreceptor reflex

Front 42

Overall effect on heart by EPI

Back 42

-HR, CO, SV, and force of contraction all increase
-also results in an increase in O2 consumption by myocardium

Front 43

Non cardiovascular effects of EPI

Back 43

-inc in blood glucose and lactate
-glucagon secretion is enhanced, and circ FA inc as well
-during exercise adrenal medulla releases EPI--> all these responses

Front 44

Therapeutic uses of EPI

Back 44

-metab rapidly by MAO and COMT, brief if given by IV, longer for subcut and IM
-emergency asthma
-prolong the act of local anesthetics (vasoconstriction)
-open angle glaucoma-->Aq H outflo

Front 45

EPI and emergency cases of cardiac arrest or complete heart block

Back 45

-revert heart back to normal rhythm
-done by IV infusion but has been accomplished by direct injection to the heart

Front 46

EPI is DOC for?

Back 46

-tx of anaphylactic shock or hypersensitivity rxns
-reverses bronchoconstriction, cardiovascular collapse, mucus mem congestion and angioedema (EpiPen)

Front 47

What are the 3 mechanism responsible for shock?

Back 47

1. Hypovolemia
2. cardiac insufficiency
3. altered vascular resistance
*DA for non-anaphylactic shock b/c can dilate renal vasculature

Front 48

NE

Back 48

-similar effect as EPI on heart B1 and vasc a-receptors but little effect on B2
-HR, force of contract, and periph R all increase
-reflex tend to reduce HR but BP and force of contract still increase

Front 49

Therapeutic uses of NE

Back 49

-only to increase BP in an acute hypotensive state
-rapidly metab by MAO and COMT--> very short half life

Front 50

Dopamine transport and what can inhibit this? If it is inhibited what occurs

Back 50

-DA is trans into vesicles by a high affinity catecholamine carrier
-this carrier can also transport NE that has been recycled from previous synaptic activity

-Reserpine can inhibit the carrier which causes cytoplasmic accumulation of DA and NE, whic his then degraded by MAO --> depletion of catecholamines/reduction of synaptic transmission

Front 51

Therapeutic uses of Isoproterenol

Back 51

-relatively resistant to MAO, but met by COMPT in liver--> longer 1/2 life
-historically bronchodil but replaced by more select agents, still maybe useful for acute asthma
-emerg cases of bradycardia or heart block or ventricular arrhythmia this maybe use to stimulate HR

Front 52

Lower doses of Dopamine

Back 52

-low doses act D1-->dilation of renal, coronary and mesenteric arteries
-GFR, renal Q and Na+ excretion all increase
-Presynapt D2 at adrenergic nerve terminals inhib release of NE

Front 53

Higher doses of DA

Back 53

-can act B1 receptors on the heart thus + inotropic
-also a-receptors and cause inc in periph R
-can stim an incr release of NE -->contribute to actions on heart

Front 54

Therapeutic uses of DA

Back 54

-only IV (but can't cross BBB)
-tx of severe CHF, particularly in pts w/ olguria and normal peripheral vasc R
-septic or cardiogenic shock
-historically used for tx or prevention of acute renal failure, but not anymore

Front 55

Why should pts receiving IV DA be monitored?

Back 55

-for changes in urine flow, tachycardia or development of arrhythmias--> indicate that a slowing or term of infusion is necessary
-intensity of effect closely related to rate of infusion

Front 56

Fenoldopam

Back 56

-D1 DA receptor selective agonist w/ short duration of action
-lowers BP in severe hypertension
-mod affinity for a2

Front 57

Dobutamine

Back 57

-synthetic catechoamine acts prim at B1 receptors w/ some act at a-receps
-full agonist on B1
-either act or antagonize a1s
-on heart, racemic mixtures inc force of contraction more than rate when compared to isoproterenol

Front 58

Therapeutic uses of Dobutamine

Back 58

-indicated for short term tx of cardiac decomp that may occur after heart surgery, in CHF or acute MI
-increases CO and SV w/out much effort on heart (1/2 life of 2 mins)

Front 59

Phenylephrine

Back 59

a1-selective agonist
-sim to EPI, missing one -OH group -more resistance to COMT but MAO, >oral avail, lower potency
-causes vasoconstriction and inc in BP w/ associated sinus bradycardia

Front 60

Therapeutic uses of Phenylephrine

Back 60

-potent vasopressor w/ no direct ino or chrono effects on heart
-tx paroxysmal ventric tachy due to dec in HR from reflex-->a1 vasocons
-reduces splanchnic Q in septic shock (DA or NE better)
-good for shock states w/ tachy
-cold: decongestion, mydriasis

Front 61

Metaraminol

Back 61

-a1 selective agonist
-direct action at a-adrenergic receptors
-indirect inc NE release from adrenergic terminals

Front 62

Therapeutic uses of metaraminol

Back 62

-reverse or prevent hypotension associated w/ spinal anesthesia
-adjunctive therapy for hemorrhagic hypotension (also hypo w/ med/surg)
-shock associated w/ brain damage due to trauma or tumor

Front 63

Midodrine

Back 63

-a1 selective agonist
-converted to desglymidodrine--> causes increased BP through stim arterial and venous contraction

Front 64

Therapeutic uses of Midodrine

Back 64

-pts w/ autonomic insufficiency
-POSTURAL HYPOTENSION
-effective for canceling fall in P when pt is standing, but may cause hypertension if pt is supine
-avoid near bedtime

Front 65

Clonidine

-a1 selective agonist

Back 65

-prim mechanism of its hypotensive actions due to act of a2 in brain stem which depresses symp outflow resulting in a dec in periph R, renal vasc R, HR, and BP

Front 66

IV infusion of high doses of Clonidine

Back 66

--> acute rise in BP due to act of postsynapt a2s on vasc SM
-this hypertensive effect does not occur w/ oral admin and even w/ parental admin it is quickly followed by a longer lasting hypotens effect

Front 67

Therapeutic uses of clonidine

Back 67

-prim used as antihypertensive agent given orally
-for diagnosis of phaeochromocytoma
-epidurally for tx pain in cancer pts that are refractive to opioid tx

Front 68

Off label uses of clonidine

Back 68

-ADHD
-reduce adverse sympathetic nervous activity associated w/ opiate, nicotinic and alcohol w/drawal
-vasc headaches, diabetic diarrhe, glaucoma, colitis, Gilles de la tourette's syndrome, hot flashes

Front 69

Gaunfacine

Back 69

-a2 selective agonist
-more selective than clonidine and same applications

Front 70

Guanabenz

Back 70

-a2 selective agonist similar to guanfacine and clonidine

Front 71

Apraclonidine

Back 71

-a2 selective agonist used topically to reduce IOP
-mech thought to be due to reduction in prod of aq humor thru presynaptic autoreceptor mechanism

Front 72

Brimonidine

Back 72

-a2 selective agonist administered topically to lower IOP in pts w/ ocular hypterension or open-angle glaucoma through the reduction in aq humor prod via presynaptic autoreceptor activation

Front 73

Beta-2 selective agonists

Back 73

-tried to isolate effects of B2 w/out B1
-not totally specific for B2
-inhalation formulations isolate the bronchodilatory effects and reduce the systemic B1 effects--> relax bronch SM and decrease airway R
-for bronchospasm and asthma

Front 74

B2 receptors and preterm labor

Back 74

-in uterus cause relaxation, so useful in preterm labor

Front 75

Albuterol

Back 75

-Beta-2 selective agonist
-inhalation or orally to tx asthma bronchospasm
-also preterm labor

Front 76

Terbutaline

Back 76

-Beta-2 selective agonist
-inhalation, subcut, or orally to treat emergency asthma, bronchospasm
-also preterm labor

Front 77

Metaproterenol

Back 77

-Beta-2 selective agonist
-less selective than albuterol or terbutaline
-inhalation or orally for bronchospasm

Front 78

Salmeterol

Back 78

-Beta-2 selective agonist w/ loong duration of action (>12 hrs)
-50fold more selective than albuterol
-slow onset of action so not useful as monotherapy for acute attacks of bronchospasm
-asthma, bronchospasm, COPD

Front 79

Formoterol

Back 79

-Beta-2 selective agonist
-sim to salmeterol but has more rapid onset of action, while retaining long duration

Front 80

Miscellaneous sympathomimetics

Back 80

-Amphetamine, Methamphetamine
-Methylphenidate, Pemoline
-indirect actin sympathomimetics, work by stim NE release or by blocking reuptake of NE, some have direct actions on adrenergic receptors as well

Front 81

How do Misc sympathomimetics work?

Back 81

-agents are stimulants of central and symp NS
-orally active and cross BBB
-main action is to increase the synaptic concentration of DA and NE

Front 82

How is methylphenidate different?

Back 82

-acts by blocking reuptake of DA at central synapses while the others increase the release of all catecholamines

Front 83

Effects of misc sympathomimetics

Back 83

-in CNS stim effects due to increased dopaminergic act
-in periphery increase systolic and diastolic P--> reflex reduction in HR

Front 84

Amphetamine

Back 84

-potent CNS stim--> wakefulness, altertness, elevation of mood, inc self confidence, inc conc, elation, euphoria inc motor act and speech
-increase work down but also errors

Front 85

Obesity and misc sympathomimetics

Back 85

-historically used for obesity
-decrease food intake not increase metabolism, tolerance develops rapidly
-use instead for ADHD (esp methylphenidate due to lack of periph CV effects and narcolepsy

Front 86

Why shouldn't misc sympathomimetics be given w/ monoamine oxidase inhbitors (MAOIs)?

Back 86

-result in massive increases of peripheral NE which could cause hypertensive crisis and death

Front 87

What causes disturbances of preception and psychotic behavior w/ very high doses of amphetamine/methamphetamine?

Back 87

-increased serotonin release as well as increased dopamine release in the mesolimbic system

Front 88

Ephedrine

Back 88

-first orally active sympathomimetic, is in the herbal medication Ma-haung
-prolonged/less potent than EPI
-inc the release of catecholamines, but can also directly act a and B receptors
-enter the CNS as a stimulant

Front 89

Therapeutic doses of ephedrine

Back 89

-raises BP by inc CO and by inducing peripheral vasoconstriction
-ephedrine salts used in symptomatic relief of nasal congestion and parenterally to combat a fall in BP during spinal or epidural anesthesia

Front 90

Pseudoephedrine

Back 90

-stereoisomer of ephedrien but less potent
-used in cold formulations as an OTC decongestant

Front 91

Cocaine

Back 91

-local anestheic also blocks reuptake of catechoamines
-CNS effects due to excess DA act in the pleasure center or brain
-potent periph sympathomimetic can cause hypertens & tachycardia
-convulsions, cerebral hemorrhage, arrhythmias and MIs

Front 92

Tyramine

Back 92

-normal by-product of tyrosine metabolism and found in [high] in fermented foods like cheese and red wine
-act as indirect acting sympathomimetic and in pts taking MAOIs it can precipitate a hypertensive crisis

Front 93

AEs of sympathomimetics

Back 93

-IV infusions can inc BP--> increases cardiac work which might precip cardiac ischemia and failure
-B agonists cause sinus tachycardia and provoke ventricular arrhytmias