Sympathomimetic Agents

Question 1

What is a Catecholamine?

Answer 1

A Catecholamine is a compound that has a catechol nucleus (a benzene ring with 2 adjacent hydroxyl groups attached specifically to the 3 and 4 carbon positions) and an amine side chain.

Question 2

What are the 3 endogenous Catecholamines?

Answer 2

Epinephrine, Norepinephrine and Dopamine

Question 3

what is a Sympathomimetic Agent?

Answer 3

Any drug whose action mimics the Sympathetic Nervous System via activation of the sympathetic (adrenergic) receptors?

Question 4

What are the classic effects of Sympathomimetics on the following systems:

1) Cardiac
2) Blood Vessels
3) Lungs
4) GI

Answer 4

1) Cardiac - Increased SV, HR, and force of contraction and chance of dysrhythmias.
2) Blood Vessels. - Increased SVR, BP via alpha1 receptors causing vasoconstriction.
3) Lungs - Bronchodilation and increased pulmonary blood flow.
4) GI - Increased motility and tone; decreased secretions.

Question 5

How does Sympathomimetics affect metabolic function?

Answer 5

1) Liberates free fatty acid from adipose tissue

2) Increases rate of hepatic and muscle glycogenesis

Question 6

How does the SNS affect insulin secretion?

Answer 6

Modulation of insulin secretion is seen but the predominant effect seen by the SNS is inhibition of insulin.

Question 7

How do Sympathomimetic drugs (especially Epi) affect the Potassium shift in the plasma?

Answer 7

B2 agonism by plasma epinephrine (or exogenously administered epinephrine) can produce hypokalemia as K+ is driven into RBCs and muscle cell via stimulation of Na+K+ pump.

Question 8

Why is it that you hardly ever see CNS side effects (i.e. restlessness, tremor, and respiratory stimulation) from sympathomimetics?

Answer 8

Because of their inability, especially epinephrine, to cross the BBB. Epi is a very polar molecule and therefore not a powerful CNS stimulant.

Question 9

(T/F?) Not all Sympathomimetics show the “classic” pharmacological effects to the same degree?

Answer 9

True - The effects depends on their mechanism of action at the adrenergic receptors.

Question 10

Which factor is most important in determining the response of any cell or organ/tissue to sympathomimetic agents?

Answer 10

The density and proportion of alpha and beta adrenergic receptors in various tissues.

Question 11

When sympathomimetic agents increase or raise bp, how does the body compensate for this when it needs to?

Answer 11

Compensatory reflexes are mediated by the carotid-aortic baroreceptor system, which can diminish sympathetic tone and enhance vagal tone (and vice versa) when needed.

Question 12

Describe the chemical and structural make-up of Sympathomimetic Amines?

Answer 12

Sympathomimetic amines are derived from beta-phenylethaylamine , which consists of a benzene ring and ethyl amine side chain.

Question 13

Why can’t Catecholamines be administered PO?

Answer 13

1) Their polar hydroxyl group makes them non-lipid soluble
2) They would be rapidly inactivated by intestinal mucosa and in the liver by both MAO and COMT before reaching systemic circulation.

Question 14

All Adrenergic receptors are G-protein regulated, which usually activates a 2nd messenger inside the cell? What is the result of this activation?

Answer 14

Usually the 2nd messenger of a G-protein is the cAMP which alters the concentration of calcium inside the cell.

Question 15

(T/F?) Adrenergic receptors can be found in BOTH the CNS and THE PNS?

Answer 15

True

Question 16

Which receptors do the following sympathomimetics bind to:

1) NE
2) EPI
3) Dopamine
4) Isoproterenol
5) Phenylephrine
6) Dobutamine

Answer 16

1) NE - A1, A2, B1
2) EPI - A1, A2, B1, B2
3) Dopamine - A1, A2, B1
4) Isoproterenol - B1, B2
5) Phenylephrine - A1
6) Dobutamine - A1, A2, B1

Question 17

Characteristics of Synthetic Non-Catecholamines?

Answer 17

1) Generally don’t have hydroxyl group on benzene ring (phenylephrine is an exception)
2) CNS stimulation is prominent because they are able to penetrate the BBB.
3) Loss of hydroxyl group also results in a loss of direct sympathomimetic activity

Question 18

Describe how the potency or affinity of agents to the adrenergic receptors varies between Isoproterenol, Epi, and NE at the A1, B1, and B2 receptor sites?

Answer 18

1) A1 - Epi > NE&raquo_space;»»> ISO
2) B1 - ISO > EPI > NE
3) B2 - ISO > EPI&raquo_space;»NE

Question 19

What are some the clinical uses of Sympathomimetics?

Answer 19

1) Shock - increases BP, HR, FOC and SVR
2) Positive inotrope - increases CO
3) Tx of bronchospasm in PTs with asthma or COPD
4) In addition to local anesthetics to decrease systemic absorption, which increases duration on action of local anesthetics
5) Mgmt of allergic rxns
6) Topical nasal decongestants
7) Opthalmolgy - A1 agonist, so dilation of pupil and increase ocular pressure
8) Narcolepsy
9) ADHD

Question 20

What are the 3 classifications of sympathomimetic drugs?

Answer 20

1) Endogenous Catecholamines - EPI, NE, and Dopamine
2) Synthetic Catecholamines - Isoproterenol and Dobutamine
3) Synthetic non-catecholamines - Direct acting (phenylephrine) and non direct acting (amphetamines and ephedrine.

Question 21

What are the 3 classification of Synthetic Non-catecholamines based on how they activate adrenergic receptors?

Answer 21

1) Direct-Acting
2) Indirect-Acting
3) Mixed-Acting

Question 22

Pharmacological characteristics of Direct Acting Sympathomimetics?

Answer 22

1) Their actions are independent of endogenous stores of NE
2) Denervation or depletion of neurotransmitters DOES NOT alter activity of these drugs.
3) Potency/Affinity depends on structure binding
4) Receptor numbers can alter response
5) Selective agents bind primarily to adrenergic receptors
6) Non-selective agents bind to more than 1 adrenergic receptors

Question 23

Why is it that NE can never decrease BP?

Answer 23

Because it only binds A1, A2, and B1 receptors and not B2 receptors. There are special types of B2 receptors on blood vessels that act to trigger baroreceptor which signals the heart to slow down, via the vagal parasympathetic pathway.

Question 24

What are Indirect Acting Sympathomimetic Agents? What are the 3 different types?

Answer 24

Agents that increase the release of endogenous NE to stimulate adrenergic receptors via 3 different mechanisms:

1) Releasing NE
2) Inhibiting re-uptake of NE (cocaine and TCAs)
3) Enzyme Inhibitors

Question 25

The actions of indirect acting sympathomimetics are subject to Tachyphylaxis. What is tachyphylaxis?

Answer 25

Rapidly diminishing response to successive doses of a drug, rendering it less effective. This happens due to the stimulation of the drug to the release NE, which eventually depletes its supplies.

Question 26

What are mixed acting sympathomimetics?

Answer 26

Agents that both indirectly release NE AND also directly bind to and activate adrenergic receptors. (Their effects can be unpredictable).

Question 27

Two examples of mixed acting sympathomimetics?

Answer 27

1) Ephedrine

2) Dopamine

Question 28

Two enzymes responsible for inactivating catecholamines?`

Answer 28

1) MAO (2 types - MAO-A and MAO-B) - present in the liver, kidneys, GI, and CNS
2) COMT - primarily metabolizes the circulating catecholamines like ephedrine, NE, dobutamine, and isoproterenol.

Question 29

How are Synthetic non-catecholamines metabolized?

Answer 29

1) Synthetic non-catecholamines that lack a 3-hydroxyl group are primarily metabolized by MAO.

Question 30

Why can Synthetic Non-catecholamines be administered PO and catecholamines cannot?

Answer 30

The absence of the 3 and 4 hydroxyl groups, or the presence of an alpha methyl group increases oral absorption.

Question 31

Why don’t you see CNS effects after giving epinephrine?

Answer 31

Because EPI is poorly lipid soluble and does not cross the BBB.

Question 32

(T/F?) The cardiovascular effects of epinephrine are dose-dependent?

Answer 32

True - the higher you go on the dose, the more alpha responses predominate and too high dose can cause severe metabolic acidosis.

Question 33

Explain the mechanism of the rise in BP, mainly systolic, due to epinephrine?

Answer 33

1) Positive inotrope
2) Positive chronotrope
3) Vasoconstriction

Question 34

Effects of epinephrine at a low dose (.01 to .03 mcg/kg/min)?

Answer 34

1) Beta effects predominate
2) B2 stimulation results in vasodilation, which decreases DBP (so be careful in Its with Aortic Stenosis)
3) B1 stimulation increases HR and contractility, which causes SBP to increase.
4) The net effect = Increased CO and PP, and decreased SVR and BP, MAP usually stays the same.

Question 35

Effects of epinephrine at a intermediate dose (.03 to .15 mcg/kg/min)?

Answer 35

1) Mixed Alpha and Beta effects, depending on how high the dose is.
2) B1 stimulation becomes more pronounced
3) A1 stimulation (arteries and veins) increases, which also contributes to increasing SVR and increased BP
4) The net effect = modest increase in PP and MAP. SBP increases more than DBP.

Question 36

Effects of epinephrine at a high dose (> .15 mcg/kg/min)?

Answer 36

1) Stimulation of A1, B1, B2 still occurs but A1 predominates causing increased vasoconstriction and after load which triggers the bars-recepter reflex.
2) Venoconstriction enhances venous return
3) BP is further increased bco increase in CI and SVR
4) SVT is common

Question 37

Describe the cardiovascular effects of Epinephrine and why it may cause dysrhythmias?

Answer 37

Epinephrine increases HR by accelerating the rate of spontaneous phase 4 depolarization of nodal tissue, which also increases the risk of dysrhythmias.

Question 38

How does Epinephrine affect Renal blood flow?

Answer 38

1) Renal blood flow is decreased by Epi because it is 2 to 10x more potent than NE as a renal vasoconstrictor.
2) The secretion of renin is increased due to Epi-induced stimulation of Beta 1 receptors in the kidneys.

Question 39

Effects of a 2-8mcg IV Epinephrine Bolus?

Answer 39

Produces transient cardiac stimulation that lasts about 5 mins without an overshoot of systemic BP and HR.
During a continuous infusion of Epi, administration of a vasodilator can offset vasoconstriction, especially in splanchnic and renal circulations.

Question 40

Effect of B2 and B3 receptors by Epinephrine?

Answer 40

1) Liver glycogenolysis/gluconeogenesis (B2)

2) Adipose tissue lipolysis (B2 and B3)

Question 41

Overall metabolic effects of infusions of epinephrine?

Answer 41

Increased plasma concentrations of glucose, lactate, free fatty acids, cholesterol, phospholipids, and low density lipoproteins.

Question 42

How is Epinephrine Extravasation treated?

Answer 42

Regitine (Phentolamine mesylate) 5-10mg diluted to local tissue area.
Mix 5-10mg with 10ml Nacl and inject a small amount SQ at site of extravasation.
Phentolamine is a competitive, non-selective, A1 and A2 antagonist.