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Flashcards in Adrenergic Agonists Deck (171):
1

What are catecholamines?

general term for neurotransmitters/hormones of the sympathetic nervous system

2

How are catecholamines named?

named for their structure

contain an amine side chain -NH2

3

What are the 3 major catecholamines?

Dopamine

Norepinephrine

Epinephrine

4

What are the 4 basic categories of adrenergic receptors?

Alpha1 type (a1A, a1B, a1C)

Alpha2 type (a2A, a2B, a2C)

Beta type (B1, B2, B3)

Dopamine type (D1, D2, D3, D4)

5

What type of receptor are adrenergic receptors?

All = G-protein coupled cell membrane bound receptors

6

What increases the complexity of the nervous system signaling?

the various subtypes of receptors

will differ by potency and type of response

7

Which G protein are alpha1 receptors coupled with? And what is the G protein coupled to?

Alpha1 = coupled to Gq proteins

Gq proteins = coupled to phospholipase C

8

When alpha1 receptors are activated what happens?

results in activation of protein kinases --> activate other enzymes --> physiologic actions

9

Which G protein are alpha2 receptors coupled with? And what is the G protein coupled to?

Alpha2 = coupled to G1 proteins

G1 proteins = coupled to adenylyl cyclase

10

When alpha2 receptors are activated what happens?

results in inhibitory activity --> lowers cAMP

lowered cAMP reduces transduction of activating types of enzymatic messages

**no message is still a message (negative message)

11

Which G protein are beta receptors coupled with? And what is the G protein coupled to?

Beta = coupled to Gs proteins

Gs proteins = coupled to adenylyl cylase (some can be coupled to Gq proteins)

12

When beta receptors are activated what happens?

activation of beta receptors increases conversion of ATP --> cAMP

will activate multiple kinases --> activate additional enzymes --> physiologic action

13

What does activation of Dopamine D1 receptors do?

stimulate adenylyl cyclase --> increase cAMP

14

What does activation of Dopamine D2 receptors do?

inhibit adenylyl cylase (decrease cAMP)

15

What are the 4 main factors that can alter the degree to which an adrenergic receptors respond to a stimulus?

Selectivity

Regulation

Polymorphisms (genetic alterations)

Catecholamine metabolism

16

What does receptor selectivity allow for?

sympathomimetic drugs to bind to one subgroup of receptors w/o binding to others

** Drug X binds to alpha1 but not alpha2 or beta receptors

17

What is the result of selective binding?

selective actions

18

What is the degree of selective binding dependent on?

Concentration

Low concentrations = selective binding

High concentrations --> nonselective binding; so much of it around it'll just start binding to everything

19

How does the body regulate receptors?

it'll increase or decrease receptor response over time

Up regulation

Down regulation

20

What is the effect of receptor regulation?

you will see a change in receptor response to sympathomimetic drugs

21

What is an example of receptor regulation?

desensitization

22

Name 3 synonyms for desensitization

Tolerance

Refractoriness

Tachyphylaxis

23

When does desensitization occur?

after long term exposure to catecholamines or drugs

24

What is the result of desensitization?

decrease responsiveness of that cell/tissue to additional stimulation

25

What are the 4 mechanisms of desensitization?

altered transcription/translation of receptor DNA and/or RNA

modification of receptors --> interactions w/ enzymes or other proteins

Long term exposure to an agonist --> the mechanism of action of several drugs

Interactions or messages from other receptors

26

Is desensitization used for therapeutic benefit or is it purely an unintended consequence?

Can be used for therapeutic benefit

have an initial increase in response followed by desired decrease physiologic reaction

27

What is the mechanism of using desensitization of therapeutic benefit?

Drug X binds to alpha1 receptor --> exaggeration of expected physiologic response

body doesn't like exaggerated response and will decrease production of alpha1 receptor to try to maintain homeostasis

ultimately means less neurotransmitter will be able to bind to those alpha1 receptors --> desired therapeutic effect

28

What is receptor polymorphism?

changes in amino acid sequence of receptors

normal genetic variation between people

29

What can be the result of receptor polymorphism?

can alter receptor response:

+/- risk to develop some diseases (i.e. HTN)

alter degree of susceptibility to desensitization

alter degree or responsiveness to drugs

30

What are some therapeutic consequences of receptor polymorphisms?

Some drugs may work in some patients but not others

31

What are the 4 ways adernergic neurotransmitter actions are terminated?

Norepinephrine transporter (NET) --> binds norepinephrine and brings back to axon terminal

Movement of NE out of synaptic cleft into blood stream

Metabolism by catecholamine-o-methyltransferase (COMT)

Metabolims by monoamine oxidase (MAO)

32

What is the SITE of action of NET (norepinephrine transporter)?

synaptic cleft

33

What is the MAJOR method of norepinephrine clean-up?

NET (norepinephrine transporter)

removes 90% of released NE

34

What is the mechanism of NET action?

acts as pre-synaptic pump to remove NE from synapse and back into axon terminal in neuron

allows NE to be recycled

35

Can NET be used as a therapeutic target?

Yes

36

What is the point of binding to NET?

inhibit its action --> prolong presence of NE in synaptic cleft --> increased stimulation of adrenergic receptors

37

Name the 2 drugs that bind NET

Atomoxetine (ADHD)

Cocaine

38

Besides direct inhibition what is another mechanism to reverse NET action?

increase the release of NE that has been taken up

39

What does COMT (catechol-o-methyl transferase) do?

metabolizes ALL catecholamines

assist in terminating actions of norepinephrine, epinephrine and dopime

40

What is the effect of inhibiting COMT?

prolong the effects of catecholamines

41

What is an example of a drug that inhibits COMT and what is it used in?

Entacapone --> adjunct for Parkinson's

42

What is the mechanism of action of Entacapone?

inhibits metabolism of levodopa (precursor of dopamine)

43

What does MAO (monoamine oxidase) do?

metabolizes endogenous monoamines:

Norepinephrine

Epinephrine

Seratonin

Dopamine

44

How many MAO forms are there?

2: A and B

45

What does inhibition of MAO result in?

increase in NE, epinephrine, seratonin, dopamine levels

46

What types of problems could you have with MAOIs (MAO inhibitors)?

increase in neurotransmitter levels can be dangers

need proper dosing and need to avoid drug interactions

47

What are sympathomimetics?

drugs that mimic actions of norepinephrine, epinephrine, and dopamine

48

What are direct sympathomimetic agonists?

Drugs w/ a structure that allows for binding of adrenergic receptors --> activation

49

What are indirect sympathomimetic agonists?

Can't directly bind to adrenergic receptors but will still have same result of sympathomimetic agonists

50

What are the mechanisms of indirect sympathomimetic agonists?

Multiple mechanisms:

can cause release of stored catecholamines

can inhibit reuptake of catecholamines that have already been released

51

What have medicinal chemists been able to do with direct sympathomimetics over the years?

Been able to create drugs w/ similar structures to natural catecholamines --> able to bind to adrenergic receptors

52

What is an example of a direct sympathomimetic of norepinephrine?

phenylephrine

53

What will modifications of sympathomimetics do?

alter the affinity for alpha or beta receptors --> compounds w/ varying levels of agonist/antagonist activity

54

what will happen if you add a hydroxyl group (-OH) to C3 AND C4 (opposite to alkyl (carbon side chain)) of a benzene ring?

maximize alpha and beta activity

creates catecholamine compounds --> susceptible to COMT breakdown

55

What will happen if you add hydroxyl (-OH) group to C3 OR C4 of a benzene ring?

reduce adrenergic potency

increase drug duration of action --> resistance to COMT

56

What happens if there are no -OH groups on benzene ring?

drug = lipophilic --> enter CNS

57

What happens when you increase the size of alkyl substitutions on the amino group of the benzene ring?

increase beta activity

lower alpha activity

58

What happens if you add an isopropyl group to the amino nitrogen (it'll be the @ the end of the molecule)?

Will further increase beta activity

59

What will substitutions of the alpha carbon (carbon right next to terminal NH2) do?

block oxidation by MAO --> prolonged duration of action

60

What happens if you add a methyl group to the alpha carbon (carbon right next to terminal NH2)?

increase ability to act as indirect sympathomimetics --> release stored NE/direct agonists

61

What happens with a beta carbon substitution (side group added to 2 carbon away from terminal NH2)?

Less significant impact on activity

62

What happens if you add a hydroxyl (-OH) to beta carbon (carbon 2 away from terminal NH2)?

compound is able to act as direct agonist; but don't not necessary to have

63

What is the main pharmacologic target of sympathomimetics?

Cardiovascular System

64

List the other systems that are effected by sympathomimetics (8)

Pulmonary

Ocular

Genitourinary (GU)

Salivary glands

Apocrine Sweat Glands

Metabolism

Hormone Release

CNS

65

In the cardiovascular system where are Alpha and Beta receptors found?

Heart

Blood Vessels

Other systems that regulate BP

66

What is the outcome of sympathomimetics on the cardiovascular system dependent on?

Selectivity --> alpha1/2 or beta1/2

Action @ receptor --> agonist/antagonist

Action of body's compensatory mechanisms to maintain homeostasis --> desensitization

67

What are the 4 key sympathomimetic effects in the cardiovascular system?

Changes in:

Heart Rate (HR)

Cardiac output (CO)

Peripheral vascular resistance (BP)

Venous Return

68

Where do you find alpha1 receptors in the cardiovascular system?

vascular beds

69

What happens when sympathomimetics activate alpha1 receptors?

Arterial/venous vasoconstriction

70

After alpha agonist binding causes vasoconstriction, what else happens?

increase in BP (increase in peripheral vascular resistance) --> reflux slowing of HR (then decrease cardiac output) BUT venous return increases --> stroke volume and maintains cardiac output

CO = HR x SV

71

What drug is a alpha1 cardiovascular sympathomimetic, and what would you use it for?

phenylephrine

maintain BP in pt w/ poor organ perfusion --> vascular shock

treat stuffy nose --> constrict vessels in nasal passage ways

72

Where would you find alpha2 receptors in the cardiovascular system?

vascular beds

CNS

73

What does activation of peripheral alpha2 receptors by a sympathomimetic do?

causes vasoconstriction BUT only when given locally, as IV push, or in very high oral doses

74

What would systemic administration of an alpha2 sympathomimetic result in?

activate CENTRAL alpha2 --> inhibit sympathetic vascular tone

decrease sympathetic activity

decrease BP

75

What can a central alpha2 sympathomimetic be used to treat, what is the name of the drug?

treat hypertension

clonidine

76

What are the cardiovascular effects of a beta agonist?

vary depending on which beta receptors are activated

drugs vary in beta selectivity --> different observed responses

77

Where are beta1 receptors found in the cardiovascular system, and what do they do?

in the heart

increase contractility and increase HR --> increase cardiac output

78

Where are beta2 receptors found in the cardiovascular system, and what do they do?

in the vasculature

decrease peripheral resistance (vasodilation) --> decrease BP

79

Which dopamine receptors would you find in the cardiovascular system, and where would you find them?

D1 receptors

Renal

Splanchnic (small intestine)

Coronary

Cerebral

80

What is the effect of the stimulation of D1 receptors in the cardiovascular system?

vasodilation in some areas

Renal

Splanchnic (small intestine)

Coronary

Cerebral

81

What other receptors can dopamine bind to, and what is the response dependent on?

Bind to alpha and beta receptors

response = dose-dependent

82

Which receptors (besides D1) will low dose of dopamine bind to, what effect would you see?

acitvate beta2 receptors --> vasodilation --> lower BP

83

Which receptors (besides D1) will medium dose dopamine bind to, what effect will you see?

activate beta2 receptors --> stimulate heart

84

Which receptors (besides D1) will high dose dopamine bind to, what effect will you see?

activate alpha1 receptors --> vasoconstriction --> increase BP

85

Which receptors do sympathomimetics bind to in the lungs, and what is the effect?

beta 2 ONLY

bronchodilation

86

Which receptors do sympathomimetics bind to in the eye, what are the effects?

alpha receptors in radial muscles

mydriasis (widening of pupil)

increase outflow aqueous humor and reduce IOP in glaucoma

87

Which receptors do sympathomimetics bind to in the genitourinary (GU), what are the effects?

alpha receptors in bladder, urethral sphincter, prostate, others

promote urinary retention

mediate ejaculation

88

Which receptors do sympathomimetics bind to in the salivary glands, what are the effects?

beta receptors

increase salivation

89

Which sweat glands are affected by sympathomimetics and what are the effects?

apocrine sweat glands (palms of hands)

increase sweat production in response to STRESS

90

Which receptors do sympathomimetics bind to that are involved in metabolism, what are the effects?

Beta receptors in the liver: increase glycogenolysis --> increase serum glucose

Beta receptors increase lipolysis; alpha2 decrease lipolysis

beta2 receptors promote K+ uptake into cells --> hypokalemia

beta2 receptors also increase insulin release from islet cells

91

What is the sympathomimetic effect on Renin?

increased release by beta1

decreased release by alpha2

92

Besides insulin and renin, which other hormones are mediated by adrenergic receptors?

Parathyroid hormone

Calcitonin

Thyroxine

Gastrin

93

What are the effects of sympathomimetics on the CNS dependent on?

ability of the drug to cross the blood brain barrier (BBB)

94

If a drug is able to cross the BBB what receptors are involved?

complex reactions involving alpha, beta, and dopamine receptors

95

What are the effects of sympathomimetics that are able to cross the BBB?

Nervousness

Adrenaline rush

Feelings of impending disaster

Altertness/improved attention

Elevation of mood

Euphoria

Anorexia

Psychosis

96

Name the endogenous catecholamines

Epinephrine

Norepinephrine

Dopamine

97

What are the classes of direct sympathomimetic agonists?

alpha1 agonist

alpha2 agonist

beta1 agonist

beta2 agonist

98

What is a synonym for epinephrine?

adrenaline

99

Which receptors do epinephrine bind to?

agonist to alpha1 and beta1 receptors in the heart

100

What is the physiologic response to epinephrine?

potent vasoconstrictor and cardiac stimulant

alpha1 = increase systolic BP

beta1 = increase HR and cardiac output

101

Besides alpha1 and beta1 receptors, which receptors does epinephrine bind to?

Beta2 receptors in some blood vessels --> esp.. in skeletal muscle

causes drop in diastolic BP during exercise

102

What is a synonym for norepinephrine?

noradrenaline

103

Which receptors bind to norepinephrine?

agonist of alpha1, alpha2, beta1 (minimal beta2)

104

What is the physiologic response to norepinephrine?

potent vasoconstrictor and cardiac stimulant

alpha1 receptors = increase systolic/diastolic BP

beta1 receptors = incrase HR and cardiac output

105

What is the effect of dopamine dependent on?

dose-dependent

106

What are the effects of dopamine in CNS?

addiction --> reward stimuli (cocaine/crack addiction)

dopamine receptors = targets for antipsychotics

107

What can a deficiency of dopamine lead to?

Parkinson's

108

Name 2 direct alpha1 agonists

Phenylephrine

Midodrine

109

How does phenylephrine work and what is it used for?

not inactivated by COMT --> prolongs duration of action

used as decongestant and to raise BP

110

What is midodrine used for?

increase BP

treat orthostatic hypotension

111

Name some alpha2 agonists, what are they all used for?

Clonidine

Methyldopa

Guanfacine

Guanabenze

act in CNS

reduce BP/ treat HTN

112

What is dexmedetomidine, and what is it used for?

direct alpha2 agonist

acts in CNS

used for sedation of patients in ICU

113

Name a drug that is a direct alpha1 AND alpha2 agonist and it's action for each receptor

Oxymetazoline (afrin)

alpha1 = vasocontriction --> decongestant

alpha2 = similar action to clonidine (decrease BP)

114

Name a nonselective Beta (beta1 and beta2) agonist and its action for each receptor

Isoproterenol

beta1 = heart --> positive chronotropic/inotropic effects --> increase HR and cardiac output

beta2 = vasculature --> vasodilation --> decrease diastolic BP and mean arterial pressure

115

Name a beta1 selective agonist

Dobutamine

116

What is dobutamine used for?

increase cardiac output w/o a reflux increase in HR

117

What is unique about dobutamine?

racemic mixture of 2 isomers w/ different activity

118

Name the receptor each isomer of dobutamine binds to and its effect on the receptor it binds to

(+) isomer = beta1 agonist and alpha1 antagonist --> increase cardiac output w/o increase BP

(-) isomer = alpha1 agoinst --> increase BP

119

What is the effect of the racemic mixture of dobutamine?

positive inotropic action w/ little change in BP

120

What are the beta2 selective agonist that cause bronchodilation and are used to treat asthma and COPD?

Albuterol

Terbutaline

Metaproterenol

Pirbuterol

Salmeterol

Formoterol

121

What is the beta2 selective agonist that relaxes uterine smooth muscle during labor?

Ritodrine

122

What do mixed-acting sympathomimetics do?

provides both alpha and beta effects, potency of action varies from drug to drug:

vasoconstriction

decongestion

bronchodilation

CNS effects --> appetite suppression, stimulation, etc

123

What are 2 examples of a mixed-acting sympathomimetic?

Ephedrine

Pseudoephedrine

124

What are the 2 mechanisms of indirect-acting sympathomimetics?

displace stored catecholamines

inhibit reuptake of released neurotransmitters by interfering w/ NET

125

What are some examples of indirect-acting sympathomimetics?

Amphetamines

Tyramine containing compounds (aged meats, cheeses, fish, others)

Catecholamine reuptake inhibitors (doluxetine)

126

What does amphetamine do?

causes release of stored norepinephrine and dopamine

CNS stimulant: increase mood/alertness, decrease appetite

127

How would you make methamphetamine and what is its effect?

made from pseudo ephedrine

similar action to amphetamine

potent CNS actions

128

What kind of actions does phenmetrazine have?

similar actions to amphetamine

129

What is methylphenidate (Ritalin), what is its action, and what is it used to treat?

amphetamine derivative

treat ADHD

reduces reuptake of norepinephrine and improves brain function

130

What does modafinil do and what is it used for?

inhibits norepinephrine and dopamine transporters in the CNS (exact mechanism is poorly understood)

used to increase wakefulness in pts w/ narcolepsy, obstructive sleep apnea, and shift work disorder

131

What is Armodafinil and what is its action and uses?

R-enantiomer of modafinil

has similar action/uses as modafinil --> inhibits norepinephrine/dopamine transporters; used to increase wakefulness in pts w/ narcolepsey, obstructive sleep apnea, and shift work disorder

132

What is tyramine a product of and where would you find it naturally?

tyrosine metabolism

found in high concentrations of fermented foods (aged cheeses, meats, wine)

133

What do tyramines do?

causes release of stored catecholamines

similar actions to norepinephrine (alpha1, alpha2, beta1)

134

How are tyramines metabolized?

metabolized by MAO

135

Why would a pt taking an MAOI want to avoid tyramine and tyramine containing foods?

they can have side effects --> intensified sympathomimetic actions b/c tyramine isn't being broken-down --> increase in release of catecholamines

POTENTIALLY DANGEROUS HYPERTENSION

136

Catecholamine Reuptake Inhibitors - what do they do and what receptors can they work on?

vary in selectivity of reuptake activity --> imbalance between norepinephrine and dopamine --> different actions

act on other receptors --> serotonin receptors

137

What are 3 examples of catecholamine reuptake inhibitors?

Atomoxetine

Subutramine

Doluxetine

138

What is Atomoxetine and what is it used to treat?

selective inhibitor of norepinephrine reuptake

mostly CNS effects (can increase BP)

treats ADHD

139

What is Subtramine and what is it used for?

Serotonin and norepinephrine reuptake inhibitor

approved as appetite suppressant

140

What is doluxetine do, and what is it used for?

serotonin and norepinephrine reuptake inhibitor

used as antidepressant

141

What is an illegal drug that is a catecholamine reuptake inhibitor?

Cocaine

142

What does cocaine do?

inhibits peripheral reuptake of Norepinephrine by NET

Enters CNS produces INTENSE amphetamine-like actions --> inhibits dopamine reuptake in pleasure centers of brain --> addictive

143

What systems are sympathomimetics used for therapeutically?

Cardiovascular

Pulmonary

Anaphylaxis

Ophthalmic

Genitourinary

CNS

Sedation

144

What is the goal of sympathomimetics when being used to treat Hypotension?

increase BP and cardiac output

low BP due to severe blood loss, hypovolemia, arrhythmias, antihypertensive overdose, shock

need to maintain BP (ensure proper perfusion to major organs)

145

Which type of sympathomimetics would you use to treat hypotension?

alpha1 agonists --> increase vasoconstriction (BP)

norepinephrine/phenylephrine

146

Which type of sympathomimetics would you use to treat shock syndromes?

inotropic agents --> increase cardiac output

dopamine/dobutamine

147

What is the goal of sympathomimetics when being used to treat hypertension?

decrease BP

148

Which type of sympathomimetics would you use to treat hypertension?

central acting alpha2 agonists --> bind to central CNS to decrease BP

clonidine (oral tablets or topical patch)

149

What is the goal of sympthomimetics when being used to treat orthostatic hypotension?

increase BP

orthostatic hypotension is a drop in BP as pt moves from sitting/lying down to standing --> loss of consciousness and trauma due to fall

150

Which type of sympathomimetics would you use to treat orthostatic hypotension?

alpha1 agonist

midodrine

151

What is the goal of sympathomimetics when being used to treat emergency cardiac episodes?

Cardiac resuscitation --> complete heart block or cardiac arrest

152

Which sympathomimetic would you use in an emergency cardiac situation and why?

Epinephrine

alpha1 and beta1 actions redistributes blood flow from periphery --> brain and heart

used in combo w/ other agents

153

What are the 2 goals of sympathomimetic uses during surgery?

reduce blood loss @ surgical site

slow diffusion of anesthetics away from site of administration

154

Which sympathomimetics are used to reduce blood loss @ surgical site?

Epinephrine

Cocaine

155

Which sympathomimetics are used to slow diffusion of anesthetics?

Epinephrine

Norepinephrine

Phenylephrine

156

What is the goal of sympathomimetics when being used to treat sinus congestion?

decrease nasal stuffiness associated w/ hay fever or sinus colds

157

Which sympathomimetics are used to treat hay fever or sinus colds?

alpha1 agonist in nasaal spray form --> vasoconstriction

Phenylephrine

Oxymetazoline

BUT limited to no more than 3 day usage --> repeated use leads to ischemic changes followed by hyperemia with discontinuation (when you stop using you'll get massive vasodilation --> stuffy nose)

158

What is the goal of sympathomimetics when being used to treat pulmonary issues?

improve pulmonary air flow --> bronchodilation

159

Which pulmonary diseases would you use sympathomimetics to treat?

Asthma

COPD

**both cause bronchoconstriction

160

Which sympathomimetics would you use to treat either Asthma or COPD?

Beta2 selective agents in inhaler or nebulizer form

Albuterol

Metaproterenol

Pirbuterol

Salmeterol

Formoterol

161

What is the goal of sympathomimetics when being used to treat anaphylaxis?

reverse vascular complications of immune hypersensitivity

allergen --> bronchospasm, mucous membrane congestion, angioedema, severe hypotension

162

Which type of sympathomimetic would you want to use to treat anaphylaxis?

Epinephrine --> activate alpha1, beta1, beta2 receptors to reverse ALL symptoms

often used in combo w/ steroid or antihistamine

163

What are the goals of sympathomimetics when used to treat opthalmic disorders?

Mydriasis --> eye exams (alpha1 agonist)

Decongestion to r educe eye redness --> allergies (alpha1 agonist = visine)

Reduce intraocular pressure of glaucoma w/ agonists

164

Which sympathomimetics are used to treat glaucoma?

Apraclonidine

Brimonidine

165

What is the goal of sympathomimetics when being used to for a pregnant lady?

delay delivery

166

Which type of sympathomimetics are used to delay delivery of baby?

beta2 selective agents --> relax uterus during premature labor

Ritodrine

Terbutaline

167

What are some of the CNS applications of sympathomimetics?

Treat narcolepsy to increase alertness and defer sleep

Appetite suppression

Manage ADHD

168

Which sympathomimetics are used to treat narcolepsy?

amphetamine

modafinil

169

Which sympathomimetics are used to treat ADHD?

methylphenidate

Dextroamphetamine/amphetamine

Lisdexamfetamine

170

Why would sympathomimetics be used in the ICU?

improve patient comfort

pts under severe physiologic stress (mechanical ventilation, post-op) need to be sedated

171

Which type of sympathomimetics are used in the ICU?

alpha2 agonist in combo w/ opiods, benzodiazepines, propofol

dexmedetomidine