Adrenergic Pharm I

Front 1

adrenal medulla releases

Back 1

NE and EPI

Front 2

sympathetic post ganglion releases

Back 2

NE

Front 3

sympathetic post ganglion releases what to sweat glands

Back 3

ACh

Front 4

what is the biosynthetic pathway of adrenergic

Back 4

L-tyrosine
-Tyrosine hydroxylase
L-DOPA
-DOPA decarboxylase
Dopamine
-Dopamine B-hydroxylase
Norepinephrine
-Phenylephrine
Epinephrine

Front 5

Metabolic transformation of NE

What are the two primary degradative enzymes for NE?

Back 5

MAO: neuronal monoamine oxidase

COMT: non-neuronal catechol-O-methyl tranferase

Front 6

MAO

Back 6

-Monamine oxidase
-mitochondrial enzyme, outer membrane
-metabolizes NE and Dopamine that is free in the cytoplasm of the nerve terminal

Front 7

COMT

Back 7

-catechol-o-methyl transferase
-cytoplasmic enzyme
-metabolizes NE, EPI and dopamine that enters cytoplasm of mainly non-neuronal surrounding tissues

Front 8

Transport into Vesicles and Vesicular Storage of NE (vesicular uptake)

Back 8

-

Front 9

After its synthesis, Dopamine is transported into vesicles on a vesicular membrane transporter...

Back 9

-this transporter also transports NE into vesicles from the cytoplasm
-inside these vesicles Dopamine and NE are NOT subject to deamination

Front 10

Neuronal degradative enzymes

Back 10

-MAO
--NE
--DA

Front 11

non-neuronal degradative enzymes

Back 11

-COMT
--NE
--EPI
--DA

Front 12

Receptor interactions of released NE

Back 12

-

Front 13

Following its release from adrenergic nerve endings, NE interacts with receptors found... postsynaptically...

Back 13

-alpha 1
-alpha 2
-beta 1

Front 14

Following its release from adrenergic nerve endings, NE interacts with receptors found... presynpatically...

Back 14

-alpha 2

Front 15

termination of effect of released NE aka uptake

Back 15

-following NE release from adrenergic nerve endings, termination of effect is mainly by reuptake into presynaptic terminals

Front 16

NE reuptake involves two systems...

Back 16

-first, a transport system that translocates NE from the synaptic cleft into cytoplasm of adrenergic neurons = NEURONAL UPTAKE
-second, a subsequent transport system that translocates NE from the neuronal cytoplasm into vesicles = VESICULAR UPTAKE

Front 17

RESORPINE

Back 17

-blocks DA/NE into vesicles within presynaptic cell

Front 18

COCAINE

Back 18

-blocks reuptake of NE into presynaptic cell

Front 19

parasympathetic outflow

Back 19

-preganglionic neuron releases ACh onto nictotinic cholinergic R of postganglionic neuron
-postganglionic neuron releases ACh onto muscarinic cholinergic receptor of organ
-AChE breaks down ACh

Front 20

sympathetic outflow

Back 20

-sympathetic preganglionic neuron releases ACh onto nictonic receptor of symp postganglionic neuron
-symp postganglionic neuron releases NE onto adrenergic receptor of effector organ
-reuptake via MAO or COMT

Front 21

Classification of Adrenergic Agonists

Back 21

-direct acting
--alpha agonists: nonselective, alpha 1 sel, alpha 2 sel
--beta agonists: nonsel, beta 1 sel, beta 2 sel

-indirect acting
--releasers
--reuptake inhibitors

Front 22

Rank order of potencies of agonists

Back 22

-at alpha Rs: Epi> NE> ISO

-at beta Rs: ISO> EPI> NE

Front 23

Rank order of potencies of antagonists

Back 23

-at alpha Rs: phentolamine>>> propanolol

-at beta Rs: propanolol>>> phentolamine

Front 24

Effects of the sympathetic nervous system

Back 24

-

Front 25

SNS at eye

Back 25

-pupil: mydriasis @ alpha 1 R

-accomodation: NOT ALTERED

-intraocular fluid: increased formation at beta1 and beta1

Front 26

SNS at sweat glands

Back 26

-stimulated at M3

Front 27

SNS at salivary glands

Back 27

-NOT ALTERED

Front 28

SNS at Heart

Back 28

-rate: increased at beta1

-force: increased at beta1

Front 29

SNS at blood vessels

Back 29

-contracted at slpha1 and alpha2

-dilated at beta2

Front 30

SNS at transmitter release

Back 30

-reduced at alpha2

Front 31

SNS at juxtaglomerular

Back 31

-renin release at beta1

Front 32

SNS at liver

Back 32

-gluconeogenesis at beta2

-glycogenolysis at beta2

Front 33

SNS at smooth muscle

Back 33

-bronchodilation at beta2

-vasodilation at beta2

-uterine relaxation at beta2

-GI relaxation at beta2

Front 34

SNS at skeletal muscles

Back 34

-tremor at beta2

Front 35

SNS effects with beta2

Back 35

-beta2 effects mainily thru circulating EPI (from adrenal medulla)
-e.g. blood vessels dilated, inc intaocular fluid in eye, liver, smooth muscle (bronchodilation, vasodilation, uterine relaxation, GI relaxation), and tremor in skeletal muscle

Front 36

Sympathomimetics

Back 36

-B-phenethylamine
-amphetamine
-NE
-ISO

Front 37

B-phenethylamine

Back 37

1. are derived from beta-phenethylamine
2. is deaminated by MAO
3. NOT O-methylated
4. NOT direct acting at receptors
5. will enter CNS (cuz not polar)

Front 38

Amphetamine

Back 38

1.* NOT deaminated by MAO (has a-methyl)
2. NOT O-methylated
3. NOT direct acting at receptors
4. will enter CNS

Front 39

NE

Back 39

1. is deaminated by MAO
2.* is O-methylated and direct acting (has 3- and 4- hydroxyl groups)
3.* will NOT enter CNS (too polar)
4.* substrate for neuronal uptake

Front 40

ISOPROTERENOL

Back 40

1.*NOT deaminated by MAO (similar to amphetamine)
2.*is O-methylated and direct acting (has 3 & 4 hydroxyl groups)
3.* will NOT enter CNS (too polar) - (similar to NE)
4.** NOT substate for neuronal uptake BUT good beta agonist (large N substitution)

Front 41

Systemic Effects of NE and Sympathomimetics
-agonists produce their pharmacological effects by...

Back 41

1. acting directly on alpha and/or beta Rs

2. by acting indirectly thru causing NE release

3. by acting indirectly thru causing reflex effects they cause

Front 42

Cardiovascular Effects of Selected Sympathomimetics

Back 42

-

Front 43

Cardiovascular Effects of Selected Sympathomimetics

-activates alpha1 Rs...

Back 43

-vasoconstriction

Front 44

Cardiovascular Effects of Selected Sympathomimetics

-activates beta1 Rs...

Back 44

-inc HR & inc contractility...inc CO

Front 45

Cardiovascular Effects of Selected Sympathomimetics

-activates beta1 Rs...

Back 45

-inc HR and inc contractility... inc CO

Front 46

Cardiovascular Effects of Selected Sympathomimetics

-activates beta2 Rs...

Back 46

-vasodilation... dec PR

-mainly EPI
-vs alpha1 Rs
-reflex tachycardia

Front 47

Cardiovascular Effects of Selected Sympathomimetics

Back 47

-causes inc or dec in BP

Front 48

CVS Effects of Selected Adrenergic Agonists

What are their INDIRECT ACTIONS?

Back 48

-

Front 49

Drugs increasing PR and BP, cause reflex bradycardia...this occurs with...

Back 49

-alpha1 agonists

Front 50

Drugs reducing PR and BP cause reflex tachycardia...this occurs with...

Back 50

-beta2 agonists

Front 51

Cardiovascular Effects of NE and Sympathomimetics

REMEMBER: An increase in BP activates carotid/aortic baroreceptors and intitiates a compensatory reflex leading to:

Back 51

1. Reduction in Sympathetic tone (decreases HR and PR)
2. Increase in Parasympathetic tone (decreases HR)
...thus BP tends to return to lower levels

Front 52

Cardiovascular Effects of NE and Sympathomimetics

REMEMBER: A decrease in BP activates carotid/aortic baroreceptors and initiates a compensatory reflex leading to:

Back 52

1. Increase in sympathetic tone (inc HR and PR)
2. Decrease in parasympathetic tone (inc HR)
...thus BP tends to return to higher levels

Front 53

Vascular Effects of NE and EPI

-Vasoconstrictor effects dec blood flow through skin and kidney

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-substantially inc renal vascular resistance and reduces renal blood flow (40%)

-Renin release increases due to effect mediated by Beta1 Rs associated with juxtaglomerular cells

Front 54

Vascular Effects of NE and EPI

-Acting through beta2 Rs, epinephrine causes significant vasodilation which increases blood flow through skeletal muscle and splanchic vascular beds

Back 54

-Beta2 R activation mediates relaxation of bronchiolar and vascular smooth muscle and of GI smooth muscle (thru inc cAMP)

Front 55

Adrenergic Alpha R

Back 55

-potency: EPI> NE> ISO
-multiple alpha R subtypes have been identified

-alpha1 R are mainly postsynaptic
-alpha2 R are mainly presynaptic

-some drugs may be alpha1 or alpha2 selective

Front 56

Effects of activation of alpha1 Rs

-@vascular smooth muscle

Back 56

-contraction

Front 57

Effects of activation of alpha1 Rs

-@ dilator muscle of the pupil

Back 57

-mydriasis

Front 58

Effects of activation of alpha2 Rs

-@adrenergic and cholinergic nerve terminals

Back 58

-inhibits release of NE and ACh

Front 59

Effects of activation of alpha2 Rs

-@ some vascular smooth muscle

Back 59

-contraction

Front 60

What are some clinical uses of alpha1 sympathomimetics?

Back 60

1. to reduce regional blood flow
2. as nasal decongestants
3. to dilate the pupil

Front 61

What are some clinical uses of alpha1 sympathomimetics?

1. to reduce regional blood flow

Back 61

-with local anasthetics (LA):
--to retard absorption
--to prolong action of LA
--to reduce systemic toxicity of LA

Front 62

What are some clinical uses of alpha1 sympathomimetics?

2. as nasal decongestants

Back 62

-PHENYLEPHRINE
-OXYMETAZOLINE

-avoid excessive use to avoid rebound congestion
-not use more than 5 days cuz nose used to blood vessels constricted

Front 63

What are some clinical uses of alpha1 sympathomimetics?

3. to dilate the pupil

Back 63

-sensitive to light photophbia

Front 64

Example of an alpha1 sympathomimetic

Back 64

PHENYLEPHRINE

Front 65

PHENYLEPHRINE

Back 65

-specific alpha1 R agonist

-increase PR
-causes an inc in BP
-reflex bradycardia; blocked by ATROPINE (a muscarinic antagonist)

Front 66

PHENYLEPHRINE

clinical uses

Back 66

1. hypotensive states
2. mydriatic (topical)
3. nasal decongestant (topical)

Front 67

Example of an alpha2 sympathomimetic

CLONIDINE

Back 67

-alpha2 agonists
--stimulation of alpha2 Rs dec sympathetic outflow and inc vagal outflow
--stimulation of alpha2 Rs on NE terminals dec NE release

CLONIDINE
=2nd or 3rd line drug in hypertension

Front 68

Other clinical uses of alpha2 sympathomimetics

Back 68

CNS uses
-appetite suppression (not FDA approved)

Front 69

alpha 2 sympathomimetics

Back 69

-CLONIDINE
-BRIMONIDINE

Front 70

CLONIDINE

Back 70

-cental alpha2 agonist
--opiod withdrawl (dec sympathetic outflow and inc vagal outflow)
--hypertension (2nd or 3rd line)

Front 71

BRIMONIDINE

Back 71

-peripheral alpha2 agonist
--glaucoma (reduces intraocular pressure)

Front 72

alpha 2 agonist

Back 72

-note end in -ONIDINE

Front 73

Beta Adrenergic Rs

Back 73

-potency: ISO> EPI> NE

-beta Rs are divided into two major categories:
--beta1: the myocardium
--beta2: smooth muscle (bronchi; vessels in muscle; uterine etc)

Front 74

What are the effects of activation of beta Rs?

Effects of beta1 Rs

Back 74

-@heart: inc rate and force

-@juxtaglomerular cells: stimulates renin release

Front 75

What are the effects of activation of beta Rs?

Effects of beta2 Rs

Back 75

-@smooth muscle (bronchial, vascular, uterine) - relaxation

-@somatic motor nerve terminals: causes tremor

-@liver: stimulates glycogenolysis

Front 76

Direct Cardiac Effects of Beta Rs

@SA node

Back 76

-inc rate (+ve chronotropism)

Front 77

Direct Cardiac Effects of Beta Rs

@atrial muscle

Back 77

-inc contractility (+ve chronotropism)
-inc conduction velocity

Front 78

Direct Cardiac Effects of Beta Rs

@AV node, His-Purkinje system, ventricles

Back 78

-inc automaticity
-inc conduction velocity

Front 79

DIrect cardiac effects of Beta Rs

Back 79

-thus increases heart rate and cardiac output
-Beta1 R activation inc cAMP
-inc risk of arrythmias

Front 80

Please note p19

Comparative CVS effects of NE, EPI, ISO

Back 80

-NE @ alpha1 and beta1
--reflex bradycardia

-EPI @ alpha1, beta1, and beta2
-- inc HR via beta1

-ISO @ beta1 and beta2
--beta1 and reflex tachycardia

Front 81

Please note p19

How an alpha blocker reverses effects of EPI

Back 81

*

Front 82

EPINEPHRINE (EPI)

Back 82

-nonselective agonist class
--alpha1, alpha2, beta1, beta2

-uses:
1. local (with LAs)
2. general (Anaphylaxis)

Front 83

NOREPINEPHRINE (NE)

Back 83

--nonselective agonist class
--alpha1, alpha2, beta1

-uses:
1. shock

Front 84

PHENYLEPHRINE (PE)

Back 84

-selective agonist
--alpha1> alpha2

-uses:
1. local (nasal decongestant)

Front 85

CLONIDINE
BROMONIDINE

Back 85

-selective agonist
--alpha2> alpha1

-uses:
1. HTN
2. Gluacoma

Front 86

ISOPROTERENOL

Back 86

-selective agonist class
--beta1 = beta2

Front 87

DOBUTAMINE

Back 87

-selective agonist class
--beta1> beta1

-uses:
1. cardiogenic shock

Front 88

ALBUTEROL
SALMETEROL
FORMETEROL

Back 88

-selective agonist
--beta2 >beta1

-uses:
1. asthma (acute Rx)
2. asthma (chronic Rx)

Front 89

EPHEDRINE
AMPHETAMINE
METHYLPHENIDATE

Back 89

-selective agonist
--indirect acting

-uses:
1. local (nasal decongestant)
2. ADHD
3. ADHD

Front 90

Please note p20

Comparative effects of selected sympathomimetics

Back 90

*

Front 91

alpha 1 R

Back 91

-effector tissues, smooth muscles and glands
-Gq
-inc IP3 and DAG
-inc Ca2+, causes contraction, secretion

Front 92

alpha2 R

Back 92

-nerve endings, some smooth muscles
-Gi
-dec cAMP
-dec transmitter release, causes contraction

Front 93

beta1 R

Back 93

-cardiac muscle, juxtaglomerular apparatus
-Gs
-inc cAMP
-inc HR, inc F, inc renin release

Front 94

beta2 R

Back 94

-smooth muscle, cardiac muscle
-Gs
-inc cAMP
-relax smooth muscle; inc glycogenolysis, inc HR, inc F

Front 95

beta3 R

Back 95

-adipose cells
-Gs
-inc cAMP
-inc lipolysis

Front 96

delta1 R

Back 96

-smooth muscles
-Gs
-inc cAMP
-relax renal vascular smooth muscle

Front 97

Pulmonary smooth muscle effects

Back 97

-EPINEPHRINE is a significant respiratory tract bronchodilator
--caused by a beta2 R activation mediated smooth muscle relaxation

-beta2 R activation also dec mast cell release

Front 98

clinical uses of beta1 sympathomimetics

DOBUTAMINE

Back 98

- DOBUTAMINE used in short term managment of pump failure following surgery, during acute CHF, or post myocardial infarction

Front 99

clinical uses of beta1 sympathomimetics

DOBUTAMINE
DOPAMINE

Back 99

-uncertain long term effficacy
--by enhancing renal perfusion despite low cardiac output
--oliguria may be an indication of inadequate renal perfusion
-in postop cardiopulomnary bypass patients who exhibit...?

Front 100

Clinical uses of Beta2 Adrenergic Agonists used in Asthma

ALBUTEROL
TERBUTALINE (shorter acting)
SALMETEROL (longer acting)

Back 100

-at low concentrations, beta2 sel AR agonists have relatively minor beta1 cardiac receptor-mediated effects
-effective in managing asthma... beta2 sel AR agonist may be orally active
-metabolized more slowly compared to standard catecholamines
--cuz not substrate for MOA and cannot enter nerves
-beta2 sel AR agonist include ALBUTEROL, TERBUTALINE, SALMETEROL

Front 101

Pulmonary Beta2 Rs are targeted by inhalation. This route of administration results in low systemic drug concentration, thus reducing liklihood of cardio-acceleration (beta1) or skeletal muscle tremor (beta2)

Back 101

-activation of pulmonary beta2 AR result in smooth muscle relaxation and bronchodilation
-AR agonists also dec histamine and leukotriene release from lung mast cells
-Beta AR agonists enhance mucociliary activity and diminish microvascular permeability
-BUT DO NOT AFFECT UNDERLYING INFLAMMATORY CHANGES

Front 102

Adverse effects of beta sympathomimetics

due to beta2 R activation

Back 102

-skeletal muscle tremor

Front 103

Adverse effects of beta sympathomimetics

due to beta1 R activation

Back 103

-excessive cardiovascular stimulation
-sinus tachycardia
-may result in ventricular arrythmias
-and myocardial necrosis
-OVERUSAGE MAY BE A FACTOR IN MORBIDITY AND MORTALITY IN ASTHMATICS

Front 104

clinical uses of beta-sympathomimetics to delay labor

RITRODINE

Back 104

-RITRODINE (beta2 AR selective) developed as a uterine relaxant
-maybe admin IV in certain patients to arrest premature labor; if successful, oral therapy may be started
-beta2 AR sel agonists may not improve perinatal mortality and may inc maternal morbidity
-in women treated for premature labor, RITRODINE or TERBUTALINE may cause pulmonary edema