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Lecture 40 Flashcards

Sympathomimetics

1
Q

Sympathetic NS

A
  • Fight or flight

- Catecholamine receptors (NE, Epi, DA)

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2
Q

Monoamines

A
  • Catecholamines

- Serotonin (indoleamine)

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3
Q

Serotonin

A
  1. Neurotransmitter in CNS
  2. Regulator of smooth muscle function in CV and GI
  3. Regulates platelet function
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4
Q

Catecholamines

A
  • Endogenous neurotransmitters
  • DA, NE, Epi, precursor: DOPA
  • Isoproterenol - synthetic catecholamine
  • Phenylethylamine - basic structure of catecholamines
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5
Q

Catecholamine Processes

A
  1. Synthesis
  2. Storage
  3. Release
  4. Uptake
  5. Metabolism
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6
Q

Catecholamine Synthesis

A
  • Phenylalanine and Tyrosine = amino acid substrates for catecholamine synthesis
  • Phenylalanine - essential AA, hydrolyzed by phenyl. hydroxylase to tyrosine
  • Tyrosine - taken into neurons/adrenal cells and hydrolyzed at three positions by tyrosine hydroxylase into L-DOPA
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7
Q

L-DOPA - Synthesis

A
  • Forms GABA, histamine, and serotonin

- Decarboxylated by aromatic L-AA decarboxylate to dopamine

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8
Q

Dopamine - Synthesis

A
  • Stored in vesicles

- Converted into NE by dopamine B-hydroxylase

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9
Q

NE - Synthesis

A

Present in most postganglionic sympathetic NS

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10
Q

Chromaffin Cells -Synthesis

A
  • Converts NE ==> Epi in adrenal gland
  • Done by PNMT, induced by corticosteroids
  • Stored in these cells’ granules for release
  • Cofactor: S-Adenosylmethionine
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11
Q

Synthesis Regulation

A

-Tyrosine Hydroxylase is the rate limiting step

Regulated by:

  1. Acute, short term activation
  2. Chronic, long term activation
  3. End product feedback inhibition
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12
Q

Acute Activation

A
  • Phosphorylation of tyr. hyd. be protein kinases
  • Decreases the km of the enzyme for cofactor (tetrahydrobiopterin) more active
  • Increases the synthesis of catecholamines
  • Occurs in seconds/minutes and lasts minutes to hours
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13
Q

Chronic Activation

A
  • Chronic stress can induce tyr. hyd.
  • Initiation: increases in cAMP ==> Activates protein kinase A ==> Phosphorylates and activates CREB ==> enters nucleus/binds to DNA ==> increases expression of tyr. hyd.
  • Prolonged, chronic stress causes this
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14
Q

End Product Inhibition

A
  • All catecholamines inhibit tyr. hyd. activity

- Direct competition of catecholamines with cofactor tetrahydrobiopterin

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15
Q

Storage

A
  • NE, DA, Epi ==> vesicles to nerves and adrenal (NE/Epi)
  • Allows for immediate, controlled release
  • Protect catecholamines from metabolism
  • Vesicular uptake: ATP-dependent protein translocase, needs ATP to store
  • Reserpine - inhibits VMAT transport which depletes catecholamines (irreversible)
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16
Q

Release

A
  • Calcium dependent stress
  • Calcium uptake cause vesicular attachment/release
  • Increased activity of SNS increases the concentrations of NE, Epi, ATP, DBH, and chromogranins in circulation
  • Two chromaffin granules: NE (20%) and Epi (80%)
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17
Q

Catecholamine Reuptake Categories

A
  1. Neuronal (Uptake 1)

2. Extraneuronal (Uptake 2)

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18
Q

Neuronal (Uptake 1)

A
  • Primary terminator of catecholamine activity
  • Sodium dependent, high affinity, isoproterenol = exception
  • High affinity receptors for DA, 5-HT, and NE
  • Monoamine transporters - 12 transmembrane domains
  • Drug target: Fluoxetine (SSRIs), Desperimine (NE), Cocaine (DA, NE, 5-HT
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19
Q

Extraneuronal (Uptake 2)

A
  • Low affinity for NE/Epi, high affinity for isoproterenol
  • Present in glial, hepatic, myocardial, and other cells
  • Removes CIRCULATING catecholamines
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20
Q

Indirect Acting Sympathomimetics

A
  • Work via uptake pumps
  • Tyramine and Ephendrine (also act on B2 receptors)
  • Taken up by transporters and indirectly release NE
  • Compete for transporter space to enter vesicle and facilitate exchange diffusion by making carrier available
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21
Q

Nonvesicular Release

A

Calcium not needed, no ATP/DBH released

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22
Q

Tachyphylaxis

A

-Repeated tyramine administration, decreases postsynaptic response

Due to:

  1. Depleting vesicular NE
  2. Replacing NE with octopamine (false neurotransmitter)
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23
Q

Metabolism - Enzyme Types

A
  1. MAO

2. COMT

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24
Q

MAO

A
  • Removes N from monoamines
  • High concentrations in liver, kidneys, and MA neurons
  • On mitochondria surface in nerve terminal
  • Isoforms: MAO-A and MAO-B
  • Metabolizes catecholamines released intraneurally and ones taken back into the neuron
  • Inhibitors play a role to potentiate catecholamine effect
  • Parkinsons: MAO/COMT inhibition increases dopamine/L-DOPA activity
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25
Q

MAO-A

A
  • Prefers 5-HT and NE

- Inhibited by Tranylcyromine (Parnate) - used for depression, inhibits A & B, irreversible

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26
Q

MAO-B

A
  • Prefers dopamine

- Selegiline inhibits it - used for Parkinson’s, irreversible

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27
Q

COMT

A
  • Methylates catecholamines at 3 ring positions
  • Located in liver, kidney, and BBB
  • Catecholamines that enter endo/exogenously are first metabolized by this
  • Inhibitor: Tolcaponel (Tasmar) and Entacapone - adjunct therapies for Parkinson’s (inhibits DOPA metabolism)
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28
Q

Beta 1

A
  • Near regions of nerve terminals
  • Increases HR and contraction
  • Increases renin release by kidney
  • Increases lipolysis
  • Dobutamine - agonist
  • Metoprolol - antagonist
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29
Q

Beta 2

A
  • Smooth muscle relaxation (lungs, blood vessels, uterus)
  • Gluconeogenesis/glycogenolysis
  • Away form nerve terminals, adrenal Epi release via blood
  • Terbutaline - agonist
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30
Q

Beta 3

A

-Lipolysis

31
Q

Alpha 1

A
  • Vascular smooth muscle contraction
  • GU smooth muscle contraction
  • Intestinal smooth muscle relaxation
  • Mydriasis
  • Phenylephrine - agonist
  • Prazosin - antagonist
32
Q

Alpha 2

A
  • Nerve terminals, inhibition to decrease NE release
  • Decrease insulin release from B-cells
  • Clonidine - agonist
  • Yohimbine - antagonist
33
Q

Isoproterenol - Receptors

A
  • Activates B1 and B2
  • Activates B2 the most
  • Dose related activation
34
Q

Epinephrine - Receptors

A
  • Activates B1 and 2, and Alpha 1 and 2
  • Activates alpha 1 the most
  • Dose related activation
35
Q

NE - Receptors

A
  • Activates B1 and Alpha 1/2

- Dose related activation

36
Q

Adrenergic Receptors

A
  • 7-transmembrane domains

- Activate G-protein second messenger systems

37
Q

Refactoriness to Catecholamines

A
  • Repeated catecholamine agonist exposure decreases the capacity to elicit a response (desensitization/down regulation) in B-receptors
    1. Homologous desensitization - how catecholamines affect cell response to itself
    2. Heterologous desensitization - how cell responds to other neurotransmitters/hormones
38
Q

Homologous Desensitization

A
  • Phosphorylation of B-receptor by BARK, only when occupied by agonist
  • Phosphorylation of B-receptor by protein kinase A
  • Both phosphorylations decrease B-binding to Gs protein
39
Q

Heterologous Desensitization

A
  • Phosphoylation by other paths, second messenger systems
  • Receptor does not need to be activated when this occurs
  • Still decreases binding to Gs protein
  • Phosphorylation by BARK, protein kinase C, cAMP-dependent protein kinases
40
Q

Manipuation of Synthesis

A
  1. Alpha-methyltyrosine - false substrate inhibition of tyr. hyd.
  2. Alpha-methyldopa - hydroxylated the methylNE, acts as a false transmitter that displaces NE in vesicles
    * *Released from neurons and have an antihypertensive affect by activating alpha-2 receptors in CNS
41
Q

Carbidopa

A
  • Derivation of methyldopa
  • Inhibits aromatic AA-decarboxylase
  • Doesn’t cross BBB
  • No major effect on endogenous catecholamine synthesis
  • Inhibits conversion of exogenous L-DOPA to dopamine outside of brain, usually occurs in liver
  • Use with L-DOPA to treat Parkinson’s
42
Q

Manipulation of Release

A
  1. Guanethidine

2. Bretlium

43
Q

Guanethidine

A
  • Ismellin
  • Doesn’t enter CNS
  • Taken up by NE neurons and depletes stores
  • Prevents NE release in response to action
  • Generally decreases symp. tone and used to treat moderate to severe hypertension
44
Q

Bretylium

A
  • Acts the guanethidine

- IV for emergency treatment of ventricular arrhythmias

45
Q

Increases in Release

A
  • Tyramine, Ephedrine (direct B2 agonist), Amphetamine
  • Rapid release to produce sympathomimetic effect
  • Ephedrine/Amphetamine - No -OH on ring, non-cate., can cross BBB
  • Taken up by cate. pumps in exchange for cytoplasmic cate., displaces endogenous cate. from storage
  • Indirect, need cate. present for effect
  • Increased effect by MAOIs
46
Q

Amantadine

A
  • Antiviral, promotes dopamine release in brain

- Parkinson’s treatment

47
Q

Manipulation of Uptake

A
  1. Reserpine
  2. Cocaine
  3. TCA
48
Q

Reserpine

A
  • Blocks vesicular uptake of biogenic amines, depletes vesicular stores
  • Binds with VMAT, irreversible, needs new vesicle synthesis to overcome effect, takes days to recover
  • Newly synthesized cate. are broken down since they aren’t stored/protected by MAO
  • Depletes NE, DA, and 5-HT
49
Q

Cocaine and TCA

A
  • Prevent catecholamine reuptake, inhibitor of Uptake 1
  • Cocaine = drug of abuse, high affinity for dopamine uptake pump
  • TCA act on NE pump more than 5-HT and DA
  • No abuse potential, 2-3 weeks before seeing effects
50
Q

Metabolism Manipulation

A
  1. COMT Inhibition

2. MAO Inhibition

51
Q

COMT Inhibition

A
  • Talcapon (Tasmar) and Entacapine (Comton)
  • Acts in liver, kidney, and BBB
  • Use in Parkinson’s so you can use lower doses of L-DOPA
52
Q

MAOIs

A
  • Tranylcypromine (Parnate), acts on A & B, Selegline (Edepray), acts on B only
  • Used in hypertension, Parkinson’s, and depression (third and fourth choice)
  • Wine/cheese effect - hypertensive crisis due to tyramine’s release of NE (metabolism from diet usually)
  • Selegline - patch, decreased side effects, bypasses liver
53
Q

Alpha 2 Receptors Agonist

A
  • Clonidine

- Used for hypertension and glucose responses

54
Q

Alpha 2 Receptor Antagonist

A
  • Yohimbine
  • Antagonist
  • Effective for erectile dysfunction in those with variant gene: ADRA2A
  • ~40% of people with type II diabetes have that gene
  • Makes insulin-releasing cells more sensitive to inhibition effects on insulin release by stress adrenaline
  • New treatment option
55
Q

Heart - Adrenergic Stimulation

A
  • Alpha 1, Beta 1, and Beta 2 receptors
  • Beta 1 - most abundant and most important for mediating cardiac response
  • Stimulation: positive domotropic, chronotropic, and inotropic
56
Q

Positive Domotropic in Heart

A

Shortening of refractory period of AV nodal cells, increased dunction rate of AV node

57
Q

Positive Chronotropic in Heart

A

Tachycardia resulting from increasing the rate of discharge of pacemaker cells in SA node. Brings cells to firing potential quicker

58
Q

Positive Inotropic in Heart

A
  • Receptor mediated increase in contraction force leading to increased intrinsic contractility and rate of relaxation
  • Increases CO (HR * BV)
59
Q

Muscle Process

A
  1. Calcium binds to troponin molecule on actin filament (contraction)
  2. Calcium enter via voltage gated L-type calcium channels
  3. Calcium insufficient for contraction
  4. Calcium triggers release of additional calcium from SR by activating Ryanodine receptors (Calcium channels) on SR membrane
  5. Contraction is terminated when calcium is reduced from 10 uM (contraction) to 0.1 uM (resting) by pumping calcium to stores and exchanging it with sodium out of the cell
  6. Sodium does NOT build up in cell due to Na+/K+-ATPase (pumps sodium out)
60
Q

Blood Vessels - Adrenergic Stimulation

A
  • Alpha 1 receptors - constrict resistant vessels in skin, kidney, and mesentery and constricts capacitance (veins) ==> predominates arteries and veins to increase total peripheral resistance
  • Beta receptors - relaxation of vascular, smooth muscle in coronary arteries (Beta1) and in skeletal muscle (Beta2)
  • D1 (dopamine) receptors vasodilate cerebral, splanchnic, coronary, and cerebral arteries
61
Q

Respiratory - Adrenergic Stimulation

A
  1. Bronchial smooth muscle - Beta 2 relax and decrease airway resistance - works best when muscle is contracted by a disease like asthma, banned by Olympic committee unless already asthamtic
  2. Upper respiratory mucosa - Alpha 1 decrease secretions and vasoconstriction, useful as a decongestant
62
Q

GI - Adrenergic Stimulation

A
  1. Stimulation of both alpha and beta receptors relax GI smooth muscle
  2. Stimulation of Alpha2 receptors on presynaptic cholinergic nerve fibers inhibit release of ACh (contractor)
  3. Stimulation of D2 receptors on presynaptic cholinergic nerve fibers ALSO inhibit ACh release
63
Q

Metoclopromide

A
  • Reglan
  • D2 antagonist
  • Mechanism: blocks dopamine inhibition of cholinergic activity
  • Increases tone of lower, esophageal sphincter, increases force of contraction, increases gastric emptying
  • *Effective antiemetic ==> CTZ is site of action**
64
Q

GU - Adrenergic Stimulation

A
  1. Bladder
  2. Uterus
  3. Ejaculation
65
Q

Bladder - Adrenergic Stimulation

A
  • Urinary incontinence is promoted by symp. stimulation
  • Beta 2/3 relaxation (Myrbetriq) of detrusor muscle
  • Alpha 1 contraction of trigone and uretal sphincters
66
Q

Uterus - Adrenergic Stimulation

A
  • Uterine tone/contraction during last month/birth is inhibited by beta2 receptors
  • Beta 2 agonst - off label use is to delay premature labor (terbutaline)
  • Prostaglandins and oxytocin induce labor
  • Prostaglandins and progesterone antagonists induce abortions
67
Q

Ejacution - Adrenergic Stimualtion

A
  • Alpha 1 stimulation
  • Contracts smookth muscle of vas deferens, seminal vesicle, and prostate
  • Suppression of ejaculation by alpha blockers or any drug suppressing the sympathetic NS
68
Q

Ocular - Adrenergic Stimulation

A
  • Iris - contraction of radial muscle by Alpha 1 receptors leads to mydriasis (dilation)
  • Causes glassy eye appearance in coke users
  • Ciliary muscle - Beta 2 stimulation causes it to relax, increasing the tension in lens ligaments and flattening the lens and focusing on distant vision
69
Q

Alpha 2 Agonists

A
  • Decreases aqueous secretions in eye
  • EX: Apraclonidine (Iopidine)
  • Topical, post-laser topical only
70
Q

Humor Production - Adrenergic Stimulation

A
  • Beta antagonists - decrease in aq. humor production
  • Betaxolol (Betoptic S) - selective for Beta 1, antagonists, minimal heart and lung side effects
  • Timolol (Betimol) - non selective Beta antagonist, caution in those with heart and lung problems
  • *Specifically stops secretions from ciliary epithelium**
  • Topical drops
71
Q

Metabolism - Adrenergic Stimulation

A
  • Increased glucose and FFA
  • Gluconeogenesis - B2 receptor
  • Glycogenolysis - B2 activates hepatic phosphorylase A which breaks down glycogen to glucose
  • Lipolysis - stimulated by B1/3 receptors, B3 more so than B1
72
Q

B3 + Lipolysis

A
  • B3 cloned in 1989 (50% like B1)
  • Strong effects on lipolysis
  • Potential anti-obesity drug that doesn’t act on CNS
  • Clinical trials - tachycardia is a possible SE
73
Q

Endocrine - Adrenergic Stimulation

A
  • Insulin - released from B-cells in pancreas, alpha 2 inhibits its release
  • Glucagon - released by alpha-cells in pancrease, B receptors increase glucagon release (increases glucose levels)
  • Renin - release from juxtaglomerular cells in kidney, increases angiotensin II release and vasoconstricts. Beta 1 increases renin secretions

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