Chapter 10 Flashcards
1
Q
What are the major endogenous neurotransmitters of the adrenergic system?
A
Catecholamines: dopamine, epinepherine and norepinepherine
2
Q
What vital functions do catecholamines modulate?
A
- rate and force of cardiac contraction
- peripheral resistance
- release of insuline
- breakdown of fat
3
Q
Why are drugs that target catecholamines clincally relevant?
A
Drugs that target the sythesis, storage, release, and reuptake of catecholamies and their receptors are frequent therapies for treatment of:
-hypertension, shock, depression, asthma, angina
4
Q
What molecule is the base of catecholamines?
A
Tyrosine
5
Q
Where is epinepherine primarily synthesized?
A
- The adrenal medulla
6
Q
Where is norepinepherine typically found?
A
In the sympathetic neurons. It is used as their typical neurotransmiter.
7
Q
In the first step of catecholamine synthesis, tyrosine is converted to what compound? What enzyme mediates this transformation?
A
Tyrosine—-> dihydroxyphenylalanine (DOPA)
Tyrosine hydroxylase
8
Q
What enzyme constitutes the rate limiting step in catecholamie synthesis?
A
Tyrosine hydroylase
9
Q
In the third step of catecholamine synthesis, after DOPA is converted to dopamine, dopamine-beta-hydroxylase converts dopamine to what product?
A
Norepinepherine
10
Q
How is norepinepherine converted to epinepherine?
A
It is methylated by phenylethanolamine N-methyltransferase. (PMNT)
11
Q
How is dopamine transported into the synaptic vessicles to be converted?
A
By Vsicular monoamine transporter (VMAT)
12
Q
Where o the signals that activate the sympathetic nervous system orriginate?
A
In the CNS, Specifically the limbic system.
13
Q
What transmitter do preganglionic neurons use to actvate nAChRs?
A
ACh
14
Q
What trigger vessicle release from the neurons?
A
Ca2+
15
Q
What are the three (3) ways that catecholamie responses are terminated?
A
- reuptake of catechoamine into the presynaptic neuron
- metabolism of catecholamine
- diffusion of the catcholamine out of the synaptic cleft
16
Q
What transporter mediates reuptake of catecholamines?
A
**Norepinepherine transporter (NET) **
~90% recycled
17
Q
What are the two souces of catecholamine for release?
A
- Synthesized de novo
- recycled molecules
18
Q
What 2 enzymes are involved in catecholamine metabolism?
A
- MAO
- Catechol-O-Methyltransferase (COMT)
19
Q
MAO-A preferentially degrades ____(3)___, while MAO-B degrades ________ more rapidly than other catecholamines.
A
- serotonin, norepinepherine, dopamine
- dopamine
20
Q
In which organ is COMT primarily expressed?
A
The liver
21
Q
Monoamine oxygenases (MAOs) have efficacy in the treatment of what disorder?
A
Depression
22
Q
What is the name of the receptor that is selective for norepinepherine and epinepherine?
A
Adrenoceptors (adrogenic receptors)
23
Q
What is the location of Alpha1 recetors and what do they cause there?
A
- Vascular smooth muscle (contraction)
- genitourinary smooth muscle (contraction)
- intestinal smooth muscle (relaxation)
- heart (increase in excitability)
- liver (Glycogenolysis and gluconeogenisis)
24
Q
Alpha1 receptors involve Gq mediated pathways that cause increases in what?
A
IP3/DAG and intracellular Ca2+
25
When alpha2 receptors are activated, what G protein is activated? What is the result?
Inhibitory Gi protein is activated which causes a decrease in cAMP levels.
-inhibition of neuronal Ca2+ channels
26
Where are alpha2 receptors principally expressed and what does action here cause?
Pancreatic B-cells (Decrease insuline release)
Platelets (aggregation)
Nerves (Decrease in norepinepherine release)
Vasuclar smooth muscle (contraction)
27
What is the priciple treatment target of alpha2-antagonist at the CNS?
Hypertension
28
What are the primary locations and actions of the beta1 receptors?
Heart (increase in inotropy and conduction velocity)
Kidney (renin release)
29
What G protein is activated by all beta adrenoceptors?
Stimulatory Gs
30
What are the sites of the Beta2 adrenoceptor?
- smooth muscle
- liver
- skeletal muscle
31
What is the action of the Beta2 adrenoceptor at the smooth muscle, liver and skeletal muscle?
- SM--\>relaxation
- Liver--\> glycogenolysis and gluconeogenisis
- Skeletal Muscle--\> Glycogenolysis and K+ uptake
32
What is the location of Beta3 adrenoceptors?
Adipocytes
33
What is the action of activation of Beta3 adrenoceptors and what is the significance of this?
- Stimulation leads to an increase in lipolysis
- may be used to treat obesity, non-insuline dependant diabetes mellitus
34
How do G protein receptor kinases reguate adrenoceptor responses?
-phosphorylates the G protein which can then bind inhibitory proteins
35
What is the action of B-arrestin?
-binds to the phosphorylated G-protein and deactivates it through steric hinderance
36
What is the process of **down regulation**?
-receptor-b arrestin complexes are endocytosed in a clathrin-dependant manner
37
What receptors does epinepherine primarily act at in low concentrations?
Beta1 and Beta2 adrenoceptors
38
What are the physiologic effects of epinepherine acting at Beta1 adrenoceptors?
- increases in cardiac contractility and O2 consumption
- increase in systolic BP
39
What are the physiologic effect of epinepherine acting at Beta2 adrenoceptors?
- Relaxes bronchial smooth muscle
- decreases diastolic BP
- Vasodilitation
- release of glucose and fatty acids
40
What is the drug of choice for the treatment of anaphylaxis?
Epinepherine
41
Why is norepinepherine the drug of choice for treatment of hypotension and shock?
Because NE acts at alpha1 and beta1 adrenoceptors but not at Beta2.
-This means that it increase systolic and diastolic BP and increases TPR
42
At which receptors does dopamine act when in low concentrations? What is the result?
Acts at D1 Receptors in renal, mesenteric and coronary vascular beds--\> Increases cAMP
-vasodilitation
43
Where does dopamine act at an intermediate does?
Beta1 adrenoceptors
44
What is the action of dopamine at doses higher than 10micrograms/kg?
Acts at alpha1 adrenoceptors where it causes vasoconstriction.
45
What drug is an example of a catecholamine synthesis inhibitor?
-alpha-methyltyrosine
46
What is the MOA of alpha-methyltyrosine and why is it not widely used?
- Inhibits tyrosine hydroxylase
- causes severe orthostatic hypotension and sedation
- inhibits all catecholamine sythesis
47
What are examples of inhibitors of catecholamine storage?
- Reserpine
- Tyramine
- Guanethidine
- Amphetamine
- Ephedrine/Pseudoephedrine
- Methylphenidate
- Methamphetamine
48
What is the MOA of Reserpine?
- Reserpine binds to and **inhibits VMAT**.
- at high concentrations it causes neurotransmitter leakage into the synapse and a **trasient Sympathomimetic effect.**
- recovery takes days to weeks--\>depression
49
What foods contain lots of Tyramine?
-Wine and aged cheese
50
How is Tyramine able to cause acute hypertensive crisis?
- In pateints taking MAOIs, Tyramine builds up in synaptic vesicles, replacing norepinepherine.
- NE spills over into the cleft causing hypertension
51
What is the long term effect of Tyramine exposure in the presence of an MAOI?
- Replacement of noepinepherine with octopamine
- Postural hypotension
52
What is the mechaism of Guanethidine?
- Same as tyramine
- Into vesicles via NET and reduces amount of norepinepherin available
- postural hypotension and decreased cardiac preload
53
What are the three ways by which amphetamine affects the storage of catecholamines?
1. displaces endogenous catecholamine
2. inhibits MAO
3. blocks catecholamine reuptake by NET
54
What is amphetamine used to treat?
depression
55
What are the medical uses of ephedrine and pseudoephedrine?
- Ephedrine: persistant hypotension
- Pseudoephedrine: over the counter decongestant
56
What is the major use of methylphenidate?
-treatment of ADHD
57
What is the major use of Methamphetamine?
-Drug of abuse
58
What is the major mechanism of action of inhibitors of catecholamine reuptake?
-Exert powerful sympathomimetic effects by prolonging the time a neurotransmitter remains in the synaptic cleft.
59
What enzyme does cocain inhibit?
NET
60
What is the action of Tricyclic antidepressants (TCAs)?
-inhibit NET mediated reuptake of norepinepherine
61
What is the acion of an MAOI and what are they used to treat?
- Inhibits the metabolism of catecholamines in the synaptic cleft
- elogates their action
- treats depression
62
What is an example of a selective and non-selective MAOI?
- Phenelzine (non-slelective)
- Selegiline (selective for MAO-B)
63
What is the primary action of alpha1 agonists?
-Maintain or elevate blood pressure
64
What is the clinical use of methoxamine?
- alpha1 agonist
- treatment of shock
65
What are the uses of phenylepherine and oxymetazoline?
-topical use for nasal congestion
66
What receptor does Clonidine act at? What is it's use?
- Alpha2 receptors
- used to treat withdrawl from ethanol and opioid drugs
67
What are the clinical effects of guanficine?
-Similar to clonidine
68
What is important clinical effect of the alpha2 agonist dexmedetomidine?
- sedates surgical patients while stabilizing their BP
- does not depress breathing
69
What is the MOA of alpha-methyldopa? What is a noteworthy use?
- alpha2 agonist--\> lowers BP
- Treats hypertension in pregnant women
70
What are the uses of Beta (B1 and B2) receptor agonists?
B1- causes increase in heart rate and force of contraction leadin to increased cardiac output
B2- causes relaxtion of vascular, bronchial, and GI smooth muscle
71
How does isoproterenol affect beta1 and beta2 actions?
- Lowers TPR and diastolic BP (beta1)
- Systolic BP remains unchanged (beta2)
72
What is a use of isoproterenol?
-emergency situations to treat prfound bradycardia
73
What is the receptor and action of dobutamine?
- Beta1 agonist
- increases cardiac contractility and output (treats severe heart failure)
74
What two drugs are beta2 agonists that are used to treat asthma?
-Terbutaline and albuterol
75
What is an example of a long acting Beta2 agonist?
-Salmeterol
76
What is the result of the use of an Alpha-adrenergic antagonist?
- vasodilitation, decreased blood pressure, decreased periferal resistance.
- leads in increase in cadiac output reflex
77
What is the significance of phenoxybenzamine?
-alkylating agent the blocks both Alpha1 and Alpha2 receptors irreversibly.
78
What is Phentolamine used to treat?
- Hypertension.
- Non-selective alpha antagonist
79
What are 3 Alpha1 selective antagonists used to treat hypertension?
- Prazosin
- Terazosin
- Doxazosin
80
What is different between Terazosin/Doxazosin and prazosin?
-Terazosin and Doxazosin are longer acting
81
What is the drug of choice for treatment of genitourinary issues in BPH? What receptor?
- Tamulosin
- Binds to Alpha1A receptors
82
What is the result of a Beta1 blockade (beta1 receptor antagonist)?
-decrease in HR and myocardial contractility
83
What is the net result in an Alpha1 blockade?
decreased TPR
84
What is the clincal significant of a Beta2 blockade?
-can cause life threstening bronchial constriction in patients with asthma
85
Is Propranolol a B1 or B2 receptor antagonist?
-both (nonselective)
86
What is the clinical use of propranolol?
- Treatment of HTN and angina
- Contraindicated in Asthma patients but not COPD
87
What receptors are blocked by Carvedilol, and what is its clinical use?
- Blocks Alpha1, Beta1, Beta2
- Management of heart failure with decreased systolic function.
88
What is the name of the partial Beta1 and Beta2 agonist used to treat hypertension?
-Pindalol
89
What is the name of a partial Beta1 agonist used to treat HTN?
Acebutolol
90
What is the MOA and usage of Esmolol?
- Beta1 selective antagonist
- short half life---\> safer for more unstable patients
91
What is the mechanism of Alpha1 selective agonists?
-Activate alpha1 adrenergic receptors to **increase peripheral vascular resistance**
92
What are some side effects of Alpha1 receptor agonists?
- Bradycardia (vagal relfex), and cadiac arrhythmias
- hypertension
- anxiety
93
What is the mechaism of an alpha2 andrenergic receptor?
inhibit sympathetic outflow
94
What are common alpha2 agonist side effects?
Bradycardia, constipation, xerostomia, seation, hypotension
95
Side effects of beta-adrenergic agonist
tremors, bradycardia, asthma attack
96
Side effects of alpa-adrenergic antagonist
- anything with low BP
- hypotension, dizzyness, sedation, nasal congestion, urnary frequency (Alpha1A)
97
Side effects of Beta-adrenergic antaognists
broncospasm, hypoglycemia
