ANS-6,7,8 Flashcards
Monoamines contain one ___ group connected to an aromatic ring by ___ carbon chain
amino, 2
examples of monoamines include
serotonin, dopamine, norepinephrine, epinephrine, and (histamine)
Catecholamines are monoamines with a ___ group
catechol
Examples of catecholamines
dopamine, norepinephrine, and epinephrine
BioSynthesis of Catecholamines:
1) tyrosine, 2) ____, 3) Dopamine, 4) ___, 5) epinephrine
L-Dopa, Norepinephrine
What step (enzyme) of catecholamine biosynthesis is rate limiting?
tyrosine hydroxylase
What is this?
L-Tyrosine
What inhibits tyrosine hydroxylase?
it’s tyrosine with a methyl on it
Metyrosine (Demser)
What inhibits L-Aromatic Amino Acid Decarboxylase?
Carbidopa
Norepinephrine Neurotransmission: Step 1 - ___ is transported into the ___ ending or varicosity by a ___ dependent carrier
Tyrosine, noradrenergic, sodium
Norepinephrine Neurotransmission: Step 2 - tyrosine is converted to ___ by tyrosine ___ which is converted to ___ by L-dopa ___
L-dopa, hydroxylase, dopamine, decarboxylase
Norepinephrine Neurotransmission: Step 3 - ___ is transported into the vesicle by ___
dopamine, vesicular monoamine transporter (VMAT)
*VMAT also transfers NE and other amines into vesicles as well
Norepinephrine Neurotransmission: Step 4 - Dopamine is converted to ___ in the vesicles by ___
NE, dopamine-B-hydroxylase
Norepinephrine Neurotransmission: Step 5 - release of neurotransmitter occurs when an ___ opens voltage-sensitive ___ channels and increases intracellular calcium. Fusion of vesicles with the surface membranes results in expulsion of NE
action potential, calcium
Norepinephrine Neurotransmission: Step 6 - NE binds to ___ receptors on the postsynaptic cell
adrenergic
Norepinephrine Neurotransmission: Step 7 - NE binds to ___ receptors present on the ___ terminal
regulatory, presynaptic
Norepinephrine Neurotransmission: Step 8 - NE diffuses out of the cleft or is re-uptaken into the cytoplasm of the terminal by the ___ where it is metabolized by ___ or transported by ___ back into vesicles
NE transporter (NET), Monoamine oxidase (MAO), VMAT
Norepinephrine Neurotransmission: Step 9 - NE can also diffuse away from the synaptic cleft into other cells where it can be degraded by ___
catechol-O-methyltransferase (COMT)
What is this?
Dopamine
What receptors does epinephrine work on?
B1, B2, a1, a2
basically all of them
What receptors does norepinephrine work on?
a1, a2, B1
Direct acting adrenergic receptor agonists: Norepinephrine
* Potent ___ and ___ receptor agonist
* substrate for ___ and ___ (metabolized quickly)
* ___ administeration
* Sodium bisulfite used in preparations to prevent ___
* used as a ___
- a1, B1
- MAO, COMT
- parenteral
- oxidation
- pressor (vasoconstriction)
Direct acting adrenergic receptor agonists: Epinephrine
* Potent ___, ___, and ___ receptor agonist
* Substrate for ___ and ___
* ____ administration
* Sodium bisulfite used in preparations to prevent ___
* available as many salts: hydrochloride, nitrate, and bitartrate
* used for ___ in combination with local anesthetics
- a, B1, B2
- MAO, COMT
- parenteral
- oxidation
- anaphylaxis
Epinephrine:
Lower [ ] effects at ___ and ___ predominately.
Higher [ ] effects at ___ predominantly
Lower: B1 and B2
Higher: a1
Clinical use of epinephrine:
treatment of ____ or ____ ; adjunct with local ____
acute anaphylaxis, cardiac arrest, anesthetics
Problems with epinephrine: not orally active due to ___ and ___ breakdown in the liver (___ metabolism). Can produce unwanted effects through broad activation of ___ receptors
MAO and COMT, first pass, adrenergic
Main action of Norepinephrine:
* activates ___ and ___ receptors. Little affinity for ____
* ___ agonist (vasoconstriction leading to a rise in BP)
* ___ agonist (cardiac stimulation by increase in force and conduction)
- activates a and B1 receptors. Little affinity for B2
- a1
- B1
Main action of Epinephrine:
* activates __ and __ receptors
* ___ agonist (Vasocontriction leading to a rise in BP)
* ___ agonist (Cardiac stimulation by increasing in force, rate, and conduction)
* ___ agonist (Vasodilation leasing to fall in BP and bronchodilation)
- a and B
- a1
- B1
- B2
Main action of Dopamine:
Lower doses -
* ___ agonist (Vasodilation in renal, messenteric, and coronary arteries increasing blood flow)
* ___ agonist (cardiac stimulation by increasing in force, rate and conduction)
Higher doses -
* ___ agonist (Vasoconstriction leading to a rise in blood pressure)
- D1
- B1
- a1
Directly-acting receptor agonists: D1 agonist Dopamine (Intropin) Action-
* Renal D1-receptor agonist, renal vessel ___
* Direct and indirect ___ and ____ agonist (high dose)
* cardiac stimulation and systemic ____ outside the kidney
- Dilation
- B1 and a1
- vasoconstrictor
Clinical use for Dopamine (Intropin)
shock, acute congestive heart failure
T or F: Dopamine must be given via IV
True
What is this?
Fenoldopam
Selective D1 agonist used for severe hypertension in hospitalized patients
Direct acting adrenergic receptor agonists: mixed b1, a1 receptor agonists - Dobutamine (Dobutrex)
* (+)-enantiomer: potent __ receptor agonist
* (-)-enantiomer: potent __ receptor agonist, potency for B receptors reduced (10x)
* racemic exerts a much stronger ___ than chronotropic effect
- B1
- a1
- inotropic
T or F: Dobutamine (Dobutrex) is metabolized by MAO and not sensitive to COMT
False; Dobutamine (Dobutrex) is metabolized by COMT and not sensitive to MAO
Direct acting adrenergic receptor agonists: mixed b1, a1 receptor agonists - Dobutamine (Dobutrex)
* ___ half life (2 __)
* Administered via ___
* Used for acute ___, shock, and “stress tests”
- short, minutes
- IV
- heart failure
Adrenergic Receptor Subtypes-a1(Gq): Agonist uses
- nasal decongestion
- mydriasis without cycloplegia
- pressor
- vasoconstrictor in regional anesthesia (keep drug localized)
- vascular failure in shock and supraventricular tachycardia
Adrenergic Receptor Subtypes-a1(Gq): Antagonist uses
- hypertension
- benign prostatic hyperplasia
- pheochromocytoma
pheochromocytoma - benign tumor that develops in an adrenal gland.
Direct acting adrenergic receptor agonists:
a1 receptors - Examples
- Phenylephrine (Neosynephrine)
- Methoxamine (Vasoxyl)
- Oxymetazoline (Visine)
What is this?
Phenylephrine (Neosynephrine)
direct a1 agonist
Direct a 1 Agonist: Phenylephrine
Administration can be ___, ___, or ___
parenteral, oral, or local
T or F: Phenylephrine is a substrated for MAO
True
Direct a1 receptor agonists:
This is an example of…
2-aralkylimidazolines
The imidazoline cation is ___ stabilized allowing the +
charge to be spread over the entire three atom system. Thus,
imidazolines are more ___ than simple aliphatic amines.
resonance, basic
Direct a1 receptor agonists:
* ___ agonists at a receptors
* Administered ____ to promote ____
* ____ nature of imidazoline ring causes compounds to
exist in ____ form at a physiologic pH
* Tachyphylaxis/Desensitization
* Used as nasal and ophthalmic decongestants
- partial
- topically/locally, vasoconstriction
- basic, ionized
a2 (Gi) receptors are found ___synaptically and function as ___receptors to inhibit ___ output
presynaptically, autoreceptors, sympathetic
a2 agonists are used for…
hypertension, pain, glaucoma
Examples of a1 receptor agonists
Naphazoline (Privine), Tetrahydrozoline (Visine), Oxymetazoline (Afrin)
Direct acting a2 receptor agonist examples
- Clonidine (Catapres)
- Methyldopa (Aldomet)
- Guanabenz (Wytensin)
- Guanfacine (Tenex)
- Brimonidine
- Apraclonidine (Iopidine)
- Tizanidine (Zanaflex)
What is this? What kind of receptor recognizes it?
Clonidine, a2 agonist
a2 agonists ___ blood pressure by reducing ___ output from the brain
reduce, sympathetic
a2 receptors cause inhibition of NE release (decreases sympathetic tone in the CNS). What effects does decreased sympathetic tone have in the body?
- Decreased HR
- Decreased contractility
- Decreased renin release
- Decreased vasoconstriction
Direct acting a2 receptor agonist: Clonidine facts
* (___)imidazolidine
* Selective a2 receptor agonist (also imidazoline receptor)
* activation of a2 receptors in ___ (decrease SNS activity)
* Administration: ___ , ___, and ____
* Uses: Hypertension, opiate withdrawal , neuropathic pain, and ___
* Side effects: hypotension, sedation, ___
- Phenylimino
- CNS
- oral, parenteral, transdermal
- ADHD
- dry mouth
For a2 agonists: the basicity of the guanidine group (pKa = 13.6) is decreased (to pKa = 8.0) because of …
the attachment to the dichlorophenyl ring
chlorine is a e- withdrawing group (even distribution)
T or F: Drugs like Clonidine can cross into the CNS
True
double chlorine is key
Problems with Clonidine
hypotension, sedation, dry mouth, withdrawal syndrome sometimes seen after prolonged use (hypertension, tachycardia, angina or myocardial infarction)
a2 “Open-ring” imidazolidines
examples
Guanabenz (Wytensin) and Guanfacine (Tenex)
a2 open ring imidazolines:
* Two atom bridge to the guanidine group ___ the pKa so that the drug is mostly ___ at physiological pH
* ___ has the shortest t-1/2 at about ___ . Half-life of clonidine and guanfacine is 12-16 hours
* Administration: ___
* Uses: ___, ADHD (guanfacine)
- decreases, non-ionized
- Guanabenz, 6 hours
- oral
- hypertension
a2 receptor agonist: Methyldopa (Aldomet)
* A ___ metabolized to an active
a2 receptor agonist, (1___, 2___)-a-
methylnorepinephrine
* act at ___ a2 receptors to decrease sympathetic outflow
* Administration: ___
* Uses: ___ (especially during pregnancy)
- prodrug, (1R, 2S)
- CNS
- oral
- hypertension
a2 receptor agonist: Methyldopate
* Water soluble, ester hydrochloride salt, Methyldopate, is used for
___ solutions
parenteral
Steps of Methyldopa/Methyldopate prodrug activation:
* Methyldopate (esterases) = ____
* Methyldopa (____) = a-Methyldopamine
* a-Methyldopamine (____) = (1__, 2__)-a-methylnorepinephrine (active compound)
Methyldopa
L-aromatic amino acid decarboxylase
Dopamine B-hydroxylase
1R, 2S
Direct Acting a2 Agonist: Brimonidine action - Used for ___. Inhibits ___ production (acute effect) and stimulate aqueous humor ___ (chronic effect)
glaucoma, aqueous humor, outflow (drainage)
Problems with Brimonidine
allergic conjunctivitis
What is this?
Brimonidine
B1 receptors are located where? Action?
Heart and kidney,
Increases:
* force of contraction
* HR
* conduction velocity in AV node
* renin release
B2 receptors are located where? Action?
smooth muscle,
* relaxation (bronchial smooth muscle)
* vasodilation
B3 receptors are located where? Action?
urinary bladder,
* relaxation
* prevention of urination
B1 agonists are used for…
shock and congestive heart failure
B1 antagonist are used for…
- hypertension
- angina
- arrhythmias
- congestive heart failure
B2 agonists are used for…
- asthma
- premature labor
B2 antagonists are used for…
Glaucoma
B3 agonists are used for…
overactive bladder
Direct acting B receptor agonists - Non-selective example
Isoproterenol (Isuprel)
Direct acting B receptor agonists - B1-selective examples
Dobutamine (Dobutrex)
Dopamine (Intropin) (MOA complex)
Direct acting B receptor agonists - B2-selective examples
- Albuterol (Proventil, Ventolin)
- Salmeterol
- Ritodrine
- Terbutaline
- Metaproterenol
Direct acting B receptor agonists - B3-selective examples
Mirabegron (Myrbetriq)
What is this? What is it selective for?
Isoproterenol, non-selective
Isoproterenol
* ___selective
* Bronchodilation
* ___ cardiac output
* metabolized by conjugation reaction (Phase II) and by ___
* not sensitive to ___
* administration: ___, ___, and ___ (inhaled)
* uses: asthma, COPD, cardiostimulant
- non
- increased
- COMT
- MAO
- oral, parenteral, and local
Isoproterenol Action - ___ and ___ receptor agonist (non-selective):
* ___ and ___ effects (increasing cardiac output)
* in ___ vessels, stimulation of ___ receptors results in vasodilation and reduced peripheral resistance (may cause BP to ____)
B1 and B2
* inotropic and chronotropic
* Peripheral, B2, fall
Isoproterenol Clinical Use:
* Emergency use to ___ the HR in patients with ___ or heart block before pacemaker implantation
* Patients with ___ dysfunction & ___ HR with high systemic vascular resistance: after cardiac surgery in patients who previously used ___
* Asthma and COPD
- increase, bradycardia
- systolic, slow
- Beta blockers
T or F: Isoproterenol is not routinely used: epinephrine and dopamine more common
True
Cardiovascular effects of sympathomimetics: (picture)
memorize image
Direct acting selective B2 receptor agonists: Metaproterenol and Terbutaline
* ___ derivatives
* Selective B2 receptor agonist
* bronchodilation
* cardiac effects observes only at ___ doses
* not metabolized by ___ or ___
* Longer duration of action than ___
* Administration: ___, ___, or ___ (inhaled)
* Uses: Asthma, COPD
* Terbutaline used to prevent ___ labor
- Resorcinol
- high
- COMT or MAO
- Isoproterenol
- oral, parenteral, local
- premature
Direct selective B2 receptor agonists: Albuterol and Salmeterol
* ___ derivatives
* Bronchodilation
* Cardiac effects observed only at ___ doses
* Not metabolized by ___ or ___
* Longer duration of action than ___
* Administration: ___ and ___ (inhaled)
* Uses: Asthma, COPD
- Meta hydroxymethyl
- high
- MAO and COMT
- isoproterenol
- Oral and local
Direct long acting B2 receptor agonists: Salmeterol and Formoterol -
* Bronchodilation
* onset of action is ___ than other drugs. (___10-20 min, ___ <5 min)
* ___ duration of action
* Not metabolized by ___ or ___
* Administration: ___ (metered dose inhaler and powder)
* Uses: ___ term asthma, COPD
* Not recommended for ___ treatment of asthma
- slower
- Salmeterol, Formoterol
- longer
- COMT or MAO
- inhalation
- long
- acute
Structure-Activity Relationships (SAR):
T or F: The bulkier the amino group, the less MAO will act on it
True
Structure-Activity Relationships (SAR):
T or F: Resorcinol (B2) and Meta-Hydroxymethyl (B2) are metabolized by COMT
False; Resorcinol (B2) and Meta-Hydroxymethyl (B2) are NOT metabolized by COMT
Catechols (B) and only meta-OH (a1) are metabolized by COMT.
Direct-acting B3 receptor agonists: Mirabegron (Myrbetriq) -
Clinical use and problems
Clinical use: overactive bladder
Problems: slow onset (8 weeks), Hypertension
Indirect -acting Sympathomimetics: examples
amphetamine, pseudoephedrine, ephedrine, tyramine
How do indirect-acting sympathomimetics work?
Promote release of NE via reverse
action of plasma membrane
transporter
What is this?
Amphetamine
Notice that there is not a catechol or B-hydroxy
Unlike NE and Epi, ephedrine and amphetamine are orally active. This is because ephedrine and amphetamine are not ___
catechols
Amphetamine and Methamphetamine Overdose Treatment: Weak Bases
* ___ urine to increase excretion– no longer commonly used
* Sedative for ___ symptoms
* Sodium nitroprusside or alpha adrenergic ___ for severe __
- acidify
- CNS
- antagonist, hypertension
Phentermine/Topiramate (Qsymia): approved for ___ -
* Phentermine: ___ sympathomimetic
* Topiramate: ___ (block sodium channels and glutamate receptors, enhances
___ activity)
weight loss
* Indirect
* antiepileptic, GABA
Phentermine/Topiramate (Qsymia) should be avoided if the patient has any of these conditions
- hypertension
- coronary heart disease
- Pregnant
Direct vs Indirect Sympathomimetics:
D-(-)-Ephedrine vs. L-(+)-Pseudoephedrine -
* D-(-)-Ephedrine has desired (__)-configuration at B-OH and (S)-
configuration at the a carbon, so
has **direct **alpha and beta agonist activity
* L-(+)-Pseudoephedrine is the
(S,S)-diastereoisomer; (S)-configuration of B-OH reduces
agonist activity. Major mechanism is via ___
- R
*reversal of the transporter
Problems with ephedrine and pseudoephedrine
- Increased blood pressure
- increased heart rate via enhanced NE signaling from SNS
T or F: it is safe to take pseudoephedrine with an MAO inhibitor
False; contraindicated
wine and cheese effect :(
- Tyramine is an indirect sympathomimetic agent and can produce strong effects if it
reaches sympathetic nerve terminals. - Normally, almost all ingested tyramine is rapidly broken down by MAO in the liver.
- MAO inhibitors decrease the breakdown of tyramine resulting in a bolus release of NE, potentially resulting in a hypertensive crisis
Norepinephrine Transporter (NET) Inhibitors: Cocaine’s Action
* block NET
* ___ uptake
* Enhance __ signaling by keeping more transmitter in the synaptic cleft
- decrease
- NE
Cocaine: Clinical use
Local anesthetic (sodium channel blocker) for nasal mucosa and vasoconstriction
Side effects of cocaine:
Peripheral
* Increased blood pressure and heart rate
* Potential for stroke, cardiac arrhythmias, myocardial infarction and sudden death
Methylphenidate action:
* Blocks ___ and ___ reuptake transporters that transport ___ from synaptic cleft
back to presynaptic terminal
* Overall effect: enhance NE and DA signaling
- NE and DA
- monoamines
Methylphenidate Clinical use:
- ADHD, narcolepsy (similar to amphetamine)
- Recommended for preschool children with ADHD
Methylphenidate problems
- (similar to amphetamine)
- Priapism (prolonged penile erection): rare but serious
- Also addictive potential (C-II drug) via enhanced DA signaling
What is this?
Methylphenidate
NET Inhibitor: Atomoxetine action -
* Selective inhibitor of NET and thus enhances NE levels.
* used for Attention deficit hyperactivity disorder (ADHD)
* Not controlled substance – low potential for addiction
* Non-stimulant: isn’t associated with agitation or sleeplessness
BUT…
- suicidal ideation
- Priapism (prolonged penile erection): rare but serious
- May take longer than stimulants for effect
- may be less effective
bonk
