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Therapeutics > Exam 1 Sympathomimetics > Flashcards

Exam 1 Sympathomimetics Flashcards

1
Q

What are monoamines?

A
  1. contains one amino group connected to an aromatic ring by a two carbon chain
  2. includes serotonin, dopamine, norepinephrine, epinephrine, (histamine)
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2
Q

What are catecholamines?

A
  1. monoamine with catechol group (benzene with two hydroxyl side groups at C1 and C2 (one of them is a para hydoxy to the amino group)
  2. includes dopamine, norepinephrine, and epinephrine
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3
Q

Serotonin is a derivative of which amino acid?

A

tryptophan

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4
Q

What are the derivatives of tyrosine?

A

norepinephrine, epinephrine, and dopamine

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5
Q

What is the mechanism of norepinephrine neurotransmission?

A
  1. tyrosine is transported into the noradrenergic ending or varicosity by a sodium dependent carrier (A)
  2. tyrosine is converted to dopa by tyrosine hydroxylase which is converted to dopamine by dopa decarboxylase
  3. dopamine is transported into the vesicle by the vesicular monoamine transporter (VMAT) → the carrier also transports NE and other amines into vesicles
  4. dopamine is converted to NE in the vesicle by dopamine-beta-hydroxylase
  5. release of transmitter occurs when an action potential opens voltage sensitive calcium channels and increases intracellular calcium → fusion of vesicles with the surface membrane results in expulsion of NE
  6. NE binds to adrenergic receptors on postsynaptic cell
  7. NE binds to regulatory receptors present on the presynaptic terminal
  8. NE diffuses out of the cleft or is re-uptaken into the cytoplasm of the terminal by the NE transmporter (NET) where it is metabolized by MAO or transported by VMAT back into vesicles
  9. NE can also diffuse away from the synaptic cleft to other cells where it can be degraded by COMT
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6
Q

What is the biosynthesis of catecholamines?

A

L-tyrosine → L-dopa (has extra hydroxyl group to make a catechol via tyrosine hydroxylase) → dopamine (no COOH group and is considered to be the simplest catecholamine via L-aromatic amino acid decarboxylase) → norepinephrine (added OH group via beta-hydroxylase, synthesized in the presynaptic vesicle) → epinephrine (addition of methyl group on the nitrogen via N-methyltransferase in the adrenal medulla)

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7
Q

What is the metabolism of norepinephrine?

A

norepinephrine → 3,4-dihydroxyphenylglycoaldehyde (via MAO) → 3,4-dihydroxyphenylehtylene glycol (via aldehyde reductase) → 3-methoxy-4-hydroxyphenylethylene glycol (via COMT) → VMA (via alcohol then aldehyde dehydrogenases)

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8
Q

What is another mechanism of the metabolism of norepinephrine?

A
  1. norepinephrine → 3,4-dihydroxymandelic acid (via MAO and aldehyde dehydrogenase) → VMA (via COMT)
  2. norepinephrine → normetanephrine (via COMT) → VMA (via MAO then aldehyde dehydrogenase)
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9
Q

What is the final product of norepinephrine metabolism?

A

3-methocy-4-hydroxymandelic acid (vanilylmandelic acid, VMA)

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10
Q

What are the two metabolic enzymes?

A
  1. COMT (catechol-O-methyltransferase) → highest activity in the liver, important for metabolism of circulating and administered catecholamines, also at nerve terminals
  2. MAO (monoamine oxidase) → surface membrane protein of mitochondria, high concentration in nerve terminals, liver, kidney, gut
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11
Q

What happens when a catechol is oxidized?

A

becomes an ortho-quinone → the OHs become ketones

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12
Q

What are the receptor mediated cardiovascular effects of norepinephrine (NE)?

A
  1. activates alpha and beta1 receptors with little affinity for beta2 receptors
  2. alpha1 agonist → vasoconstriction leading to rise in BP
  3. beta1 agonist → cardiac stimulation by increase in force and conduction
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13
Q

What are the receptor mediated cardiovascular effects for epinephrine?

A
  1. activates alpha and beta receptors
  2. alpha1 agonist → vasoconstriction leading to rise in BP
  3. beta1 agonist → cardiac stimulation by increasing in force, rate, and conduction
  4. beta2 agonist → vasodilation leading to fall in BP and bronchodilation
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14
Q

What are the receptor mediated cardiovascular effects of dopamine?

A
  1. at lower doses:
    D1 agonist → vasodilation in renal, mesenteric, and coronary arteries increasing blood flow
    beta1 agonist → cardiac stimulation by increasing force, rate, and conduction
  2. at high doses: alpha1 agonist → vasoconstriction leading to rise in BP
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15
Q

What pathway does alpha1 receptors stimulate and what are the effects?

A
  1. Gq pathway

2. vasoconstriction, pupillary dilation, ejaculation, inhibition of peeing (micturition), GI inhibition

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16
Q

What pathway does alpha2 receptors stimulate and what are its effects?

A
  1. Gi pathway

2. vascoconstriction, prejunctional inhibition of NE release, in CNS: decrease CV SNS input

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17
Q

What pathway do beta1 receptors stimulate and what are the effects?

A
  1. Gs pathway

2. cardiac stimulation, secretion of renin

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18
Q

What pathway do beta2 receptors stimulate and what are its effects?

A
  1. Gs pathway

2. cardiac stimulation, bronchodilation, uterine relaxation, GI inhibition, vasodilation

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19
Q

Epinephrine acts on what receptors?

A

beta1, beta2 > alpha1, alpha2

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20
Q

Norepinephrine acts on which receptors?

A

alpha1, alpha2, and beta1

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21
Q

What is the selectivity of alpha 1 receptors (from high to low)?

A

isoproterenol&raquo_space; norepinephrine > epinephrine > phenylephrine

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22
Q

What is the selectivity for beta1 receptors (from high to low)?

A

phenylephrine&raquo_space; norepinephrine > epinephrine > isoproterenol

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23
Q

What is the selectivity for beta2 receptors (from high to low)?

A

phenylephrine > norepinephrine&raquo_space; epinephrine > isoproterenol

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24
Q

What are the two examples of direct acting adrenergic receptor agonists?

A

norepinephrine (Levophed) and epinephrine (Adrenaline)

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25
Q

What stereochemistry is best for binding when it comes to norepinephrine and epinephrine?

A

R configuration

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26
Q

What are important intramolecular interactions with norepinephrine?

A

H-bonding, ionic bonding → weak individually but strong with specific interactions

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27
Q

All alpha2 receptor compounds need what?

A

CNS access!

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28
Q

R1 on direct acting beta-phenylethylamine sympathomimetics do what?

A

can give selectivity for beta receptors, especially beta2 receptors

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29
Q

What are the R1 and R2 groups on norepinephrine, epinephrine, isoproterenol, and N-tert-butylnorepinephrine (Colterol)?

A

norepinephrine: R1 is H, R2 is H
epinephrine: R1 is CH3, R2 is H
isoproterenol: R1 is CH(CH3)2, R2 is H
N-tert-butylnorepinephrine: R1 is -C(CH3)3, R2 is H

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30
Q

Larger R groups have selectivity for which receptor?

A

beta2 receptors (example is N-tert-butylnorepinephrine which is selective for beta2 receptors)

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31
Q

What is the receptor selectivity as the chart goes down from norepinephrine, epinephrine, isoproterenol, and N-tert-butylnorepinephrine?

A

alpha → beta1 → beta2

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32
Q

What is the MAO activity as the chart goes down from norepinephrine, epinephrine, isoproterenol, and N-tert-butylnorepinephrine?

A

MAO activity decreases (norepinephrine has highest MAO activity while N-tert-butylnorepinephrine has the lowest MAO activity)

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33
Q

What is the catechol ring modification for isoproterenol and its receptor selectivity?

A

is a catechol selective for beta receptors

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34
Q

What is the catechol ring modification for metaproterenol and its receptor selectivity?

A

is a resorcinol (other OH group is a carbon away from the other OH group and its R group is CH(CH3)2 and is selective for beta2 receptors (no COMT since it is not a catechol)

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35
Q

What is the catechol ring modification for albuterol and its receptor selectivity?

A

is a meta-hydroxymethyl (one OH group is replaced by a hydroxymethyl group) and its R group is C(CH3)3 and is selective for beta2 receptors (no COMT since it is not a catechol)

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36
Q

What is the catechol ring modification for phenylephrine and its receptor selectivity?

A

only has a meta OH group and its R group is CH3 and is selective for alpha1 receptors

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37
Q

What are important things to know about norepinephrine?

A
  1. direct acting adrenergic receptor agonist
  2. potent alpha and beta1 receptor agonist → has effect on heart rate and vasoconstriction
  3. substrate for MAO and COMT
  4. parenteral administration
  5. used as a pressor
  6. sodium bisulfite used in preparations to prevent oxidation → since catechol groups are prone to oxidation
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38
Q

What are important things to know about epinephrine?

A
  1. direct acting adrenergic receptor agonist
  2. potent alpha, beta1, and beta2 receptor agonist
  3. substrate for MAO and COMT
  4. parenteral administration → not orally available
  5. sodium bisulfite used in preparations to prevent oxidation → since catechol groups are prone to oxidation
  6. available as many salts: hydrochloride, nitrate, bitartrate
  7. uses: anaphylaxis, glaucoma, in combination with local anesthetics
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39
Q

What is the action, clinical use, and problems associated with epinephrine (alpha and beta agonist)?

A
  1. action → at lower concentrations beta1 and beta2 predominate but at higher concentrations, alpha1 effects predominate
  2. clinical use → treatment of acute anaphylaxis or cardiac arrest, used in adjunct with local anesthetics
  3. problems → not orally active due to COMT and MAO breakdown in the liver (first pass metabolism) and can also produce unwanted effects through broad activation of adrenergic receptors
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40
Q

If a drug is a substrate for MAO and COMT (aka it is broken down in the liver by MAO and COMT) how does it affect its route of administration?

A

cannot be taken orally because of first pass metabolism

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41
Q

What is Dipiveferin?

A

it is epinephrine dipivalate, propine → adjunct of epinephrine with local anesthetic to be used to treat glaucoma → is lipophilic and activated by esterases

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42
Q

How does epinephrine counter hypoglycemia (low blood sugar)?

A

beta2 effects: glycogenolysis and gluconeogenesis → INCREASE GLUCOSE
alpha2 effects: inhibits insulin secretion → INCREASE GLUCOSE
→ is also involved in SNS early warning symptoms like sweating and anxiety

43
Q

What is the action and clinical uses of dopamine (Intropin)?

A
  1. action → is a renal D1 receptor agonist, dilates blood vessels in the kidney by binding to D1 receptor, cardiovascular stimulator and systemic vasoconstrictor outside the kidney, has sympathomimetic activity → direct beta1 and alpha1 (high dose) receptor agonist properties
  2. clinical use → shock (for emergencies), useful acute congestive heart failure → has to be given intravenously since it is a substrate for MAO and COMT
44
Q

What is Fenoldopam?

A

it is a selective D1 agonist to treat severe hypertension in hospitalized patients

45
Q

What is the mechanism of action of direct acting alpha1 agonists?

A
  1. signal via Gq pathway → mobilize Ca2+ from intracellular stores and activate PKC
  2. found on → vascular smooth muscle, genitourinary smooth muscle, intestinal smooth muscle, heart, liver
  3. mediates vasoconstriction
  4. clinically manipulated as an agonist → nasal decongestion, vascular failure in shock and supraventricular tachycardia
  5. clinically manipulated as an antagonist → hypertension, benign prostatic hyperplasia, pheochromocytoma
46
Q

What is the action, clinical use, and problems associated with phenylephrine (Neo-Synephrine?

A
  1. action → potent alpha1 receptor agonist, substrate for MAO, can be administered orally, parental, and locally
  2. clinical use → nasal decongestant, mydriatic (pupil dilation) in ophthalmic procedures without cycloplegia, hemorrhoids, vasoconstrictor in regional anesthesia
  3. problems → few (although may not be a very effective decongestant)
47
Q

Why was there a petition to remove phenylephrine from the OTC market?

A

oral administration results in high first pass metabolism (breakdown in the liver before getting to the blood) → orally administered phenylephrine does not reach the site of action so it was like a placebo in relieving nasal congestion

48
Q

How are the structure of 2-aralkylimidazolines important?

A

contains an imidazoline group in which X is a methylene or amino and R is a substituted aromatic ring structure → the imidazoline cation is resonance stabilized which allows the positive charge to be spread over the entire three atom system → imidazolines are more basic than simple aliphatic amines (more easily protonated at physiological pH)

49
Q

What are important things to know about 2-arylkylimidazolines such as naphazoline (Privine), tetrahydrozoline (Visine), and oxymetazoline (Afrin, Visine)?

A
  1. partial agonists at alpha receptors (alpha1 receptor agonist)
  2. administered locally/topically to promote vasoconstriction
  3. basic nature of imidazoline ring causes compounds to exist in ionized form at physiological pH
  4. tachyphylaxis/desensitization
  5. uses → nasal and ophthalmic decongestants
50
Q

What is the mechanism of alpha2 receptors?

A
  1. signals through Gi pathway → inhibits adenylyl cyclase, activates certain K+ channels, inhibit neuronal Ca2+ channels
  2. found presynaptically and function as autoreceptors to inhibit sympathetic output → results in decreased transmitter release
  3. clinically manipulated as an agonist → hypertension, pain, glaucoma
51
Q

How do alpha2 adrenergic agonists reduce blood pressure?

A

reduces sympathetic output from the brain by the inhibition of NE release → decreased sympathetic tone in the CNS leads to → decreased heart rate, decreased contractility, decreased renin release, and decreased vasoconstriction

52
Q

What are important thing to know about clonidine (Catapres)?

A
  1. (phenylimino)imidazoline
  2. selective alpha2 receptor agonist (also imidazoline receptor)
  3. the basicity of guanidine group (pKa is 13.6) is decreased to (pKa of 8) because of the attachment to the dichlorophenyl ring → the chlorines are electron withdrawing so it’s more acidic → has increased lipophilicity to get CNS access for alpha2 receptors
  4. clinical effect linked to activation of alpha2 receptors in the nucleus of the solitary tract (cardiovascular center)
  5. administration → oral, parenteral, transdermal
  6. uses → hypertension, opiate withdrawal, ADHD
  7. side effects → dry mouth, sedation, hypotension
53
Q

What is the action, clinical use, and problems associated with clonidine?

A
  1. action → presynaptic alpha2 receptor agonist that acts in the CNS (brainstem) to decrease sympathetic nervous system activity to the heart and blood vessels → alpha2 effects include decrease cAMP, inhibit certain Ca2+ channels, and activate certain K+ channels
  2. clinical use → hypertension, neuropathic pain, ADHD
  3. problems → hypotension, dry mouth, withdrawal symptoms with prolonged use (hypertension, tachycardia, angina, or myocardial function)
54
Q

What are important things to know about Guanabenz (Wytensin) and Guanfacine (Tenex, Intuiv)?

A
  1. alpha2 receptor agonists
  2. open ring imidazolines
  3. two atom bridge to the guanidine group that decreases the pKa so that the drug is mostly non-ionized at physiological pH
  4. Guanabenz has shortest half life at 6 hours while clonidine and guanfacine half life is 12-16 hours
  5. administration is oral
  6. uses → hypertension, ADHD (guanfacine)
55
Q

What are important things to know about methyldopa (Aldomet)?

A
  1. alpha2 receptor agonist
  2. a prodrug metabolized to active alpha2 receptor agonist (1R, 2S)-alpha-methylnorepinephrine
  3. act at CNS alpa2 receptors to decrease sympathetic outflow
  4. water soluble, ester hydrochloride salt Methyldopate is used for parenteral solutions
  5. administration → Methyldopate is parenteral but Methyldopa is oral
  6. uses → hypertension (especially during pregnancy)
56
Q

What are some other alpha2 receptor agonist drugs?

A
  1. apraclonidine (lopidine) → glaucoma (by decreasing intraocular pressure), has a para NH2 on clonidine with pKa of 9.2
  2. Brimonidine → glaucoma
  3. Tizanidine (Zanaflex) → muscle spasticity
57
Q

What are adverse effects of alpha2-adrenergic receptor agonists?

A

sedation, Na+ and water retention, dry mouth, withdrawal syndrome

58
Q

What is the action, clinical use, and problems associated with brimonidine?

A
  1. action → alpha receptor agonist that inhibits aqueous humor production (acute effect) and stimulate/increase aqueous humor outflow (chronic effect)
  2. clinical use → glaucoma (ophthalmic)
  3. problems → allergic conjunctivitis
59
Q

What does the Gs pathway stimulate (beta receptors)?

A
  1. activate adenylyl cyclase
  2. increase cAMP
  3. increase cAMP-dependent protein kinase activity
  4. results in phosphorylation of ion channels and other proteins
60
Q

Where are beta1 receptors found and what are they clinically manipulated for?

A
  1. found in the heart → increases force of contraction (inotropy), increases heart rate (chronotropy), increases conduction velocity in AV node
  2. found in kidneys → increases renin release
  3. manipulated as an agonist for → shock, congestive heart failure
  4. manipulated as an antagonist → hypertension, angina, arrhythmias, congestive heart failure
61
Q

Where are beta2 receptors found and what are they clinically manipulated for?

A
  1. found in smooth muscle → relaxation especially of the bronchial smooth muscle and vasodilation
  2. manipulated an agonist for → asthma, premature labor
  3. manipulated as an antagonist for → glaucoma
62
Q

Where are beta3 receptors found and what are they clinically manipulated for?

A
  1. found in urinary bladder → relaxation and prevention of urination
  2. manipulated as agonist for → overactive bladder
63
Q

What are some types of beta receptors and examples of them?

A
  1. non-selective → isoproterenol (Isuprel)
  2. beta1 selective → dobutamine (Dobutrex), dopamine (Intropin) (MOA complex)
  3. beta2 selective → terbutaline (Brethine, Bricanyl), metaproterenol (Metaprel, Alupent), albuterol (Proventil, Ventolin), salmeterol (Serevent), ritodine (Yutopar)
64
Q

What are important things to know about isoproterenol (Isuprel)?

A
  1. non selective beta receptor agonist
  2. bronchodilation (for asthma)
  3. increased cardiac output
  4. metabolized by conjunction reactions (phase II) and by COMT
  5. not sensitive to MAO
  6. administration → oral, parenteral, local (inhaled)
  7. uses → asthma, COPD, cardiostimulant
  8. short lasting!
65
Q

What is the action, clinical use, and problems associated with isoproterenol?

A
  1. action → non selective beta agonist that has positive inotropic and chronotropic effects to increase CO, vasodilation and reduced peripheral resistance in peripheral vessels (can cause BP to drop)
  2. clinical use → emergency use to increase heart rate in patients with bradycardia or heart block (before pacemaker implantation), in patients with systolic dysfunction and slow heart rates with high systemic vascular resistance (after cardiac surgery and have received beta blocker therapy)
  3. problems → cardiac stimulation
  4. not commonly used → epinephrine and dopamine are more common
66
Q

What are the cardiovascular effects of some sympathomimetics?

A
  1. epinephrine → increase pulse rate, BP about the same (slightly higher), peripheral resistance decreases
  2. norepinephrine → pulse rate decreases, BP increases, peripheral resistance increases
  3. isoproterenol → increase pulse rate, slightly decrease BP, peripheral resistance decreases
67
Q

What is the baroreceptor reflex when blood pressure decreases?

A
  1. activates sympathetic fibers that feedback and:
    → innervate the heart (beta1 receptors) to increase heart rate → reflex tachycardia
    →innervate blood vessels (alpha1 receptors) resulting in vasoconstriction

NET RESULT → BP INCREASES

68
Q

What is the baroreceptor reflex when blood pressure increases?

A
  1. inhibits sympathetic fibers
  2. activates vagus (PSNS) to decrease heart rate (reflex bradycardia) ut has no direct effect on blood vessels

NET RESULT → BP DECREASES

69
Q

How is blood pressure calculated?

A

BP = peripheral resistance x cardiac output

  1. peripheral resistance is influenced by vasoconstriction/dilation
  2. cardiac output is influenced by heart rate and stroke volume
70
Q

What are important things to know about metaproterenol (Alupent, Metaprel) and terbutaline (Bricanyl, Brethine)?

A
  1. resorcinol derivatives
  2. selective beta2 receptor agonists
  3. bronchodilation
  4. cardiac effects observed only at high doses
  5. not metabolized by COMT or MAO
  6. longer duration of action than isoproterenol
  7. administration → oral, parenteral, local (inhaled)
  8. uses → asthma, COPD, terbutaline used as tocolytic to prevent premature labor
  9. metaproterenol R group is CH(CH3)2 while terbutaline R group is C(CH3)3
71
Q

What are important things to know about albuterol and salmeterol?

A
  1. meta hydroxymethyl derivatives (CH2OH)
  2. selective beta2 receptor agonists
  3. bronchodilation
  4. cardiac effects observed only at high doses
  5. not metabolized by COMT or MAO
  6. longer duration of action than isoproterenol
  7. administration → oral, local (inhaled)
  8. uses → asthma, COPD
  9. albuterol R group is C(CH3)3 while salmeterol R group is CH2(CH3)5O(CH2)4Ph
72
Q

What is the action, clinical use, and problems associated with albuterol and terbutaline?

A
  1. action → beta2 receptor agonist
  2. clinical use → asthma (for both), tocolytic to relax uterus during premature labor (only terbutaline)
  3. problems → minor cardiac stimulation
73
Q

What are important things to know about salmeterol and formoterol?

A
  1. selective beta2 receptor agonists
  2. bronchodilation
  3. not metabolized by MAO or COMT
  4. onset of action is 10-20 minutes for salmeterol but less than 5 minutes for formoterol
  5. longer duration of action
  6. administration → inhaled (metered dose inhaler and powder)
  7. uses → long term asthma, COPD
  8. not recommended for acute treatment of asthma symptoms
74
Q

What are important things to know about dobutamine (Dobutrex)?

A
  1. dopamine derivative but no beta hydroxy
  2. available as racemic mixture → exerts a much stronger inotropic than chronotropic effect
  3. (+) enantiomer is a potent beta1 receptor agonist and alpha1 receptor antagonist
  4. (-) enantiomer is a potent alpha1 receptor agonist, potency for beta receptors is reduced tenfold
  5. net effect is positive inotropic effect on heart with little chronotropic effect
  6. metabolized by COMT and conjugation, not sensitive to MAO
  7. short half life of 2 minutes
  8. administered parenterally
  9. use → acute heart failure, shock (emergency use), laboratory stress test
75
Q

What are the clinical uses and effects of dobutamine?

A
  1. action → beta1 agonist
  2. sympathetic responses → cardiac stimulation, secretion of renin
  3. clinical use → cardiac failure, especially acute emergencies, laboratory stress test
  4. has to be given as an iv infusion
76
Q

What is the action, clinical use, and problems associated with Mirabegron (Myrbetriq)?

A
  1. action → beta3 receptor agonist
  2. clinical use → overactive bladder
  3. problems → slow onset (8 weeks), hypertension
77
Q

Indirect acting sympathomimetics have what kind of effect?

A

have both CNS and PNS effects, not very selective, longer lasting duration and higher concentration

78
Q

What are examples of indirectly acting sympathomimetics?

A

amphetamine, pseudoephedrine, ephedrine, tyramine

79
Q

What do indirect acting sympathomimetics do?

A
  1. promote the release of NE via reverse action of plasma membrane transporter
  2. clinical uses → amphetamines are used for ADHD, narcolepsy, and anorexiant while the others are used as nasal decongestants
80
Q

What are the difference between direct acting and indirect acting sympathomimetics?

A

no hydroxy on the ring and methyl group at the alpha carbon and missing hydroxy group on the beta carbon → MAO reduced because of the methyl group so it is oral

81
Q

What are the clinical uses and problems associated with amphetamine and methamphetamine?

A
  1. amphetamine is one of the most potent stimulators
  2. clinical use → narcolepsy, ADHD (low doses increase wakefulness, alertness, ability to concentrate), also been used as appetite suppressants but is not approved for this use
  3. problems → at therapeutic doses: anorexia, poor growth, sleep disturbances, jitters but at toxic dose → increased BP, HR via enhanced NE signaling from SNS terminals resulting in potential for stroke, cardiac arrhythmias, myocardial infarction, and death →→ CNS effects include agitation, confusion, addiction (since amphetamine drugs release dopamine which lead to CNS effects?
82
Q

What is ADHD characterized as?

A

characterized by excessive motor activity, difficulty in sustaining attention, and impulsiveness

83
Q

Why are indirect sympathomimetics orally active?

A

unlike NE and epinephrine, they are orally active because the difference in chemical structure (the methyl substitution next to the nitrogen blocks oxidation by MAO)

84
Q

How do you treat amphetamine and methamphetamine overdose?

A
  1. acidify urine to increase excretion → not commonly used
  2. sedative for CNS symptoms
  3. sodium nitroprusside or alpha adrenergic antagonist for severe hypertension
85
Q

What is the importance of Fen-Phen on weight loss?

A
  1. fenfluramine increases release of serotonin and increases satiety
  2. phentermine is an indirect sympathomimetic that has an additional methyl group on the alpha carbon which increased anorexic activity
  3. Fen-Phen is toxic as it increased heart valve abnormalities and pulmonary hypertension (due to serotonin effects) → adverse side effects so it was withdrawn from the market
86
Q

How is phentermine/topiramate (Qsymia) used for weight loss?

A
  1. used for chronic weight management with reduced calorie diet and exercise
  2. approved for obese or overweight people and with hypertension, high cholesterol, or type 2 diabetes
  3. phentermine is an indirect sympathomimetic
  4. topiramate is an antiepileptic (blocks sodium channels and glutamate receptors, enhances GABA activity)
  5. resulted in weight loss! more than the placebo (8% more)
  6. avoid → hypertension, coronary heart disease, during pregnancy (increased risk of birth defects due to topiramate)
87
Q

What is the difference between D-(-)-ephedrine and L-(+)-pseudoephedrine?

A
  1. alkaloid obtained from the stems of ephedra and also found in mahuang
  2. D-(-)-ephedrine has the desired R configuration at the beta-hydroxy and S configuration at the alpha carbon → has direct alpha and beta agonist activity at adrenergic receptors
  3. L-(+)-pseudoephedrine is (S,S) diastereomer so the S configuration at beta-hydroxy reduces agonist activity → major mechanism is via reversal of the transporter → direct binding is almost gone
88
Q

What are the clinical uses, problems, and cautions of ephedrine and pseudoephedrine?

A
  1. clinical use:
    →pseudoephedrine is for nasal decongestion
    →ephedrine has direct alpha and beta effects (no dietary supplements for weight loss)
  2. problems → increased BP, increased HR via enhanced NE signaling from SNS terminals
  3. caution → do not use if taking MAO inhibitor and these compounds can be used to synthesize methamphetamine
89
Q

Why do you want to avoid MAOI when taking ephedrine or pseudoephedrine?

A

has activity by MAO (can be metabolized) so want to avoid MAOI

90
Q

How is methamphetamine synthesized?

A

by the removal of the OH group by lithium and ammonium

91
Q

What are examples of MAO inhibitors (indirect acting sympathomimetics)?

A

phenelzine and selegiline

92
Q

What is a caution when co-administering indirect acting drugs with MAO inhibitors?

A

co-administration with other indirect acting drugs can lead to hypertensive crisis

93
Q

What are examples of NET transporter blockers?

A

cocaine, methylphenidate, tricyclic antidepressants such as desipramine and venlafaxine

94
Q

What is the action, clinical use, and problems associated with methylphenidate?

A
  1. action → blocks NE and DA reuptake transporters that transport monoamines from synaptic cleft back to presynaptic terminal → enhance Ne and DA signaling
  2. clinical use → ADHD, narcolepsy (similar to amphetamine), even recommended for preschool children with ADHD
  3. problems → at therapeutic doses: anorexia, poor growth, sleep disturbances, jitters (like amphetamine) + priapism (prolonged penile erection) which is rare but serious
    at toxic doses: vasoconstriction and increased heart rate via enhanced NE signaling from SNS terminals and potential for stroke, cardiac arrhythmias, myocardial infarction, and death + also addictive potential (C-II drug) via enhanced DA signaling
95
Q

What is the action, clinical use, notes, and problems associated with atomoxetine?

A
  1. action → selective inhibitor of NET and this enhances NE levels
  2. clinical use → ADHD
  3. of note → not a controlled substance since it has low potential for abuse and is a non-stimulant so is not associated with agitation or sleeplessness
  4. problems → black box warning for suicidal ideation, priapism (prolonged penile erection), may take longer than stimulants for effect (up to 2 weeks for initial response and up to 8 weeks for maximal effect), may be less effective than stimulants
96
Q

What are other non-stimulants for ADHD?

A
  1. guanfacine → alpha2 agonist

2. clonidine → alpha2 agonist

97
Q

What are stimulants for ADHD?

A
  1. amphetamine/methamphetamine

2. methylphenidate

98
Q

What are the classification of directly acting receptor agonists?

A
  1. endogenous catecholamines → epinephrine, norepinephrine, dopamine
  2. alpha1 agonists → phenylephrine
  3. alpha2 agonists → clonidine, brimonidine, methyldopa
  4. beta1 agonists → dobutamine
  5. beta2 agonists → albuterol, terbutaline
  6. beta1 and beta2 agonist → isoproterenol
  7. beta3 agonist → mirabegron
99
Q

Beta2 receptors do what?

A

vasodilate!

100
Q

How are these diseases treated with (with what kind of receptor)?

A

antagonist → glaucoma, angina, arrhythmia, hypertension, heart failure, benign prostatic hyperplasia (bph), hypertension, heart failure
agonist → glaucoma, asthma, premature labor, nasal congestion

101
Q

How does epinephrine affect heart rate and blood pressure?

A

increased BP and decreased HR (because of vagal tone)

102
Q

How does norepinephrine affect HR and BP?

A

increased HR but no effect on BP (since alpha1 increases BP but beta2 decreases BP)

103
Q

How does isoproterenol affect HR and BP?

A

increased HR and decreased BP

Therapeutics (15 decks)

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