Autonomic Pharmacology II. Cardiovascular System. Trachte. 9.28.09. Katelyn Rogers.
Sketch Biosynthesis of Catecholamines Pathways & Locations:
amphetamine,
Sketch: normetanephrine, catecholamines,
ephedrine
Sketch Slide 5:
Sympathetics NTs: Adrenergic Amines
Synthesis
Storage
Release
Termination
Receptors
Drugs/Catecholamines
Tyrosine
Hydroxylase
(cyto) is ratelimiting –
blocked by
-methyl
tyrosine.
In granules
w/ ATP
Normal:
-Release of Dopamine beta-hydroxylase, NE
& ATP (lose protein)
-induced by stimulation of Nic rec  depol
(Na+ influx) & Ca2+ influx.
-NE inhibs own release – 2-NEG FEEDBACK
SYST.
Removal:
-uptake
-dilution &
diffusion
-degradation:
COMTcyto or
MAOmito
1 EpiNE>>isoproterenol
Indirectly-acting sympathomimetics:
-Release of NE.
-Tachyphylaxis (desens) – can amt
released.
-TYRAMINE, AMPHETAMINE, EPHEDRINE
-Reverse direction of axoplasmic transporter
-Inactive when+ IMIPRAMINE or COCAINE
(drugs that inhib the axoplasmic pump
symp)
PARGYLINE (MAOi)
EPINEPHRINE:
Vasoconstricts (1), can
vasodilate (2), directly HR &
F, but reflex suppresses HR.
Contraind: hyperthyroidism,
HTN
Tx: hypersens (BP &
bronchospasm), w/
anesthetics vasocons prevents
diffusion.
NOREPINEPHRINE:
Vasoconstricts (1), HR & F
(1), but reflex suppresses HR.
Contraind:
Hyperthyroidism, anesthesia,
pregnancy
Tx: HypoT, shock.
ISOPROTERENOL:
Vasodilates (2) & tachycardia
(1).
Only COMT met!
Tx: cardiac stimulant.
PNMT is
confined to
adr med
(may be in
brain &
vesicle).
Enzymes are
non-specific.
Dihydroxyph
enylserine
can be
converted to
NE by DOPA
Axoplasmi
c uptake
(1/5)
Granular
uptake
(4/5)
RESERPINE: inhibs granular pump
catecholamines in vesicles (results in
depletion of them) –depression/suicidal
GUANETHIDINE: induce release from vesicle,
Inactivation:
Vanillylmandelic
acid is
predominant
urinary product.
Normetanephrine
is next.
2 EpiNE>>isoproterenol
prejxnal nerve terminal,
platelets, gut, med-obl – site
of action.
1
isoproterenol>Epi=NE
in heart, JG apparatus,
fat
2
isoproterenol>Epi>>NE
hyperglycemia is best
stimulus
Dopamingergic rec + DA
Dilates renal/mesenteric
vasc. (for shock)
Sketch receptors on the
Non-catecholamines,
sympathomimetics
Are phenyethylamines
that are indirectly
acting (release NE from
nerves by reversing the
axoplasmic pump) that
distribute even into the
brain. Only MAO met!
AMPHETAMINE: release
NE from nerves, BP
(1)
Toxicity: tachycardia &
hyperthermia
Tx: narcolepsy,
hyperkinetic synd,
obesity.
EPHEDRINE: releases NE
& has direct effects
(BP/vasocons)-1 &1
& vasodilates (2) &
less of an affect on
CNS).
slow acting, depletes NE stores, resp to
symp stim, inactive when + PARGYLINE
(MAOi) or inhibitors of axoplasmic
transporters (COCAINE) both leading to
symp. For PARGYLINE avoid foods w/
TYRAMINE or could lead to HTN crisis.
decarboxylas
e.
following eqn:
BP= HR x SV x TPR
Those on top inc BP, those
on bottom dec BP.
Vascular effects always win
over heart effects, bc of r4!
DOPAMINE:
F (1), vasodilator in renal &
mesenteric vasc at low doses
(dopaminergic),
vasoconstricts at higher doses
(1).
DOBUTAMINE: “Do b #1”
Selective B1 agonist, F
Contraind: A Fib
Tx: Emergency only for CHF/MI
Toxicity: ~ to combo of
Epi & Amph.
Tx:Cold Meds
PSEUDOEPHEDRINE:
Tx: Nasal congestion
Sympathetic Receptors & Drugs that Act Upon Them:
 receptors
 receptors
Non-selective Agonists:
EPINEPHRINE
NOREPINEPHRINE
Non-selective Agonists:
ISOPROTERENOL
EPINEPHRINE
Non-selective Antagonists:
Mech: Block 1 rec leading to TPR & BP & block 2 rec to NE release from nerves (
tachycardia)
Actions: HypoT,  Bld Flow, mucosal stiffness
Side effects: postural hypoT (blocks venoconst), nasal stiffness, tachycardia (BP is caused by
need to HR (ie. Turn on symp) and the BP does this reflexively +  NE release).
PHENTOLAMINE
Comp inhib of  & SE rec
Tx: Pheochromocytoma, shock, hypertensive crisis w/ MAOis.
PHENOXYBENZAMINE:
Noncomp inhib of -rec (irreversible binding – shifting dose resp curve down)
Non-selective Antagonists:
Mech: Comp blockade of 1 & 2 in the system & braindepr.
Actions: HR (1) & Epi-induced vasocons (2)CO.
Prevents Epi-induced hyperglycemia (2)-dangerous in diabetics.
 airway R (2)- dangerous in asthmatics.
 Renin release (1)
Q. If you take a drug and have an asthmatic attack, what drug is it? It is a -blocker.
Absorption/Tx: oral, metabolized first pass liver.
HTN – by CO, angina, arrythmias, pheochromocytoma-induced tachycardia, hyperthyroidism,
migraine prophylaxis, MI, glaucoma, CHF (blocks actions of catecholamines giving beneficial
effect over long term, not acute).
Side effects: Bradycardia (1), bronchoconstriction (2), vasopasm in Raynaud’s (2), sex
dysfxn, depression (NOT ATENOLOL), blocks hyperglycemic resp to Epi (2)- too much insulin,
can’t crank glucose up, in vasculature  Epi-induced contractions (2).
PROPRANOLOL
Not used for glaucoma.
Tx: Angina, arrhythmias, HTN.
TIMOLOL
Tx: HTN, MI, Wide angle glaucoma (aq humor formation)
PINDOLOL
Tx: HTN
Partial agonist  less bradycardia
LABETALOL
1 &  antagonist
Tx: pheochromocytoma, HTN, & CLONIDINE withdrawal.
Side effect: MORE ORTHOSTATIC HYPOTENSION
CARVEDILOL
-blocker & 1-antagonist
Tx: milder forms of CHF & HTN
1
2
1
2
Agonists
Antagonists
Agonists
Antagonists
Agonists
Antagonists
Agonist
DOPAMINE (at
high doses)
ANTIHYPERTENSIVE
Mech: Block 1 rec to
TPR & BP.
CLONIDINE “we’re
clowing around us 2.”
-METHYLDOPA
(converted to
methyl-NE by DA--
ANTIHYPERTENSIVE
No essential ones!
Yohimbine approved
clinically. Penetrates
BBB.
NOREPINEPHRINE
DOPAMINE
DOBUTAMINE
BEST PROFILE OF
ACTIVITY FOR
BLOCKING.
ANTIHYPERTENSIVE
Actions: HR, F of
Selective
METAPORTERENOL,
TERBUTALINE,
ALBUTEROL, RITODINE,
SALMETEROL
PHENYLEPHRINE
Tx: reverse HypoT
COMP 1 ANTAG:
Antagonists
&
PSVT,
decongestant,
topical vasoconst
Tx: Don’t actually
prevent CHF or stroke,
even though BP. SO
NOT FIRST LINE FOR HTN
ANYMORE.
PRAZOSIN
Comp inhib on
capacitance (venules) &
resistance (arterioles)
vessels.
Side effects:
Central drowsiness.
hydoxylase & safe in
pregnancy)
GUANABENZ
Uses:
antihypertensive, act
on med obl & symp
activity w/o
interfering w/ reflex.
Side effects:
Depr, sex dysfxn, dry
mouth, &
bradycardia
cont &  Renin
release. Bc no
blockage of 2 they
are less likely to
bronchoconstrict,
block hyperglycemic
action of Epi, or Epiinduced vasoconst.
Tx: HTN & arrhythmias
METOPROLOL
Liver met, also txs
angina & CHF.
ATENOLOL
TERAZOSIN:
No t liver met, long
Long acting PRAZOSIN
duration, also txs
Tx: benign prostatic
angina. Best profile.
hyperplasia
ESMOLOL
Short-acting, IV, used
DOXAZOSIN:
for MI, HTN, &
Long-acting PRAZOSIN.
supravent
tachyarrhy, switch to
LABETALOL CARVEDILOL
other drug, only short
(CHF)
term.
Note: only actions that differ from “non-selectives” are included in “selectives”. Selectives have same actions, with more specificity.
Tx: Asthma, delay
labor (RITODRINE,
TERBUTALINE)
Side effects:
Tachycardia &
palpitations, tremor
(skel musc B2 stim) &
headache (B2
vasodil)
CV effect w/ IV:
vasodilation, but
never used!
Ganglionic Agents: First group of antihypertensives, NOT USED/MANUFACTURED ANYMORE.
Ganglionic Nic Rec Blockade
Block ganglionic transmission – mediated by ACh released from pregang fiber acting on
Nic Rec on postgang fiber.
Nic Rec ing ganglions differs from skeletal muscle.
Actions: Inhibits all autonomic neurotransmission.
-Dilates vessels bc no NE release (1)
-Tachycardia bc blocks ACh release (M)
-Block autonomic reflexes
-Block release of NE & Epi from adr med.
Ganglionic Stimulator
NICOTINE- activates
postgang n & adr med
via Nic Rec (influx Na).
CNS stim, HR & BP, 
gut motility, tx toxicity w/
emetic, maintain
respiration.
Competitive Gang Nic Rec Antagonists:
TRIMETHAPHAN
Rapid metab, can cause histamin release, so use w/ caution in asthmatics & those w/
allergies.
Clinical use: HypoT in surgery ( bld loss), HTN in acute dissecting aortic aneurysm or
hypertensive crisis emergency.
Side effects: orthostatic hypoT; vision; constipation; sex dysfxn.
HEXAMETHONIUM
Not approved for clinical use.
Q. WHAT DRUG WOULD WIPE OUT THE EFFECTS OF NICOTINE? LABETERALOL OR CARVEDILOL.
QUESTIONS:
1.
2.
3.
4.
5.
6.
7.
8.
9.
Which of the following receptors when activated lead/s to an increase in BP? (Can choose more than one.)
a. 1
b. Muscarinic
c. 1
d. 2
e. 2
Sketch out as many charts as possible identifying Drug X as Epi, Isoproterenol, NE, 1/2/1/2-agonists & antagonists, & Trimethaphan/Nicotine. (Sarah, maybe this is something we can
do for one another, make up graphs and then have the other interpret them to compare our understanding? I will try to make some over the weekend.)
Write out his equation for BP & the receptors.
All of the following drugs cause vasoconstriction except? (There may be more than one answer.)
a. Epi
b. NE
c. Isoproterenol
d. Dopamin
e. Dobutamine
f.
Ephedrine
Which class/es of drugs decrease TPR & BP? List some drugs in this/these category/ies.
Which drug has the best antihypertensive profile? Why?
Which of the following drugs would be best for treating CHF?
a. Doxazosin
b. Carvedilol
c. Metropolol
d. Esmolol
e. Albuterol
Do -blockers increase or decrease the release of renin? Why? What does this result in?
Which drug is most likely to portray orthostatic hypotension as a side effect?
ANSWERS:
1.
2.
3.
4.
5.
6.
7.
8.
9.
a (cAMP) & c(IP3-Ca)
See sketches.
See sketch.
C & e.
Non-selective -blockers or 1-antagonists. “–azosin”, Labetalol, Carvedilol, Phentolamine, Phenoxybenzamine.
Atenolol- most direct acting effect and less side effects. Plus, it does not get into the brain.
B & c.
Decrease. They dec symp stimulation, which is required to increase renin release. This results in increased U.O.
Labetalol.