6 - Sympatholytic Pharmacology Flashcards by Chris Rodarte

Receptor agonists for Sympathetic NS activate what signal transducton cascade (ex. a1 receptor)

Gq -> PLC –> IP3 and DAG

IP3–> Increase Ca++

DAG –> activate Protein Kinase C

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Receptor antagonists block ______

agonist binding to the receptor

(antagonize the effect of agonist, not the receptor itself)

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What effect would antagonist alone have on receptor activation?

None!

If no agonist, no action

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nonselective alpha antagonists

Phenoxybenzamine

Phentolamine

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a1 receptor antagonists

Prazosin

Terazosin

Doxazosin

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AE’s of a1 antagonists

Orthostatic HoTN**
Inhibition of ejaculation
Nasal congestion
Reflex tachycardia

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Clinical uses for a1/2 receptor antagonists

Pheo
Hypertensive crisis

(Phentolamine also used for male impotence)

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a1 antagonists are all ____ adminstered except _____

orally

Phentolamine (parrenteral)

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____ can be relieved with a1 blockers to cause __________

BPH

bladder base relaxation

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Non-selective alpha receptor groups

B haloalkylamines (Phenoxybenzamine)

Imidazolines (phentolamine)

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Phenoxybenzamine effects

Also blocks receptors for:

Ach
Histamine
Serotonin

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Phenoxybenzamine PD

irreversible antagonist = covalent binding to receptor is permanent

***Therefore very LONG duration

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Competitive (reversible) non-selective alpha receptor blocker

Phentolamine

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Phentolamine is a _____ but induces ______

potent vasodilator

Induces pronounced reflex tachyardia

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Phentolamine also blocks..

5HT receptors

and is a muscarinic and histamine receptor agonist

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Phentolamine block of _____ may promote release of NE

presynaptic a2

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Components of Quinazolines

Quinazoline ring

Piperazine ring

Acyl moiety

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Quinazolines vary in

half life

Praz = 3h

Teraz = 12h

Doxaz = 20h

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Quinazolines undergo extensive

metabolism, excreted in bile

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Quinazoline effects

Vasodilation

relaxation of sm. muscle in enlarged prostate and in bladder base

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Quinazolines exhibit _____

“first dose” effect

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Quinazolines are all _______

a1 antagonists

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Yohimbe MOA

blocks a2 receptors = increase symptathetic discharge

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Aryloxypropanolamines structure

Aromatic ring attached to non-carbon atom in side chain

R group (bulky alkyl group…isopropy or tert-butyl) on a terminal NH group

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Aryloxypropanolamines general function

B receptor antagonists

Nonselective B agonists

* Propanolol * Nadolol * Timolol * Pindolol * Carteolol

Nonselective B antagonists - 2 properties

Lipophilic Local anesthetic properties

B antagonist blockde is \_\_\_\_\_\_\_\_\_

activity-dependent

B antagonists (e.g. Propanolol) pharmacologial effects (6)

1. Decreased **CO** (and HR) 2. Decreased **Renin** release (imp. for HTN relief) 3. Increase **VLDL**, Decrease HDL 4. Inhibit **lipolysis** 5. Inhibit compensatory **glycogenolysis** during Hypoglycemia 6. Increase **bronchial resistance**

Positive effects of nonselectve B blockers on Heart Failure is largely due to \_\_\_\_\_

_decreases in the RAAS_ Ultimately lowers vasoconstruction (AT2) and fluid volume (aldosterone)

8 Therapeutic uses for nonselective B blockers (propanolol)

1. HTN 2. angina 3. arrythmia 4. CHF (types 1 and 2) 5. glaucoma 6. migraine 7. stage fright 8. thyrotoxicosis

Non-selective B adrenergic receptor antagonists that are NOT propanolol

Nadolol Timolol Pindolol

Nadolol is less \_\_\_\_

lipophilic than propanolol

Nadolol PK

Long T1/2 (20h) Mostly excreted unchanged in urine

Nadolol use

HTN Migraine Angina

Timolol structure

thiadiazole nucleus with morpholine ring

Timolol uses

HTN Angina Migraine GLAUCOMA

How will B blockers affect pupil size

they wont! Doesn't have same effect as cholinergic

Pindolol possesses \_\_\_\_\_\_\_\_ It is a \_\_\_\_\_\_\_\_\_

intrinsic sympathomimetic activity (ISA) partial agonist

Pindolol less likely to...

cause bradycardia and lipid abnormalities

Pindolol use

HTN, angina, migraine

(PIndolol) Dose response curves and partial agonists

\*\*\*\*REVIEW SLIDE\*\*\*\*

Drugs that possess intrinsic sympathomimetic activity

ISA

Nonselective B *partial* agonists

Pindolol and Carteolol

Carteolol less likely to cause \_\_\_\_\_\_

bradycardia and lipid abnormalities

Carteolol use

HTN and glaucoma

Nonseletive B antagonists that are used in glaucoma

Timolol, Carteolol

Selective B1 antagonists are considered \_\_\_\_\_\_ Examples?

Cardioselective 1. Metoprolol 2. Bisoprolol 3. Atenolol 4. Esmolol 5. Nebivolol

3rd gen B1 selective antagonists

Nebivolol

Very short acting B1 selective antagonist

Esmolol | (half life 9 minutes)

Moderate lipophilicity B1 selective antagonists

Metoprolol and bisoprolol

Which B1 selective antagonist has significant first pass metabolism

Metoprolol, bisoprolol

Esmolol metabolism

undergoes rapid metabolism by esterases in RBC's

Metoprolol and bisoprolol use

HTN angina CHF antiarrhythmic

Atenolol use

HTN, angina

Esmolol use

SVT Afib/Aflutter Peri-op HTN

Nebivolol causes... Use?

vasodilaion due to nitric oxide production \*\*used for HTn

Mechanisms underlying vasodilating actions of B blockers

**Ca++** --X-\> **L-type VGCC** --\> **Intracell. Ca++** --\> **Contraction** _Vasodilation occurs via two pathways_ * **B2 Agonist** -- functions via **cAMP** * **NO** -- functions via **cGMP**

Mixed adrenergic receptor antagonists

Labetalol Carvedilol

Labetalol is a _____ mixture

racemic

Labetalol structure

Two asymmetric carbons | (1 and 1')

Isomers of labetalol

1S, 1'R = **a1 block** both 1 + 1' R = **B block**

where does the 'mixed' effect come into play with labetalol

The blockade of B (nonselective) stops the reflex tachycardia you'd normally expect with an a1 blocker

Labetalol use

HTN, hypertensive crisis

Carvedilol isomers effects

Both enatomers block a1 Only S-enantiomer blocks B

Mixed effect for carvedilol

Nonselective bet blocking prevents reflex tachycardia from a1 block

Carvedilol use

HTN, CHF 1 and 2

5 AE's of beta blockers

1. Bradycardia 2. AV block 3. sedation 4. mask hypoglycemia Sx 5. WIthdrawal

Chronic B blockade results in ...

pronounced withdrawal due to upregulation of the B receptors

CI's for beta blockers

Asthma, COPD, CHF type 4 (final stage)

Catecholamine depleter

reserpine

Reserpine MOA

block vesicular monoamine transporters (NET, DAT) ## Footnote **Depletes vesicular pool of NE!**

Reserpine PK

slow onset, sustained effect (weeks)

Reserpine use

HTN treatment (refractory)

Due to it's slow onset of action, reserpine will \_\_\_\_\_\_\_

NOT activate the baroreceptor response