mcmp 407 sympatholytic pharmacology l selective vs. non-selective l antagonist vs. partial agonist l...

MCMP 407

Sympatholytic pharmacologySympatholytic pharmacology

Selective vs. Non-selective Antagonist vs. Partial Agonist Reversible vs. Irreversible

MCMP 407

NH3

COOH

Gq

Phospho-lipase C

(+)

PIP2

IP3 Diacylglycerol

Increase Ca2+ Activate ProteinKinase C

Response

Receptor agonists activate signal transduction pathwaysReceptor agonists activate signal transduction pathways

1 adrenergic

receptor

HO

HO CH

OH

CH2 NH2

Norepinephrine

MCMP 407

Receptor antagonists block agonist binding to the receptorReceptor antagonists block agonist binding to the receptor

NH3

COOH

Gq

Phospho-lipase C

Antagonist

HO

HO CH

OH

CH2 NH2

Norepinephrine

What effect would an antagonist alone have on receptor activation?

MCMP 407

Clinical pharmacology of Clinical pharmacology of -adrenergic -adrenergic receptor antagonistsreceptor antagonists

Drug ReceptorRoute ofadmin. Clinical uses

Side effects of 1 receptor antagonists:

Orthostatic hypotension, inhibition of ejaculation, nasal stuffiness, tachycardia

Phenoxybenzamine Oral Pheochromocytoma, hypertensive crisisPhentolamine Parenteral Pheochromocytoma, hypertensive crisis,

male impotencePrazosin Oral Hypertension, benign prostatic

hypertrophyTerazosin Oral Hypertension, benign prostatic

hypertrophyDoxazosin Oral Hypertension, benign prostatic

hypertrophy

MCMP 407

Non-selective adrenergic receptor antagonistsNon-selective adrenergic receptor antagonists-Haloalkylamines

N CH2 CH2 XR

RR= aromatic, alkyl

X= Cl-, Br-, etc.

MCMP 407

-Haloalkylamines

NO

CH3

Cl

Phenoxybenzamine (Dibenzyline)

Non-selective receptor antagonist

Also blocks acetylcholine, histamine, and serotonin receptors

Irreversible antagonist resulting from covalent modification of receptor

Non-selective adrenergic receptor antagonistsNon-selective adrenergic receptor antagonists

MCMP 407

-Haloalkylamines: Mechanism of receptor inactivation

receptor alkylated

receptor

N

Cl

R RN

R R Cl-

Aziridinium ion

NR R Cl-

Nu

NR R

Nu


MCMP 407

Imidazolines

Phentolamine (Regitine)

Non-selective receptor antagonist

Competitive (reversible) blocker

Potent vasodilator, but induces pronouced reflex tachycardia

Block of presynaptic 2 receptors may promote release of NE

Also blocks 5-HT receptors, and is a muscarinic and histamine receptor agonist


N

NH

N

HO

H3C

CH2

MCMP 407

Reversible vs. Irreversible receptor blockadeReversible vs. Irreversible receptor blockade

-10 -8 -6 -40

50

100

Log [Norepinephrine]

1

Ad

rene

rgic

rec

epto

r ac

tiva

tion

-10 -8 -6 -40

50

100

Log [Norepinephrine]

1

Ad

rene

rgic

rec

epto

r ac

tiva

tion1 M Phent

+ Phentolamine + Phenoxybenzamine

10 M Phent

1 M Phenox

10 M Phenox

MCMP 407 -adrenergic receptor antagonists-adrenergic receptor antagonists

“Quinazolines” Vary in half-life:

Prazosin 3 hrs Terazosin 12 hrs Doxazosin 20 hrs

Undergo extensive metabolism, excreted mainly in the bile

Vasodilators Relaxation of smooth muscle in

enlarged prostate and in bladder base “First-dose” effect

N

NH3CO

H3CO

NH2

N

N R

O

O

O

O

O

Prazosin: R =

Terazosin: R =

Doxazosin: R =

Quinazoline ring

Piperazine ring

Acylmoiety

(Minipres)

(Hytrin)

(Cardura)

MCMP 407

OtherOther adrenergic receptor antagonists adrenergic receptor antagonistsErgot alkaloids

N

N

O

R'O

R

O NH

O NCH3

NH

Derivatives of Lysergic Acid Product of the grain fungus

Claviceps purpura 5 Major alkaloids based on R and

R’; Ergotamine the most common Used in the treatment of migraine Ergots possess strong oxytocic

action

MCMP 407

-adrenergic receptor antagonists-adrenergic receptor antagonists

Yohimbine (Yocon)

Indole alkaloid Found in Rubaceae and

related trees. Also in Rauwolfia Serpentina.

Blockade of 2 receptors increases sympathetic discharge

Folklore suggests use in the treatment of male impotence

NH

N

H

H

H3CO2C

H

OH

MCMP 407


Ar

O NH R

OH

Ar = aromatic ring structure

R = bulky alkyl group (isopropyl or tert-butyl)

Aryloxypropanolamines

Note: non-carbon atom

in side chain

MCMP 407


Non-selective Lipophilic Local anesthetic

properties Blockade is activity-

dependentPropranolol(Inderal)

O NH

OH

CH

CH3

CH3

MCMP 407


Pharmacological effects Decreased cardiac output and

heart rate Reduced renin release Increase VLDL, Decrease HDL Inhibit lipolysis Inhibit compensatory

glycogenolysis and glucose release in response to hypoglycemia

Increase bronchial airway resistance

Propranolol(Inderal)

Therapeutic uses for -adrenergic receptor antagonists:

Hypertension, angina, cardiac arrhythmias, migraine, stage fright, thyrotoxicosis, glaucoma, congestive heart failure (types II and III)

O NH

OH

CH

CH3

CH3

MCMP 407

Non-selective Non-selective -adrenergic receptor antagonists-adrenergic receptor antagonists

Thiadiazole nucleus with morpholine ring

Administered: Oral, Ophthalmic Uses: Hypertension, angina,

migraine, glaucoma

O NH

OH

C

CH3

CH3

CH3

N S

NNO

Timolol (Timoptic, Blocadren)

O NH

OH

CH

CH3

CH3HO

HONadolol (Corgard)

Less lipophilic than propranolol Long half-life: ~20 hours Mostly excreted unchanged in urine Administered: Oral Uses: Hypertension, angina, migraine

How will -blockers affect

pupil size?

MCMP 407


Pindolol (Visken)

Possesses “Intrinsic sympathomimetic activity (ISA)

Partial agonist Less likely to cause bradycardia and lipid

abnormalities Administered: Oral Uses: Hypertension, angina, migraine

O NH

OH

CH

CH3

CH3

NH

What would a pindolol dose-response curve look like?

MCMP 407

Dose-Response Curves and Partial AgonistsDose-Response Curves and Partial Agonists

-10 -8 -6 -40

50

100

Log [Drug]

1

Ad

rene

rgic

rec

epto

r ac

tiva

tion

-10 -8 -6 -40

50

100

Log [Drug]

% In

hib

itio

n o

fN

E R

es

po

nse

NE

PindololNE +Pindolol

NE +Propranolol

%

MCMP 407


Possesses “Intrinsic sympathomimetic activity (ISA)

Partial agonist Less likely to cause bradycardia and lipid

abnormalities Administered: Oral, Opththalmic Uses: Hypertension, glaucoma

Carteolol (Cartrol, Ocupress)

NH

O

O NH

OH

C

CH3

CH3

CH3

MCMP 407

Selective Selective -adrenergic receptor antagonists-adrenergic receptor antagonists

“Cardioselective” Less bronchconstriction Moderate lipophilicity Half-life: 3-4 hours Significant first-pass metabolism Administered: Oral, parenteral Uses: Hypertension, angina, antiarrhythmic,

congestive heart failureR

OH

O NH

CHCH3

CH3

Metoprolol (Lopressor, Toprol)R= CH2

Bisoprolol (Zebeta)R= O

O CH3

CH2CH2

OCH

CH3

CH3

MCMP 407


Atenolol (Tenormin)

“Cardioselective” Less bronchconstriction Low lipophilicity Half-life: 6-9 hours Administered: Oral, parenteral Uses: Hypertension, angina

O NH

OH

CH

CH3

CH3

NH2

O

MCMP 407


Esmolol (Brevibloc)

Very short acting Half-life: 9 minutes Rapid hydrolysis by esterases found in red

blood cells Administered: Parenteral Note:

incompatible with sodium bicarbonate Uses: Supraventricular tachycardia, atrial

fibrillation/flutter, perioperative hypertension

O NH

OH

CH

CH3

CH3

OCH3

O

MCMP 407

Side effects of -blockers: Bradycardia, AV block, sedation, mask symptoms

of hypoglycemia, withdrawal syndrome

MCMP 407

Action Potential

Na+

Effect of chronic -receptor blockade

Presynaptic neuron

H+

Effector organ

Ca2+

Na+

Tyrosine

Tyrosine

Dopamine

DA

NE

Uptake 1Na+, Cl-

NE

NENENE

NE

MAO

MCMP 407

Action Potential

Na+

Effect of chronic -receptor blockade: Receptor up-regulation

H+

Effector organ

Ca2+

Na+

Tyrosine

Tyrosine

Dopamine

DA

NE

Uptake 1Na+, Cl-

NE

NENENE

NE

MAO

MCMP 407

Side effects of -blockers: Bradycardia, AV block, sedation, mask symptoms

of hypoglycemia, withdrawal syndrome

Contraindications: Asthma, COPD, congestive heart failure (Type IV)

MCMP 407

Mixed adrenergic receptor antagonistsMixed adrenergic receptor antagonists

Labetalol (Normodyne, Trandate)

Non-selective receptor antagonist 1 receptor antagonist Two asymmetric carbons (1 and 1’) (1R, 1’R)-isomer possesses -blocking activity (1S, 1’R)-isomer possesses greatest 1 receptor blocking

activity -blocking activity prevents reflex tachycardia normally

associated with 1 receptor antagonists Administered: Oral, parenteral Uses: Hypertension, hypertensive crisis

HN

OH

CH3HO

CONH2

11'

MCMP 407

Mixed adrenergic receptor antagonistsMixed adrenergic receptor antagonists

Carvedilol (Coreg)

Non-selective receptor antagonist 1 receptor antagonist Both enantiomers antagonize 1

receptors Only (S)-enantiomer possesses -

blocking activity

OCH3

ONH

O

OH

NH

-blocking activity prevents reflex tachycardia normally associated with 1 receptor antagonists

Administered: Oral Uses: Hypertension, congestive

heart failure (Types II and III)

MCMP 407

Action Potential

Na+

Pharmacologic manipulation of the adrenergic system

Presynaptic neuron

H+

Effector organ

Ca2+

Na+

Tyrosine

Tyrosine

Dopamine

DA

NE

Uptake 1Na+, Cl-

NE

NENENE

NE

MAO

1

2

3

MCMP 407

Inhibition of Inhibition of norepinephrine norepinephrine synthesissynthesis

HO CH2 CH NH2

HO

HO CH

OH

CH2 NH

CH3

HO

HO CH

OH

CH2 NH2

COOH

HO CH2 CH NH2

COOH

HO

HO

HO CH2 CH2 NH2

TYROSINE

DOPA

DOPAMINE

NOREPINEPHRINE

EPINEPHRINE

tyrosine hydroxylase

aromatic L-amino acid decarboxylase

dopamine -hydroxylase

phenylethanolamine-N-methyltransferase

MetyrosineX

MCMP 407

Action Potential

Na+

Drugs that reduce storage or release of NE

H+

Effector organ

Ca2+

Na+

Tyrosine

Tyrosine

Dopamine

NE

NE

NE

MAO

ReserpineGuanethidine

GuanethidineGuanethidine,

Bretylium

MCMP 407

Catecholamine depletersCatecholamine depleters

Slow onset of action Sustained effect (weeks) Used in the treatment of

hypertension May precipitate depression

NH

N

H3CO2C

H3CO

H

H

H

OC

OCH3

OOCH3

OCH3

OCH3Reserpine (Serpasil)

Indole alkaloid obtained from the root of Rauwolfia serpentina

Block vesicular monoamine transporters

Deplete vesicular pool of NE

MCMP 407

Possess guanidino moiety (pKa > 12) Resonance stabilization of cation “spreads”

positive charge over the entire four atom system

Almost completely protonated at physiological pH

“Pharmacologic sympathectomy” Effects can be blocked by transport blockers Uses: Hypertension

Guanethidine (Ismelin)

N

HN

CNH2

NH

Drugs that reduce storage or release of NEDrugs that reduce storage or release of NE

MCMP 407

Action Potential

Na+

Drugs that reduce storage or release of NE

H+

Effector organ

Ca2+

Na+

Tyrosine

Tyrosine

Dopamine

NE

NE

NE

MAO

Guanethidine

GuanethidineGuanethidine,

MCMP 407

Drugs that reduce storage or release of NEDrugs that reduce storage or release of NE

Aromatic quaternary ammonium Precise mechanism unknown Displace and release NE and prevent

further release (depletion) Local anesthetic Administered: Parenteral Uses: Antiarrhythmic (ventricular

fibrillation)

Bretylium tosylate (Bretylol)Br

CH N

CH3

CH3

CH2CH3 CH3O3S

mcmp 407 sympatholytic pharmacology l selective vs. non-selective l antagonist vs. partial agonist l...

Documents