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Adrenergic Receptors

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Samantha Plumb

on 27 April 2014

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Transcript of Adrenergic Receptors

phosphodiesterase inhibitor originaly for angia pectoris, but best for ED
inhibits 5 cGMP phosphodiesterase (enzyme in the corpus cavernosum)
relaxation of sm. m. (via NO and cGMP)
increased blood flow
metabolites: n-desmethyl
major: CYP450 3A4
minor: CYP450 2C9
side effects: headache and flushing

ethanolamines
dichloroisoproterenol: partial agonist

pronethalol: carcinogenic in animals


aryloxypropanolamines
propranolol: decreased HR and renin release
penetrates nerve tissue and exerts cardiodepressant activity
practolol (toxic)
blocks cardio but lacks
brochi activity
led to beta1 and beta2 differentiation
phentolamine (Regitine)
competitive (increased EC50, Emax reached- can be overcome)
vasodilator
cholinergic agonist
blocks 5-HT to release histamine
blocks K+ channels

phenoxybenzamine (Dibenzyline)
(initially competitive) irreversible, non-competitive (incresed EC50, Emax not reached (cannot be overcome)
slower onset and longer duration
blocks 5-HT and muscarinic
tx: phenochromocytoma
entcapone (Comtan)
selective, reversible
adjunct with levodopa/carbidopa for Parkinson's "wearing off" dose syndrome
caution: watch L-DOPA levels
COMT is its metabolizing enzyme
metabolism: isomerization (z isomer) and glucuronidation

tolcapone (Tasmar)
risk of fulminant liver failure- BBW

nitecapone

CGP28014

selegline (Deprenyl)
tx for Parkinson's disease
MAO-B specific (no tyramine effect)

pargyline (Eutonyl)
antiHTN and antidepressant (michael type acceptor)

rasagiline (propargyl compound)
MAO-B selective (no tyramine effect)
tx of Parkinson's disease
lasts 1 week after dose

phenelzine (Nardil)
irreversible for antidepression

isocarboxazid (Marplan)
hydrazide hydrolysis antidepressant

tranylcypromine (Parnate)
numerous drug interactions (Fifer story)
hypersensitivity with tyramine
Neurotransmission
1. Biosynthesis of NE
2. Storage of NE
3. Release of NE
4. Adrenergic Receptor Interaction
5. Termination of Neurotransmission
Antagonists
Agonists
1: Indirect: increase NE by stimulating release- do not interact with receptor

2: Mixed: both indirect and direct

3: Direct: interact at receptor to release NE
Adrenergics
Adrenergic Receptors
Adrenergic nerves: postganglionic SNS fibers that use NE
Adrenergic Drugs: exert effects at peripheral sites to affect the activity of the SNS
enhance effects: sympathomimetics, adrenomimetics, adrenergic stimulants
reduce effects: sympatholytics, adrenomimetics, antiadrenergic agents, adrenergic blockers

Post-Receptor Binding Events
cAMP


cGMP
Biosynthesis of NE
Chemistry
Catechols: aromatic compounds with two hydroxy groups ortho to one another in the aromatic ring (pka of 10, second is 12)
Amphoteric: contain acidic and basic FG
water solubility
at pH 7.4: 95% exists as cation
highly susceptible to oxidation (so add antioxidant)
Tyrosine hydroxylase
Fe 2+ containing enzyme (requires O2)
coenzyme: tetrahydrobiopterin
occurs in cytosol
RATE LIMITING STEP
subject to end product inhibition

inhibited by: metyrosine (used for HTN)
L-Aromatic Amino Acid Decarboxylase
coenzyme: pyridoxal phosphate(oxidized form of pryridoxine- vitamin B6)
occurs in the cytosol

inhibited by: carbidopa (treats Parkinson's disease)
leads to an increase of DA in the brain (slows the conversion of DOPA to DA in the periphery) because DOPA can cross the BBB and DA cant
net effect: increases DA brain levels so lower doses of DOPA are admin.
Dopamine Beta-hydroxylase
coenzyme: ascorbate
cofactor: oxygen (Cu2+ dependent enzyme)
occurs within the storage vesicle

inhibited by: disulfram (Antabuse) (used for alcohol addiction as it inhibits aldehyde dehydrogenase to build up acetaldehye >> vomiting and nausea)
inhibits via chelation of Cu2+ (not the reason its used)
Phenylethanolamine N-methyltransferase
coenzyme: S-adenosylmethionine
occurs in the adrenal medulla (and some in the heart and brain)
Storage
vesicles located in the adrenergic nerve terminals as a 4:1 complex with ATP
vesicular storage protects NE from intraneuronal oxidation by MAO
(Epi is stored in the adrenal gland)

drug affecting storage: reserpine (from the Rauwolfia serpentina in India)
blocks active transport of DA from the cytosol into the vesicle
MAO then metabolizes them
leads to a depletion of NE
prevents NE accumulation
loss of SNS effect

Release
NE is released via exocytosis due to: neuronal depolarization by an AP (causes Ca2+ influx into the cell)
regulated bia alpha2 receptors

inhibited by: bretylium (Bretylol)
depresses postganglionic nerve transmission and prevents release
sympathetic blocker and antiarrhythmitic
tx for ventricular arrhythmias
Receptor Interaction
alpha: excitatory with smooth muscle contraction (Epi > NE > ISO)
1: Gq that activates PLC
2: Gi that inhibits adenylate cyclase
beta: inhibitory with smooth muscle relaxation (ISO > Epi > NE)
1: Gs with cardiac stimulation
2: Gs with bronchodilation
3: Gs with fat
Termination of Activity
1: NE reuptake via NET (major)
may then get stored or metabolized by MAO

2: diffusion into the circulation

3: catabolism via COMT or MAO
COMT (catechol-o-methyl transferase)
extraneuronal enzyme
exists as a soluble rm in the cytoplasm and as a membrane bound form
metabolizes catechols in circulation
regio-specific for 3-hydroxy group of catecholamines
MAO (monoamine oxidase)
located in the outer mitochondrial membrane and other cells
produces an inactive aldehyde metabolite
subtypes:
A: substrate selectivity: NE, Epi, serotonin
B: beta-phenylethylamine, benzylamine
inhibited by: cocaine and imipramine
Indirect
NE depletion decreases activity
CNS stimulants (lack phenolic OH)
anorexogenics
nasal decongestants (can cause rebound effect)
SAR is very relaxed
the terminal methyl may decrease metabolism (if present)
requires a primary or secondary amino group
Releasing Agents
amphetamine
+ isomer (dextroamphetamine) more potent
CNS stimulant

methamphetamine
less pressor activity but more CNS

tyramine
causes NE release
Uptake Inhibitor
Cocaine
MAO Inhibitor
COMT Inhibitor
Other Indirect
phenmetrazine (anorexic agent)

methylphenidate (tx of ADHD)

increased anorexic effect with less CNS
MAO
contains flavin
localized in the mitochondrial membrane
removes two e- to form an imine
coenzyme: pyridoxal phosphate (B6)
mechanism based inhibitors (black widows, suicide inhibitors)
all increase NE concentration at the receptor
Mixed
ephedrine
found in the Chinese Ma Huang
first indirect acting agonist
first oral agonist
- ephedrine (Erythro)
D: pressor
L: weak pressor

+ pseudoephedrine (Threo)
D: weak pressor
L: depressant (opposite)
Direct
SAR requirements

a: phenylethylamine
b: ring substituents
3-hydroxy, 4-hydroxy, 3 4-dihydroxy (best), 3 5-hydroxy, or 3-hydroxymethyl 4-hydroxy
c: beta hydroxy group
d: small substituent (H, Me, or Et)
e: primary or secondary amine
Selective
Can have alpha1, alpha2, beta1, or beta2 selectivity
Non-selective
Can be alpha non-selective, beta non-selective, or alpha/beta non-selective
alpha2 (inhibitory)
clonidine
originally a vasoconstrictor, but now tx for HTN
CNS activity and imidazoline receptor activity

alpha1 (excitatory)
phenylephrine
agonist binds > GPCR (Gq) > PLC > cleave PIP2 > DAG (> PKC) and IP3 (> Ca2+ > PK > phosphorylation)
tissue: postsynaptic sm. m. and glands
causes: constriction to (increase BP, drop HR [baroreceptors], decrease tachycardia
tx: hypotension, decongestion, mydriasis
not a COMT substrate
causes increased activity at a denervated neuron
beta1
dobutamine (Dobutrex)
+ isomer used clinically
- isomer: alpha1 agonist
+iomer: alpha1 antagonist
- and +: beta agonist
contains DA in its structure
direct stimulation of cardiac beta1
IV tx: inotropic support
metabolized by COMT and conjugated
beta2
SAR
one phenolic OH required
alpha-methyl on phenyethyl group (improved vascular effect)
large N- substituent
removal of alpha methyl group and addition of N-t-butyl adds bronchial selectivity
Fifer structures
requires ortho lipophillic substituent for alpha activity
bulky meta or para groups make them alpha1 selective
arylimidazolines
Fifer Structures
guanabenz and guanfacine
ring opened clonidine

methyldopa
prodrug (to alpha-methylNE)
CNS activity

tizanidine (Zanaflex)
CNS skeletal relaxant (decreases spinal spasms)
inhibits motor neurons via presynaptic alpha2 receptors (decreases the release of excitatory AA)
some tx for HTN
Fifer Structures
nylidrin (Arlidin)
tx: vascular disorders, tinnitis, premature labor
vasodilator

isoxsuprine (Vasodilin)
t: vascular disease, premature labor
vasodilator
beta2 agonist and alpha antagonist
Fifer Structures
albuterol (Proventil, Ventolin)
salbutamol in Europe
sulfate salt
not a COMT substrate
bronchodilator
metabolite: 4- sulfate

pirbuterol (Maxair)
acetate salt
bronchodilator
pyridine analogue of albuterol
metabolite: 4-sulfate
alpha
oxymetazoline (Affrin)

tetrahyrozoline

xylometazoline

propylhexidrine
beta
isoproterenol
beta2: relaxation of bronchi
beta1: stimulation of the heart
metabolized by COMT (to: 3-o-methyllisoproterenol
tx: asthma, shock, pulmonary HTN, bradycardia
parenteral or aerosol
poor MAO sutate
longer duration of action than Epi
alpha and beta
epinephrine
found in adrenal medulla- chromaffin cells
stress hormone
alpha: blood from viscera
beta: blood towards muscle

norepinephrine
major regulator of TPR and BP (via alpha)

naphazoline (Vasocon, Naphcon Forte)
midodrine (ProAmatine)- orthostatic hypotension
alpha
non-selective, alpha1 selective, and alpha2 selective

uses:
vasospastic disorders, shock, HTN, BPH

large structural variety

Ergot family were the first discovered (St. Anthony's Fire from fungus on rye bread)- vasoconstrictors and vasodilators (also have oxytocic effects)
tx: migraines and postpartum uterine bleeding
beta
tx:
HTN, angina, palpitations, arrhythmias
syncope, post MI
hypertrophic obstructive cardiomyopathy
acute dissecting aortic aneurysm
hyperthyroidism, pheochromocytoma
migraines, decrease intraocular pressure
anxiety and panic, alcohol withdrawal or OD
adverse effects
bronchoconstriction
bradycardia, HF
cold extremities
hypoglycema
abrupt discontinuation- heart attack/death
Mixed
carvedilol
carbazole ring system
lipid soluble
more beta than alpha
metabolism: ring oxidation and glucuronidation
antioxidant

labetalol
as size of the N-sub. increases, alpha affinity returns
non-selective
alpha1 selective
alfuzosin (Uroxatral - not the Mayan ruin)
prazosin (Minipress) (A: bladder, B: sm. m, D: coronary)
vasodilator (risk: orthostatic hypotension
1000:1 affinity
inhibitor of cAMP
tx: HTN and CHF
terazosin (Hytrin)
doxazosin (Cardura)
Tamsulosin (Flomax)
tx: BPH
metabolized in the liver
alpha2 selective
rauwolscine
yohimbine (Aphrodyne)
use: ED
blocks 5-HT
tolazoline (Priscoline)
Fifer
beta-haloethylamines (nitrogen mustards- irreversible, blockade will last several days)
dibenamine

phenoxybenzamine

Ergot alkaloids

imidazolines
phentolamine

tolazoline
first generation
third generation
non-selective
nadolol
penbutolol
pinbutolol
propranolol
local anesthetic effect (membrane stabilizer)-metabolized in the liver
risk with asthma, hypoglycemia
timolol
soltalol
levobunolol
metipranolol
beta1 selective
acebutolol
atenolol
bisporolol
esmolol
metoprolol
non-selective
carteolol
bucindolol
beta1 selective
betaxolol: Ca++ blocker
nebivolol: iNOS/eNOS
decreased HR and force of contraction: HTN, angina, arryhthmias, HF, glaucoma
Fifer
cAMP
cGMP
sildenafil-Viagra
contraindications: nitrates, alpha blockers, hypersensitivity
tadalafil (Cialis)
longer half-life
tx: ED
metabolized by CYP450 3A4






selectivity for PDE5:
tadalafil > vardenafil > sildenafil
vardenafil (Levitra)
use: ED
adverse effects: headache, flushing, rhinitis, dyspepsia, nausea, visual effects, priapism
metabolized in the liver via CYP450 3A4
reduced cardiovascular effects
Full transcript