DR ISHOLA IO DEPT OF PHARMACOLOGY THERAPEUTICS AND TOXICOLOGY CMUL ADRENERGIC TRANSMISSION Adrenergic transmission is restricted to the sympathetic nervous system Norepinephrine is the transmitter at postganglionic sympathetic nerves except sweat glands ID: 749184
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ADRENERGIC SYSTEM PHARMACOLOGY
DR. ISHOLA I.O.
DEPT OF PHARMACOLOGY, THERAPEUTICS AND TOXICOLOGY
CMULSlide2
ADRENERGIC TRANSMISSION
Adrenergic transmission is restricted to the sympathetic nervous system
Norepinephrine
is the transmitter at post-ganglionic sympathetic nerves – except sweat glands
Epinephrine (Epi)
– major hormone of the adrenal medulla
Dopamine- the predominant transmitter of the mammalian extrapyramidal, mesocortical and mesolimbic neuronal pathways Slide3
ADRENERGIC TRANSMISSION
Naturally occurring catecholamines - Epinephrine, Norepinephrine, Dopamine.
Synthesis of Epi from tyrosine was proposed by Blaschko in 1939
Some of the enzymes for synthesis are not specific except tyrosine hydroxylase (TH)(Rate limiting)
Stimulation of adrenergic nerves activate TH
TH is a substrate for cAMP-dependent, Ca-calmodulin sensitive protein and PKCSlide4
Cont’d
TH is subject to feedback inhibition by catechol compounds
The storage vesicles contain NA (approx. 21%), Aa, ATP, chromogrannins, DBH, NPY, & enkephalins
2 types of storage vesicles:
Large dense core (chromafin granules)
Small dense core (NA, ATP, DBH)Slide5
SUMMARY OF SYNTHESIS
3-Hydroxylation of Tyrosine to DOPA
Decarboxylation of dopa to DA
AT of DA to vesicle or else deaminated to DOPAC or O-methylated to HVA
β
-hydroxylation of DA to NANA diffuse into cytoplasm N-methylated to EpiEpi enters chromaffin cells until release
Glucocorticoid controls the release of EpiSlide6
Cont’d
Hydroxylation of tyrosine by tyrosine hydroxylase in the presence of THB, O
2,
ferric ion (rate limiting step in biosynthesis of catecholamines)
Slide7Slide8Slide9
ADRENERGIC TRANSMISSION
STORAGE
:
The granules take up dopamine from the cytoplasm and synthesis of NE occurs within the granules.
NE is stored in the granules within the adrenergic terminal .
Released by exocytosisStorage decreases intraneuronal metabolism of NTVesicular monoamine transporter (VMAT-2) is driven by pH and potential gradientsSlide10
Cont’d
For every molecule of amine taken up, 2 hydrogen ions are extruded
Reserpine inhibits monoamine transport into storage vesicles
There are two neuronal membrane transporters for catecholamines; NET and DAT
NET is sodium ion dependent (blocked by cocaine, TCA (imipramine)
Indirectly acting sympathomimetic (ephedrine, tyramineSlide11
ADRENERGIC TRANSMISSION
RELEASE
:
Nerve impulse effects the release of NE
Entrance of calcium ion into cells results in the extrusion by exocytosis of granular contents (ADR, ATP, NPY, Chromogranins and DBH)The release of CA takes by exocytosis .
Indirectly acting amines (tyramine and amphetamine) induce the release of NE by displacing it from the nerve endings.They make carrier available at the inner surface of the membrane for the outward transport of NE (facilitated diffusion)Reserpine inhibit uptake -1Uptake-2 not sodium ion dependentSlide12
CONT’D
Influx of Ca2+ plays an important role in coupling nerve impulses, membrane depolarization, and opening of voltage gated Ca2+ channels with the release of NE
Blockade of N-type Ca2+ channels lead to hypotensionSlide13Slide14Slide15
ADRENERGIC TRANSMISSION
UPTAKE OF CA
:
It is an efficient mechanism after the release of NE –
Axonal uptake (Uptake 1 ) : Transports NE at a higher rate than E.
It is the most important mechanism for the termination of the NE.Cocaine, Imipramine inhibits this uptake 1. Slide16
Termination of the action of CAT
Reuptake into nerve terminals by NET
Dilution by diffusion out of the junctional cleft and uptake at extraneuronal sites by ENT,
Metaboilic transformation (MAO, COMT and sulphotransferases) –little effect
Termination of action of ACh by AChE is absentSlide17Slide18
ADRENERGIC TRANSMISSION
METABOLISM :
by two enzyme systems –
MAO
and
COMT.
NE after uptake -1 into the axoplasm is acted upon by MAO.NE which diffuses into the circulation is acted upon by COMT, mainly in the liverThe major metabolites excreted in urine is VMA (Vanillyl mandelic acid)Slide19Slide20
ADRENERGIC TRANSMISSION
Adrenergic receptors are
G protein coupled receptors
which acts by increasing or decreasing the production of c AMP
ADRENERGIC RECEPTORS
ALPHA – 1 -- A , B , DALPHA – 2 -- A , B , CSlide21
ADRENERGIC TRANSMISSION
ALPHA 1
:
Acts by activating Phospholipase C – production of inositol triphosphate (IP3) and DAG
IP3 promotes the release of calcium from the intracellular stores ---increase cytoplasm calciumSlide22
Adrenergic System
ALPHA 1 receptors
EYE
– radial fibers – contraction –mydriasis
Arterioles and veins – contraction – can increase peripheral resistance.
Bladder trigone and sphincter – contraction – urinary retentionLiver – Glycogenolysis.Vas deferens – ejaculation.Slide23
Adrenergic System
ALPHA 2
: acts by
inhibiting adenylyl cyclase
– cAMP
Platelets - aggregationPrejunctional receptors – decrease release of transmitter (NE)Pancreas -- decrease insulin release (predominant)Slide24
Adrenergic System
BETA
: beta receptors stimulate adenylyl cyclase
–
increasing the cAMP
Beta 1Heart JG cells in kidney (increase renin release).Slide25
Adrenergic System
Beta 2 receptors :
cAMP
Blood vessels to skeletal muscle
– Vasodilation
Uterus – Relaxation
Bronchioles – DilatationSkeletal muscles – tremorsLiver - GlycogenolysisSlide26
Adrenergic System
Dopamine 1 receptors
:
Acts by stimulation of adenylyl cyclase and increased cAMP
Renal and mesenteric vasculature
– vasodilation and increase blood flow and Na excretion.
Dopamine 2 receptors : Acts by inhibition of adenylyl cyclase, decrease cAMP, open potassium channels,Brain Slide27
Adrenergic System
Adrenergic Drugs:
Directly acting
:
Epinephrine, Norepinephrine, Phenylephrine, Albuterol
Indirectly acting
: acts by release of NE : Tyramine, AmphetamineMixed : EphedrineSlide28
Adrenergic System
Epinephrine
acts on alpha 1, 2
beta 1, 2
Norepinephrine
acts on alpha 1, 2
beta 1Isoprenaline acts on beta 1 , 2Dopamine 1 receptors agonist : Dobutamine, FenoldopamSlide29
Adrenergic System
AGENTS ACTING AT DIFFERENT SITES
INTERFERE WITH THE SYNTHESIS :
Metyrosine
BLOCKADE OF UPTAKE 1 AT NERVE TERMINAL : Cocaine, ImipramineBLOCKADE OF STORAGE IN GRANULE OR GRANULAR UPTAKE : ReserpinePROMOTION OF RELEASE : AmphetaminePREVENTION OF RELEASE : Bretylium, GuanethidineSlide30Slide31
Adrenergic System
MAO
MAO –A
present in the nerves /intestine/ liver or
A
nywhereMetabolizes NE, 5-HT and tyramine
Inhibitors are Phenelzine, TranylcypromineMAO – BPresent mainly in the BrainMetabolizes preferentially dopamineInhibitors are SelegilineSlide32
Adrenergic System
COMT INHIBITORS :
Tolcapone
-- Long acting
Entacapone -- Short actingSlide33
Adrenergic System
Agonist acting on Alpha 1
receptors
Phenylephrine, Methoxamine
Given systemically they increase the mean blood pressure via vasoconstriction with minimal effect on pulse pressure (PP).
The increase in BP can elicits reflex bradycardia.Slide34
Adrenergic System
Agonist acting specifically on
Alpha 2
receptors :
Clonidine, Alpha Methyldopa
Beta 1 and beta 2 : IsoproterenolBeta 1 : DobutamineBeta 2 : Terbutaline, Albuterol, Ritodrine, MetaproterenolSlide35
Adrenergic System
Beta agonists :
Beta 1 and Beta 2
Isoproterenol
It cause a decrease in peripheral resistance, a decrease in mean BP due to beta 2 receptor action and a reflex increase in heart rate. Systolic blood pressure does not fall significantly as diastolic, due to beta 1 receptor action, so the pulse pressure increases .Slide36
Adrenergic System
Norepinephrine :
It has little effect on beta 2 receptors.
It increases TPR and both diastolic and systolic blood pressure.
Positive inotropic action results in increase of pulse pressure.
Compensatory vagal reflexes tend to overcome the direct chronotropic action of NE -- reflex bradycardia may occur.Slide37
Adrenergic System
Epinephrine :
Acts on alpha 1, 2 and beta 1 and 2.
Epinephrine increase the HR, systolic BP and PP.
Its effects on diastolic blood pressure depends on dose.Slide38
Adrenergic System
Epinephrine :
At low dose, beta 2 activation predominates
resulting in decrease of diastolic pressure and TPR, although mean BP may not decrease significantly.
At medium dose
,
increase in heart rate, increase in mean blood pressure and increase in pulse pressure due to both beta 1 and 2 receptor action.Slide39
Adrenergic System
ALPHA BLOCKERS:
Non-selective
Phenoxybenzamine, Phentolamine
Alpha -1 selective
Prazosin, Terazosin, Tamsulosin
Alpha-2 selective YohimbineSlide40
Adrenergic System
BETA BLOCKERS:
Non selective :
Propranolol, Nadolol, Timolol
With Partial agonist :
PindololBeta 1 selective : Atenolol, MetoprololBeta and alpha 1 blocker : Labetolol, CarvedilolSlide41
Clinical pharmacology of a
-adrenergic
receptor antagonists
Drug
Receptor
Route of
admin.
Clinical uses
Side effects of a
1 receptor antagonists:Orthostatic hypotension, inhibition of ejaculation, nasal stuffiness, tachycardia
Phenoxybenzaminea
1
, a2
Oral
Pheochromocytoma, hypertensive crisis
Phentolamine
a
1
, a
2
Parenteral
Pheochromocytoma, hypertensive crisis,
male impotence
Prazosin
a
1
Oral
Hypertension, benign prostatic
hypertrophy
Terazosin
a
1
Oral
Hypertension, benign prostatic
hypertrophy
Doxazosin
a
1
Oral
Hypertension, benign prostatic
hypertrophySlide42
Non-selective adrenergic receptor antagonists
b
-Haloalkylamines
R= aromatic, alkyl
X= Cl
-
, Br-, etc.Slide43
b
-Haloalkylamines
Phenoxybenzamine (Dibenzyline)
Non-selective
a
receptor antagonist
Also blocks acetylcholine, histamine, and serotonin receptorsIrreversible antagonist resulting from covalent modification of receptor
Non-selective adrenergic receptor antagonistsSlide44
Imidazolines
Phentolamine (Regitine)
Non-selective
a
receptor antagonist
Competitive (reversible) blocker
Potent vasodilator, but induces pronouced reflex tachycardiaBlock of presynaptic a2 receptors may promote release of NE
Also blocks 5-HT receptors, and is a muscarinic and histamine receptor agonist
Non-selective adrenergic receptor antagonistsSlide45
a1-adrenergic receptor antagonists
“Quinazolines”
Vary in half-life:
Prazosin 3 hrs
Terazosin 12 hrs
Doxazosin 20 hrs
Undergo extensive metabolism, excreted mainly in the bileVasodilatorsRelaxation of smooth muscle in enlarged prostate and in bladder base“First-dose” effectSlide46
Other a adrenergic receptor antagonists
Ergot alkaloids
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 migraineErgots possess strong oxytocic actionSlide47
a2-adrenergic receptor antagonists
Yohimbine (Yocon)
Indole alkaloid
Found in
Rubaceae
and related trees. Also in
Rauwolfia Serpentina
.Blockade of a2 receptors increases sympathetic dischargeFolklore suggests use in the treatment of male impotenceSlide48
b-adrenergic receptor antagonists
Non-selective
Lipophilic
Local anesthetic properties
Blockade is activity-dependent
P
r
o
pr
a
no
l
ol
(
I
n
d
e
r
a
l
)Slide49
b-adrenergic receptor antagonists
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 hypoglycemiaIncrease bronchial airway resistance
P
rop
r
an
o
l
o
l(
I
n
d
e
r
a
l
)
Therapeutic uses for
b
-adrenergic receptor antagonists:
Hypertension, angina, cardiac arrhythmias, migraine, stage fright, thyrotoxicosis, glaucoma, congestive heart failure (types II and III)Slide50
Non-selective b
-adrenergic receptor antagonists
Thiadiazole nucleus with morpholine ring
Administered: Oral, Ophthalmic
Uses: Hypertension, angina, migraine, glaucoma
Timolol (Timoptic, Blocadren)
Nadolol (Corgard)
Less lipophilic than propranolol
Long half-life: ~20 hoursMostly excreted unchanged in urine Administered: Oral
Uses: Hypertension, angina, migraine
How will -blockers affectpupil size?Slide51
Non-selective b
-adrenergic receptor antagonists
Pindolol (Visken)
Possesses “Intrinsic sympathomimetic activity (ISA)
Partial agonist
Less likely to cause bradycardia and lipid abnormalities
Administered: OralUses: Hypertension, angina, migraine
What would a pindolol dose-response curve look like?Slide52
Selective b1
-adrenergic receptor antagonists
“Cardioselective”
Less bronchconstriction
Moderate lipophilicity
Half-life: 3-4 hours
Significant first-pass metabolismAdministered: Oral, parenteralUses: Hypertension, angina, antiarrhythmic, congestive heart failureSlide53
Selective b1
-adrenergic receptor antagonists
Atenolol (Tenormin)
“Cardioselective”
Less bronchconstriction
Low lipophilicity
Half-life: 6-9 hoursAdministered: Oral, parenteralUses: Hypertension, anginaSlide54
Selective b1
-adrenergic receptor antagonists
Esmolol (Brevibloc)
Very short acting
Half-life: 9 minutes
Rapid hydrolysis by esterases found in red blood cells
Administered: Parenteral Note: incompatible with sodium bicarbonateUses: Supraventricular tachycardia, atrial fibrillation/flutter, perioperative hypertensionSlide55
Side effects of
b
-blockers:
Bradycardia, AV block, sedation, mask symptoms of hypoglycemia, withdrawal syndromeSlide56
Side effects of
b
-blockers:
Bradycardia, AV block, sedation, mask symptoms of hypoglycemia, withdrawal syndrome
Contraindications:
Asthma, COPD, congestive heart failure (Type IV)Slide57
Mixed adrenergic receptor antagonists
Labetalol (Normodyne, Trandate)
Non-selective
b
receptor antagonist
a
1 receptor antagonistTwo asymmetric carbons (1 and 1’)(1R, 1’R)-isomer possesses b-blocking activity
(1S, 1’R)-isomer possesses greatest a1 receptor blocking activityb-blocking activity prevents reflex tachycardia normally associated with
a1 receptor antagonistsAdministered: Oral, parenteralUses: Hypertension, hypertensive crisisSlide58
Catecholamine depleters
Slow onset of action
Sustained effect (weeks)
Used in the treatment of hypertension
May precipitate depression
Reserpine (Serpasil)
Indole alkaloid obtained from the root of
Rauwolfia serpentina
Block vesicular monoamine transportersDeplete vesicular pool of NESlide59
Drugs that reduce storage or release of NE
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)