Download Adrenergic Receptor Agonists

Adrenergic Nervous System
Lec 1-3
By
Nohad AlOmari Atrushi
SYMPATHOMIMETIC
– Sympathomimetic drugs mimic the effects of
sympathetic nerve stimulation
– Also adrenergic agonists
– Adrenergic receptors
Summary of the neurotransmitters released and the types of receptors
found within the autonomic and somatic nervous system.
(according to Lippincott´s
Pharmacology, 2006)
Preganglionic
neuron
Ganglionic
transmitter
AUTONOMIC
Sympathetic innervation
Parasympathetic
of adrenal medulla
Sympathetic
Acetylcholine
Acetylcholine
Nicotinic
receptor
Adrenal medulla
Neuroeffector
transmitter
SOMATIC
No ganglia
Nicotinic
receptor
Nicotinic
receptor
Postganglionic
neurons
Epinephrine release
into the blood Norepinephrine
Adrenergic
receptor
Acetylcholine
Adrenergic
receptor
Effector organs
Acetylcholine
Muscarinic
receptor
Acetylcholine
Nicotinic receptor
Striated muscle
Adrenergic Agonists
• Chemical classification
– Catecholamines
– Non-catecholamines
Adrenergic Agonists
Differences
Catecholamine
– Cannot use orally
– Cannot cross BBB
Short-half live
Examples:
Norepinephrine
Epinephrine
Isoproteronol
Dopamine
Dobutamine
Noncatecholamines
• Can use orally
• Can cross BBB
Longer half life
Examples:
Ephedrine
Phenylephrine
Terbutaline
ENDOGENOUS CATECHOLAMINES
Naturally occurring in body:
Norepinephrine -Sites: postganglionic
sympathetic sites (except sweat glands ,
erector pillorie, hair follicles, )
• Epinephrine- Secreted by adrenal medulla
• Dopamine- Major transmitter in basal ganglia,
CTZ, limbic system, anterior pitutory.
BIOSYNTHESIS
Catecholamine s
In dopaminergic
neurons, synthesis
stops here
Final step only in
adrenal medulla
and CNS neurons
Tyrosine
↓
Dopa
↓
Dopamine
↓
Norepinephrine
↓
Epinephrine
In noradrenergic
neurons,
synthesis stops
here
STORAGE, RELEASE, UPTAKE
L-Phenylalanine
Hepatic
hydroxylase
Adrenergic Receptors
• These are mainly 2 types
(α) Alfa
(β) Beta
These are again subdivided into various types
ADRENERGIC RECEPTORS
ADRENERGIC DRUGS
Symphathomimetics
• DIRECT SYMPHATHOMIMETICS
•
•
•
•
•
•
•
Adrenaline
Noradrenaline
Isoprenaline
Phenylephrine
Methoxamine
Salbutamol
Xylometazoline
• INDIRECT SYMPHATHOMIMETICS
• Tyramine
• Amphetamine
• MIXED SYMPHATHOMIMETICS
• Ephedrine
• Dopamine
• Mephenteramine
THERAPEUTIC CLASSIFICATION OF ADRENERGIC
DRUGS
Pressor agents
Noradrenaline Phenylephrine
Ephedrine
Methoxamine
Dopamine
Mephentermine
Cardiac stimulants
Adrenaline
Isoprenaline
Dobutamine
Bronchodilators
Adrenaline
Isoprenaline
Salbutamol
(Albuterol)
Terbutaline
Salmeterol
Formoterol
Bambuterol
Nasal decongestants
Phenylephrine
Xylometazoline
Oxymetazoline
Naphazoline
Pseudoephedrine
Phenyl propanolamine
CNS stimulants
Amphetamine Dexamphetamine Methamphetamine
Anorectics
Fenfluramine Dexfenfluramine Sibutramine
Uterine relaxant and vasodilators
Ritodrine
Isoxsuprine
Salbutamol
Terbutaline
PHARMACOLOGICAL ACTIONS
Cardiac effects
• Positive chronotropic effect
– An action that increases heart rate
• Positive dromotropic effect
– An action that speeds conduction of electrical
impulses (↑ conduction velocity through AV
node)
• Positive inotropic effect
– An action that increases the force of contraction
of cardiac muscle
Cardiac effects of epinephrine
Cardiac output is determined by heart rate and
stroke volume
CO = HR x SV
Epi→ β1receptors at SA node→↑HR
Epi→ β1receptors on ventricular myocytes→
↑ force of contraction
vascular smooth muscle
α1
• In blood vessels
supplying skin, mucous
membranes, viscera
and kidneys, vascular
smooth muscle has
almost exclusively
alpha1-adrenergic
receptors
• Also biphasic response
vascular smooth muscle
• In blood vessels supplying skeletal muscle, vascular
smooth muscle has both alpha1 and beta2 adrenergic
receptors
α1
α1 stimulation
β2
β2 stimulation
Effects of epinephrine on blood vessel caliber
α1
• Blood vessels to
skin, mucous
membranes,
viscera and
kidneys
• Stimulation of α1adrenergic
receptors causes
constriction of
vascular smooth
muscle
Effects of epinephrine on blood vessel caliber: skeletal
muscle
• At low plasma concentrations of Epi, β2 effect
predominates→ vasodilation
• At high plasma concentrations of Epi, α1 effect
predominates→ vasoconstriction
α1
β2
Effects of Epi on arterial blood pressure
Arterial BP = CO x PVR
Epinephrine:
– ↑ CO
– Low doses ↓ PVR (arteriolar dilation in
skeletal muscle)
– High doses ↑PVR
Effects of epinephrine on airways
• Epi→β2-adrenergic
receptors on airway
smooth muscle→
rapid, powerful
relaxation→
bronchodilation
Effects of epinephrine in the eye
• Epi at α1adrenergic
receptors on
radial smooth
muscle →
contraction→
mydriasis
α1
β2
• Epi at B2adrenergic
receptors→
relaxation of
ciliary muscle
Mnemonic for therapeutic uses of
adrenaline ABCDEG
A- Anaphylactic shock
B- Bronchial asthma
C- Cardiac arrest
D- Delay absorption of local anesthetics
E- Epistaxis, Elevate BP
G- Glaucoma
Others : Reduce nasal congestion, Induces
mydriasis
Therapeutic uses
• Shock (moderate doses)
– ↑ blood flow to kidney and mesentery
– ↑ cardiac output
• Refractory congestive heart failure
– Moderate doses ↑ cardiac output without
↑PVR
Structures of Norepinephrine and Epinephrine
Norepinephrine
Epinephrine (Adrenaline)
•Belong to chemical class of substances known as the
Catecholamines.
•Polar compounds, containing both basic and acidic functional
groups.
•Chiral compounds. Natural enantiomer has R-configuration.
•Undergoes oxidation in prolonged exposure to air.
•Limited therapeutic use.
Chemical Property of Catecholamines
Structures of several important adrenergic
agonists. Drugs containing the catechol ring
are shown in pink.
(according to Lippincott´s
Pharmacology, 2006)
Structure-activity relationships among catecholamines and related compounds
Selective b-agonists
OH
HO
Selective a-agonists
N
HO
N
HO
HO
a-Me-noradrenaline
N
HO
HO
OH
Metaraminol
N
HO
HO
Propranolol
OH
HO
HO
N
Adrenaline
N
Non-selective agonist
Noradrenaline
N
Dopamine
N
HO
N
O
Isoprenaline
OH
HO
HO
OH
OH
OH
HO
Selective b-antagonists
Salbutamol
Tyramine
OH
N
Ephedrine
Indirectly acting sympathomimetic amines
N
Amphetamine
Norepinephrine
4-((R)- 1-hydroxy-2-aminoethyl)- 1,2-benzenediol
•Potent stimulant of both α and β
adrenoceptors
•Limited therapeutic value
•Used to maintain blood pressure in acute
hypotensive states
•Substrate for MAO and COMT, not
effective orally
•Chiral compounds. Natural enantiomer
has R-configuration. Racemization occurs
in heat or acid condition.
•Undergoes oxidation in prolonged
exposure to air. Sodium bisulfite used as
antioxidant in NE preparations
Epinephrine
• Potent stimulant of both α and β adrenoceptors;
• Drug of choice for reversal of acute hypersensitivity
reactions (anaphylaxis,
• Enhances the action of local anesthetics (restricts local
blood flow);
• Poor oral absorption. Rapidly metabolized by MAO and
COMT;
• Degrades on exposure to air and light;
• Serious side effects include cerebral hemorrhage and
cardiac arrhythmias .
ALPHA1 AGONISTS
Direct Acting Agents
• These are agents which directly active the alpha1 adrenergic receptor. They are less potent than the
endogenous agonists epinephrine or norepinephrine.
However, because of structural modifications they are
orally active and have longer plasma half-lives. There
are 2 structural classes of alpha1 agonists the
phenylethylamines which are close structural analogs
of epinephrine and norepinephrine and the structurally
unrelated imidazolines. The major action of these
agents is to produce alpha1-receptor mediated
vasoconstriction.
SAR of Direct.
general, a primary or secondary aliphatic amine separated
by 2 carbons from a substituted benzene ring is minimally
required for high agonist activity
-OH Substituent:
1. By default must be present at β position to primary
amine (i.e. spaced 2 carbons away).
2. being a chiral center the 1 position must be in R
configuration for maximum activity (but many drugs sold
as racemic i.e. R/S mixture)- exception dobutamine.
Amine moiety
as the size increases – selectivity for β
receptor increases over α receptors.
2. α and β activity is maximum when
R1= methyl (e.g. epinephrine).
3. R1= isopropyl (e.g. isoproterenol) –
α activity is negligible and only β
activity present.
Benzene substituted
3′,4′- dihydroxy substitued benzene
ring provides excellent receptor
activity for both α and β sites.
2. However, there is poor oral
bioavailablity due to COMT
Sites of action of direct-, indirect-, and
mixed-acting adrenergic agonists.
INDIRECT-ACTING
Drug enhances release of
norepinephrine from
vesicles.
Neuron
MIXED-ACTING
Drug acts both
directly and indirectly.
Synapse
DIRECT-ACTING
(according to Lippincott´s
Pharmacology, 2006)
Drug directly activates
receptor.
Postsynaptic
target cell
membrane
•
•
•
•
Phenylethylamines
Phenylephrine
Pseudoephedrine
Methoxamine,
•
•
•
•
•
•
Imidazolines
Oxymetazoline
Naphazoline
Metaraminol
Tetrahydrozoline
Tetrahydrozoline
α-Adrenergic Receptor Agonists
α1−Selective Adrenergic Agonists:
• Stimulation of vascular smooth muscle.
• Maintenance of blood pressure in hypotension or shock
Phenylephrine
Methoxamine
Metaraminol
b-Adrenergic Receptor Agonists
Most of the b-selective adrenergic agonists are used primarily as
bronchodilators in asthma and other constrictive pulmonary
conditions.
Isoprenaline
•Highly potent bronchodilator
•Non-selective (β1 and β2) and leads to
cardiac stimulation caused by its β1activity.
•Metabolized primarily by COMT
(Poor substrate for MAO)
b2-Agonists (Phenylethanolamines)
•Primarily used as bronchodilators in the treatment of
asthma
•Selectivity (β1 vs. β2) is poor at high doses
•Administration by inhalation (aerosol，
enhances β2-selectivity (pulmonary)
Specific agents:
Salbutamol, Salmeterol
Salbutamol (Albuterol)
2-[(1,1-Dimethylethyl)amino]-1-[4-hydroxy-3- (hydroxymethyl)phenyl]ethanol
•Selective β2 agonist
•Orally active drugs, also available for inhalation therapy;
•Not metabolized by MAO or COMT;
•Bronchodilator used for the treatment of asthma, chronic
bronchitis, and other breathing disorders
The Synthesis of Salbutamol
Metabolism of Salbutamol
Salmeterol
•Long lipophilic substituent
•Prolonged duration of action (~ 12 hrs)
•Slow onset (not suitable alone for prompt relief of
bronchospasm，
b1-Adrenergic Agonists
Dopamine
Dobutamine
Dopamine
•Not strictly an adrenergic drug, acts on dopamine receptors.
•Stimulates cardiac b1-AR through both direct and indirect
mechanisms.
•Used to correct hemodynamic imbalances induced by shock,
trauma, or congestive heart failure.
•Rapidly metabolized by MAO and COMT. Not effective
orally.
Indirect Acting Agents
• These agents require the presence of endogenous
monoamine neurotransmitters (norepinephrine,
epinephrine, dopamine, serotonin) to produce their
effects. Indirect acting agonists work at the nerve
terminal to promote the release and/or block the
reuptake of endogenous neurotransmitters. These
agents have little activity if these neurotransmitters are
depleted. Cocaine and amphetamine interact with cell
surface monoamine transporters for dopamine (DAT),
serotonin (SERT) and norepipephrine (NET). These
transporters are expressed peripherally and in specific
brain loci and are the site of action of psychostimulants
and antidepressant drugs.
• Amphetamine: Promotes the release of monoamines
from nerve endings from the terminal cytoplasm.
There is only a limited amount of neurotransmitter in
this pool. Amphetamine also blocks the reuptake of
monoamines. Several structural analogs of
amphetamine and "amphetamine like" agents are
available for clinical use. These include:
• Dexamphetamine (the resolved and more potent disomer of amphetamine)
• Hydroxyamphetamine
• Methamphetamine
• Methylphenidate
Sympathomimetics with Mixed
Mechanism of Action
Ephedrine Hydrochloride
(1R,2S)-2-methylamino-1-phenylpropan-1-ol hydrochloride
Actions and Uses
① not be affected by COMT, prolonged duration
Decreased molecular polarity, easily enter CNS, cause
stimulation.
② ：a-methyl group, not be easily affected by MAO.
prolonged duration, decreased molecular polarity, increased
CNS toxicity.
Ephedrine Hydrochloride
•Natural product, isolated from various species of Ephedra.
•Long history of use in traditional Chinese medicine (Ma Huang)
•Four isomers of Ephedrine
(-)-Ephedrine
(+)-Ephedrine
(+)-Pseudoephedrine
(-)-Pseudoephedrine
(+)-Pseudoephedrine
• An alkaloid. A diastereoisomer of ephedrine,
• Used as a nasal decongestant (many OTC preparations
available)
• To be used with caution in hypertensive individuals
Enantiomer：
Synthetic Catecholamines: Isoproterenol
• Very powerfully
stimulates β1- and
β2-adrenergic
receptors
– No significant effect
at α1-adrenergic
receptors
β1 SA nodal cells→↑HR
β1 AV nodal cells→↑
conduction velocity
β1 Ventricular muscle
cells→ ↑ force of
contraction
Synthetic Catecholamines: Isoproterenol
• Very powerful β-adrenergic receptor agonist; no
effect at α-adrenergic receptors
α1
α1 stimulation
β2
β2 stimulation
Isoproterenol
↓arterial BP = ↑CO x ↓↓PVR
Decreased arterial blood pressure triggers
autonomic reflex arc
Effects of isoproterenol on airways
• Powerfully
stimulates β2adrenergic receptors
on airway smooth
muscle→ rapid,
powerful
relaxation→
bronchodilation
Synthetic Catecholamines: Dobutamine
• It’s a derivative of DA but not a D1 or D2
receptor agonist
• Stimulates β1- and β2-adrenergic receptors,
but at therapeutic doses, β1-effects
predominate
• Increases force of contraction more than
increases heart rate
↑CO = ↑HR x ↑ ↑ SV
Dobutamine: Therapeutic uses
•
•
•
•
Shock
MI
Cardiac surgery
Refractory congestive heart failure
Major toxic effects of catecholamines
• All are potentially arrhythmogenic
– Epi and isoproterenol more arrhythmogenic than
dopamine and dobutamine
• Some can cause hypertension
• Epinephrine, in particular, can cause CNS
effects – fear, anxiety, restlessness
• Dobutamine can cause vomiting and seizures
in cats – must be used at very low doses
Adverse effects
• CNS:
• Restlessness
• Palpitation
• Anxiety, tremors
• CVS:
• Increase BP….cerebral haemmorrhage
• Ventricular tachycardia, fibrillation
• May precipitate angina or AMI
Non-catecholamine direct-acting
adrenergic agonists
Ephedrine
Stimulates α1-, β1 and β2-adrenergic receptors
and ↑ NE release from noradrenergic fibers
Repeated injections produce tachyphylaxis
It is resistant MAO, orally
Longer acting (4-6), cross BBB
– Marketed as dietary supplement promoted
to aid weight loss, ↑ sports performance
and ↑ energy. Ingredient in OTC nasal
decongestants and bronchodilators
Uses : Mild chronic Bronchial asthma,
hypotension during spinal anaesthesia
,occasionally for postural hypotension
– Sale prohibited by FDA in 2004 due to risks
of life-threatening cardiac arrhythmias,
stroke and death
Non-catecholamine direct-acting adrenergic
agonists: Phenylpropanolamine (PPA)
• Actions much like ephedrine in the PNS
• In veterinary medicine, used to treat urinary
incontinence in dogs
• Available in OTC products for treatment of
nasal decongestion and as appetite
suppressant
• FDA has requested all companies discontinue
marketing products containing PPA due to
risk of hemorrhagic stroke
β2-selective adrenergic agonists
• Due to selectivity for β2 receptors at
recommended doses, little-to-no direct
stimulation of β1 receptors in heart
• Inhalant administration maximizes local effect
and minimizes systemic effects
Mephenteramine
• It is mixed sympathomimetic
• COP, BP, heart rate are increased
• Active orally with longer DOA (2-6 hrs),can crosses BBB
Uses:
 To treat hypotension due to spinal anesthesia and
surgical procedures
 Shock in MI and other hypotensive states
Adrenergic Agonists
• Indirect:
– Cause NE release only
– Example:
– Amphetamine
• CNS stimulant
• Increases BP by alpha
effect on vasculature,
beta effect on heart
Summary of blocking
agents and drugs affecting
neurotransmitter uptake or release
Adrenergic blockers
a - blockers
Doxazosin
Phenoxybenzamine
Phentolamine
Prazosin
Tamsulosin
Terazosin
b - blockers
Acebutolol
Atenol
Carvediol
Esmolol
Labetalol
Metoprolol
Nadolol
Pindolol
Propranolol
Timolol
Drug affecting neurotransmitter
uptake or release
(according to Lippincott´s
Pharmacology, 2006)
Cocaine
Guanethidine
Reserpine