Adrenergic Agents

Autonomic nervous system: (2) and its neurotransmitters

are agent/drugs that mimic and initiate
a response

_____ stimulate more than one of the
adrenergic receptor sites (also known as ___)

Adrenoceptors:

Symphathomimetics(___)
Sympatholytics (____)

Biosynthesis of catecholamines

Adrenergic Agents
Affects the following Neurotransmitters:

Examples Adrenergic agents: (3)

proposed and designated α and β adrenoceptors based on their apparent drug sensitivity.

a1 -receptors : (3)

a2- receptors : (5)

B-receptors:

Non-selective

b1-selective (2)

b2-selective (5)

postsynaptic α-receptor

presynaptic α-receptor

Were designated as those that were excitatory

-Present in skin and blood vessels
-As Nasal Decongestant and Vasoconstrictors
which causes hypertension

-Blocks α1A-receptor in prostate smooth
muscle and relax the muscle with implication of treating benign prostatic hyperplasia (BPH)
-Vasodilator and Hypotensive with clear implications of treating Hypertension

-Act at CNS sites to decrease sympathetic outflow to the periphery, resulting in decreased NE release at sympathetic nerve terminal and therefore relaxed vascular smooth muscle
-Treatment for Hypertension (e.g.Clonidine)

__ suggested that β-receptors could be subdivided into β1 and β2 types

Postsynaptic receptors :

-Causes  an increase in rate and force of contraction when β1 receptors in heart is activated
-should be expected to slow the heart rate and decrease the force of contraction
-Tx for Hypertension, Angina, and certain Cardiac Arrythmias

-Relaxes the smooth muscles in the bronchi,
thus dilating and opening airways.
-In uterus, it relaxes also the muscle and used to inhibit uterine contractions

Indirectly acting and sympathomimetic

Mechanism for removing the NE from the
synapse and terminating its action at the receptors. these mechanism include: (3)

•  Recycling the NE
•  Involves Na+ / Cl- dependent transmembrane (TM)
•  This reuptake system also transports
certain amines other than NE into the nerve terminal, and can be blocked by
such drugs

• Extraneuronal uptake process
• Play a role in disposition of circulating CA’s

• Second mechanism of CA removal

Second enzyme of importance in the metabolism of Cas

-   first enzyme of importance in the metabolism
of Cas in the adrenergic neurons of human brain
- Oxidatively deaminate Cas to the corresponding acid by the enzyme aldehyde
dehydrogenase(AD)

Two types of MAOs

major end product of several pathways of NE
metabolism

– major metabolite of brain DA
- Methylhydroxyphenylglycoaldehyde (MOPEG) is indicative of NE levels

- Used for preoperative management of PHEOCHROMOCYTOMA

Metyrosine
- Lowers CA production by __ - __ %
- Given orally ranging ___ grams / day

chromaffin cell tumor that produce large amounts of NE and E

Side effects of  Metyrosine

- Depletes the vesicle storage of NE
- Depletes the storage of serotonin and DA in their respective neurons in the brain
- Blocks the VMAT that transports NE and other biogenic amines from the cytoplasm in to the storage vesicles

Reserpine

Reserpine is an indole alkaloid obtained from the root of

- Used orally as active antihypertensives
- They both accumulate within the neuronal storage vesicles.
- They bind to the storage vesicles and stabilize the neuronal storage vesicle membranes, making them less responsive to nerve impulses

Guanethidine contains 2 basic nitrogen atoms with pKa __ and __

Guanethidine forms into:

Guanethidine is:
Absorbed orally %
Half-life of about

- Treat moderate-to-severe hypertension
- Orally absorbed
- Half-life

• produce effects resembling those produced by stimulating of the sympathetic NS
• Produce effect through Direct, Indirect, Mixed mechanism of action

- Elicit a sympathomimetic response by interacting directly with adrenergic receptor

- Maximal activity is seen in B-phenylethylamine derivatives contantaining cathecol and a –OH group on the ethylamine portion of the molecule

- Critical factor in the interaction of adrenergic agonists with their receptors is stereoslectivity

- the greatest adrenergic activity occurs when 2 carbon atoms separate the aromatic ring from the amino group

- Stereoselectivity is based on the presumed interaction of these 3 critical pharmacophoric groups with 3 complementary binding areas on the receptor and is known as the __________

-this is important for direct agonist activity because replacing nitrogen with carbon
results in a large decline in activity

- Substitution by small alkyl group (e.g. CH3 or C2H5)
- It helps the increase of the resistance to metabolism and lipophilicity

- generally decreases CNS activity largely because it lowers lipid solubility
- greatly enhances agonist activity at both a and b receptor

- it can bring about selectivity at a-receptors as it appears that the cathecol moiety is more important for a2 activity than for a1 activity

- it can bring about selectivity at a-receptors as it appears that the cathecol moiety is more important for a2 activity than for a1 activity

- If it lacks OH groups on the ring and the B-OH group in the side chain act almost exclusively by causing the release of NE from sympathetic nerve terminals and thus results
to direct sympathomimetic activity.

- it increases the blood flow to the kidney and enhances the glomerular filtration rate
- Increase cardiac output
- Immediate precursor of NE and is a central NT particularly
- important in the regulation of movement

- It is used to counteract various hypotensive crises because a-activity raises BP and as an adjunct treatment in cardiac arrest because its B-activity stimulates the heart.

- It is used in aqueous solution for inhalation as the free amine
- Stimulates the heart in cardiac arrest
- Differs from NE only by the addition of
an N-methyl group

prodrug of Epinephrine

- Differs from E only in lacking a p-OH group
- Orally active and its DOA is about twice that of E
- Potent vasoconstrictor
- Treatment of severe hypotension

- It is bioactivated by O-demethylation to an active m-phenolic metabolite
- Slows the ventricular rate because of activation of the carotid sinus reflex
- It has cardiac stimulatory properties

- It has vasoconstrictor properties
- Treatment of symptomatic orthostatic hypotension

-  Exhibit vasoconstrictive  as a result of stimulation of peripheral a-receptors
-  Much longer lasting hypotensive effect
-  It providesbeneficial effects in several other situations including glaucoma, spasticity,
migraine prophylaxis, opiate withdrawal syndrome and anaesthesia

- Does not cross Blood Brain Barrier
- Produces hypotension and sedation
- Selective a2 agonist
- It is used specifically to control elevations in intraocular pressure that can occur during laser surgery on the eye
- First line tx ofglaucoma

- It is much more selective a2 agonist
- Lower intraocular  pressure by reducing aqueous humor production and increasing uveoscleral outflow

- The bridge of this compound is a –CH=N- group
- Same with Guanfacine, conjugation of the quanidino moiety with the bridging noiety helps to decrease the pKa of the basic group, so that at physiological pH a significant portion of each drug exists in its nonionized form.

- The bridge is –CH2CO- moiety
- CNS penetration and
high bioavailability (>80%)
- It is more selective for a2 receptor than clonidine

-  Differs structurally from L-dopa only in the presence of a a-methyl group
-  Ultimately decreases the concentration of DA, NE, E and serotonin in the CNS and periphery
- Originally synthesized as an AADC inhibitor
- Affected by food (about 40%) and converted to methyldopa-O-sulfate

• Act by releasing endogenous Norepinephrine.

• Enter nerve ending by way of the
active-uptake process and displace norepinephrine from its storage granules.

• It differs from amphetamine in the presence
of p-OH group and so it has little or no CNS-stimulating action.
• Used for diagnostic eye examinations and for surgical procedures on the eye.
• Sometimes used with cholinergic blocking
drugs like atropine.

• Produces vasoconstriction and a decongestant
effect on the nasal membranes and produces fewer side effects on CNS.
• Major use is for a local vasoconstrictive
effect on nasal mucosa in the symptomatic relief of nasal congestion caused by
common cold, allergic rhinitis, or sinusitis.
• Aromatic ring has been replaced with a cyclohexane
ring.

•  Diasterior of ephedrine.
•  Acts mostly by indirect mechanism and has
virtually no direct activity.
• Lack of direct activity affords fewer CNS
effects than does ephedrine.

• Although it is less prone to increase blood
pressure than ephedrine, it should be used with caution in hypertensive individuals, and it should not be used in combination with MAO inhibitors

L- (+)-Pseudoephedrine is a naturally occuring alkaloid from _____ species

•  Drug acts on both α- and ß-receptors.
•  Lacking H-bonding phenolic OH groups,
ephedrine is less polar.
• Drug is metabolized by either Mao or COMT and therefore has more roal activity and longer DOA than E.

Ephedrine has two asymmetric carbon atoms;
thereby creating four optically active isomers.

Erythro racemate is called

Threo racemate is called

- Used locally to constrict the nasal mucosa
and cause decongestion and to dilate the pupil or the bronchi.
- Effective for asthma, hay fever, and
urticaria.

plant containing ephedrine, was known to the Chinese in 2000 BC but ephedrine was not
isolated until 1885.

Slightly higher vasopressive action and lower central stimulatory action than ephedrine.

- Used parenterally as a vasopressor in the treatment and prevention of the acute
hypotensive state occuring with spinal anesthesia.

—- Used to treat severe hypotension brought on by other traumas that induce shock.

Nonselective  α-blockers

is used to treat Raynaud syndrome and other peripheral vasospasm

- used to prevent/control hypertensive episodes. In combination with papaverine, it is used to treat impotence.

- Agents in this class, when given in adequate doses, produce a slowly developing, prolonged adrenergic blockade that is not overcome by Epinephrine.

- Old but powerful α-blocker, is a haloalylamine that blocks α1- and α2- receptors irreversibly.

- It is capable of blocking acetylcholine, histamine, and serotonin receptors, its
primary pharmacological effects, especially that of vasodilation, may be attributed to its α-adrenergic blocking capability.

—- Administration is frequently associated with tachycardia, increased cardiac output and
postural hypotension.

- Onset of action is slow, but the effect of single dose of drug may last 3 to 4 days.

—- Principal peripheral effects following its administration are an increase in systemic
blood flow, increase in skin temperature, and a lowering of blood pressure.

—- It has no effect on parasympathetic system and little effect on the gastrointestinal tract.

—- Most common side effects are miosis, tachycardia, nasal stuffiness and postural
hypotension.

Selective α1-blockers

- They are quinazoline α1-blockers.

-These drugs dilate both arterioles and veins and are used in the treatment of
hypertension.

-They produce peripheral vasodilation without an increase in heart rate or cardiac output

selective a1 blockers are consist of three components:

Yohimbine is an indole alkylamine alkaloid and is found in the bark of the tree ___________ and in _____ root.

Yohimbine is a selective __ -blockers;
Corynanthine is a selective __ -blocker.

increases heart rate and blood pressure as a result of its blockade of α2-receptors in the CNS. It has been used experimentally to treat male erectile impotence.

◦  Used as antidepressant.

◦  It is a potent blocker of 5-HT2 and 5-HT3, serotonin receptors and at histamine H1-receptors.

• First ß-Blockers

• Was reported in 1958 by Powell and Slater

•  Unfortunately, not a pure antagonist but a partial agonist.

It had much less intrinsic sympathomimetic activity (ISA) than DCI, it was withdrawn from clinical testing because of reports that it caused thymic tumors in mice.

- One of the most thoroughly studied and widely used drugs in the therapeutic armamentarium.

—- It is the standard against which all other ß-blockers are compared.

—- belongs to the group of ß-blockers known as aryloxypropanolamines

- prototypical

—- nonselective ß-blocker.

—- It blocks the  ß1 and ß2 receptors with
equal affinity, lacks ISA, and does not block α –receptors

- is approved for use in the United States for hypertension, cardiac arrhythmias,
angina pectoris, postmyocardial infarction, hypertrophic cardiomyopathy,
pheochromocytoma, migraine prophylaxis, and essential tremor.

is also used in the long-term management of angina pectoris.

use in the prophylaxis of migraine headaches and in the therapy following
myocardial infarction.

used as an antiarrhythmic in treating ventricular arrhythmias and atrial fibrillation

are used topically to treat open-angle glaucoma

possesses modest membrane-stabilizing activity and significant intrinsic  ß-agonistic activity.

have half-life values in the same range as Propranolol.

undergoes very little hepatic metabolism and most of this drug is excreted unchanged in
the urine.

Cardioselective  ß-blockers should provide two important therapeutic advantages.

are also approved for use in treating angina
pectoris and in therapy following myocardial infarction.

is the only  ß1-selective blocker indicated
for the treatment of glaucoma.

was designed specifically to possess a very short DOA; it has an elimination
half-life of 9 minutes. Its effects disappear within 20 to 30 minutes after the
infusion is discontinued.

are also indicated for treating certain cardiac arrhythmias.

with a half-life ranging between 14 and 22 hours,has the longest DOA of the
ß1-selective blockers

is absorbed well from the gastrointestinal tract, but it undergoes extensive
first-pass metabolic conversion to diacetolol by hydrolytic conversion of the amide.

- Phenylethanolamine derivative, is representative of a class of drugs that act as competitive blockers at α1-, ß1-,and ß2-receptors.

- more potent  ß-blocker than α-blocker.

— - clinically useful antihypertensive agent.

—- The rationale for its use in the management of hypertension is that its α-receptor–blocking effects produce vasodilation and its α-receptor–blocking effects prevent the reflex tachycardia usually associated with vasodilation

—- ß-blocker that possesses α-blocking activity.

—- Its ß-blocking activity is 10- to 100-fold of its α-blocking activity.

- Possesses antioxidant activity and an anti-proliferative effect on vascular smooth muscle cells.

- It has a neuroprotective effect and the ability to provide major cardiovascular
organ protection.

—- Used in treating hypertension and congestive heart failure.