Medicinal Chemistry Unit -2.pptx

Medicinal Chemistry - I
B. Pharma
4th Semester
Unit – 2nd
Prepared by –Nikita Gupta
(Assistant Professor)

Chapter- 1
Drugs acting on Autonomic
Nervous System

NERVOUS SYSTEM
The nervous system provides the body with a rapid means of
internal communication that allows us to move about, talk,
and coordinate the activity of billions of cells. Thus, neural
activity is critically important in the body’s ability to maintain
homeostasis.

The nervous system is a complex network of nerves and cells that
carry messages to and from the brain and spinal cord to various parts of
the body.
The Central nervous system is made up of the brain and spinal cord
and
The Peripheral nervous system is made up of the Somatic and the
Autonomic nervous systems.

SOMATIC SYSTEM:
the somatic system; there is NO ganglia here but the fibers that come
from the CNS to the skeletal muscles forming neuromuscular junctions
that release acetylcholine as neurotransmitter & stimulate receptors
which are referred to as Nicotinic receptors.

AUTONOMIC NERVOUS SYSTEM (A.N.S.)
Autonomic Nervous System is a peripheral complex of nerves,
plexuses and ganglia that are organized to modulate the
involuntary activity of the secretory glands, smooth muscles and
visceral organs. This system functions to sustain homeostatic
conditions during periods of reduced physical and emotional
activity, and equally important, to assist in internal bodily
reactions to stressful circumstances.

It is classically divided into two subsystems:
1) SYMPATHETIC NERVOUS SYSTEM:
Allow body to function under stress
Fight or flight
Primes body for intense skeletal muscle activity

2) PARASYMPATHETIC NERVOUS SYSTEM:
Maintenance functions
Rest-and-digest
Counterbalances sympathetic function

A) Sympathetic Division: Epinephrine, norepinephrine and dopamine
are the principle neurotransmitters present in the sympathetic nervous
system. In many cases, synaptic transmission may be mediated by the
release of more than one neurotransmitter. Dopamine is a predominant
transmitter in the human extrapyramidal system, mesocortical and
mesolimbic neuronal pathways.

The first evidence for norepinephrine as a principal neurotransmitter
in ANS was given by Euler in 1946. The sympathetic system is
distributed to effector cells throughout the body. It is also called as
thoracolumbar division.

B) Parasympathetic Nervous System: Acetylcholine is the
neurotransmitter which propagates impulse transmission in the
parasympathetic division. Besides this, acetylcholine also functions as
a neurotransmitter in,
(i) Motor nerves to skeletal muscles and
(ii) Certain neurons within CNS.

Chapter- 2
Adrenergic Neurotransmitters:
Biosynthesis and catabolism of
catecholamine. Adrenergic
receptors (Alpha & Beta) and
their distribution.

 ADRENERGIC NEUROTRANSMITTERS
An adrenergic nerve fiber is a neuron for which the neurotransmitter
is either adrenaline (epinephrine), noradrenaline or dopamine. These
neurotransmitters are released at a location known as the synapse,
which is a junction point between the axon of one nerve cell and the
dendrite of another.

• Naturally occur in our body
• Both Agents that activate adrenergic receptors are called
Sympathomimetics
• The agents that block the activation of adrenergic receptors are called
Sympatholytics

Adrenergic Neurotransmitters are 3 types -
Collectively called catecholamines.
1. Noradrenaline (NA) - at postganglionic sympathetic sites(except
sweat glands, hair follicles) & in certain areas of brain.
2. Adrenaline(Adr) - secreted by adrenal medulla
3. Dopamine(DA)- transmitter in basal ganglia, limbic system, CTZ,
anterior pituitary

• L-Phenylalanine is converted into L-tyrosine by an aromatic amino acid
hydroxylase (AAAH) enzyme (phenylalanine 4-hydroxylase), with
molecular oxygen (O2) and tetrahydrobiopterin as cofactors.
• L-Tyrosine is converted into L-DOPA by another AAAH enzyme
(tyrosine 3-hydroxylase) with tetrahydrobiopterin, O2, and ferrous iron
(Fe2+) as cofactors.
• L-DOPA is converted into dopamine by the enzyme aromatic L-amino
acid decarboxylase (AADC), with pyridoxal phosphate as the cofactor.

• Dopamine itself is also used as precursor in the synthesis of the
neurotransmitters nor epinephrine and epinephrine.
• Dopamine is converted into nor epinephrine by the enzyme dopamine β-
hydroxylase (DBH), with O2 and Lascorbic acid as cofactors.
• Nor epinephrine is converted into epinephrine by the enzyme phenyl
ethanolamine N-methyltransferase (PNMT) with S-adenosyl-L-
methionine as the cofactor.

 Metabolism of neurotransmitter:
• Endogenous & exogenous catecholamines are metabolized mainly
by two enzymes, monoamine oxidase & catechol-O-methyl
transferase (COMT).
• MAO occurs within cells bound to surface membrane of
mitochondria, abundant in noradrenergic nerve terminals.

• COMT a widespread enzyme that occurs in both neuronal and
nonneuronal tissues, acts on both catecholamines & its deaminated
products, produced by action of MAO.
• Main final metabolite of adrenaline & noradrenaline is 3-
methoxy- 4-hydroxymandelic acid (VMA).

 Catabolism of Catecholamine
• Catecholamines are deactivated by L-monoamine oxidase (MAO)
and Catechol-O- methyltransferase (COMT) leading to synthesis of
homovanillic acid (from dopamine) or vanillylmandelic acid from
norepinephrine or epinephrine. Alternatively, as shown for dopamine
metabolism order of reaction may be change with COMT acting first
followed by MAO.

 ADRENERGIC RECEPTORS ( α AND β) AND THEIR
DISTRIBUTION
The adrenergic receptors or adrenoceptors are a class of G protein-
coupled receptors that are targets of many catecholamines like
norepinephrine (noradrenaline) and epinephrine (adrenaline) produced by
the body, but also many medications like beta blockers, β2 agonists and
α2 agonists, which are used to treat high blood pressure and asthma.

• Many cells have these receptors, and the binding of a catecholamine to
the receptor will generally stimulate the sympathetic nervous system
(SNS).
• The SNS is responsible for the fightor-flight response, which is
triggered by experiences such as exercise or fear-causing situations.

• This response dilates pupils, increases heart rate, mobilizes energy,
and diverts blood flow from non-essential organs to skeletal
muscle.
• These effects together tend to increase physical performance
momentarily.

Chapter -3
Sympathomimetic agents: SAR of Sympathomimetic agents
Direct acting: Nor-epinephrine, Epinephrine, Phenylephrine*,
Dopamine, Methyldopa, Clonidine, Dobutamine, Isoproterenol,
Terbutaline, Salbutamol*, Bitolterol, Naphazoline, Oxymetazoline
and Xylometazoline.
Indirect acting agents: Hydroxy amphetamine, Pseudoephedrine,
Propylhexedrine.
Agents with mixed mechanism : Ephedrine

 SYMPATHOMIMETIC AGENTS
• Sympathomimetic drugs are stimulants compound which mimic the
effect of endogenous agonist of the sympathetic nervous system.
• Drug can make the action partially or completely or it may also be
defined as the substance which sympathetic system is known as
sympathomimetic agent or sympathomimetic drugs Sympathomimetic
agent.

Classification of sympathomimetic agent
1. Direct acting
2. Indirect acting
3. Mixed acting

 SAR OF SYMPATHOMIMETIC AGENTS
SAR- Structure activity relationship
SAR:- It is define as the relationship between the chemical structure of a
molecule and its biological activity.
This allows modification of the effect or the potency of a bioactive
compound(typically a drug) by changing its chemical structure.
Many of the sympathomimetic drugs contain β-phenyl ethylamine as
parent structure.
phenyl ethylamine

Structurally, substitution or modification is occur on:
Catechol or aromatic ring
β- Carbon
α- Carbon
Amino group
β – Hydroxyl group
 Phenyl ring substitution-
1. The modification of β-phenylethylamine influence not only the
mechanism of action, the receptor selectivity but also their absorption,
oral activity, metabolism and thus duration of action(DOA).

2. Naturally occurring catecholamine is active at both α and β receptor
but have a poor oral activity as it is rapidly metabolized by COMT.
Thus the change in position of hydroxyl group from meta and Para
position gives a drug with good metabolic activity.
3. When hydroxy group is adjacent with meta position then α2 agonist
activity of the drug increase.

4. When hydroxy group is replaced by methoxy group then the β2
activity of the ring will increase. 4. When we increase the chain
length of the hydroxy group then the α2 activity increase and β2
activity decrease.
5. When both hydroxy group will remove from the aromatic ring, then
they will easily cross BBB and have more CNS activity.
e.g. Amphetamine.

 β- Hydroxyl Group
The β carbon contain one hydroxy group and β carbon is the
asymmetric carbon that means it is a chiral compound.
When this chiral compound exist is ‘R’ form its activity is 100% or
activity increase.
When this chiral compound exist is ‘S’ form its activity is decrease.

 α- Carbon
When in the α- carbon, the hydrogen is replaced by methyl group
and the chain length then the bulkiness of the compound is increase
then the activity of the compound is decreased.

 Amine Group
Amine group is the deciding factor for the activity of catecholamine.
When amine group is Primary and secondary in nature then the α-
activity is increase and β- activity is decrease. i.e.
Epinephrine(Adrenaline)
When amine group is Tertiary and quaternary in nature then the α-
activity is decrease and β- activity is increase.
.More the size of alkyl substituent, higher will be β- activity and lower
The α- activity.
i.e. Isoprenaline, Solbutamole.

 Direct acting sympathomimetic agent
• They act through complexation with specific receptors they are
represented by noradrenaline for the activation of beta receptor
phenolic hydroxy function in meta at the catechol nucleus and at the
side chain Hydroxide in beta and Amine especially the phenolic
hydroxyl seems to be relatively more critical for activation of beta
receptors.

These are those drugs and Agents which directly bind with
adrenergic Receptors(Both α and β) and gives its Pharmacological
action.
The action produced are of rapid onset and of short duration.

1. Nor-epinephrine
• Chemical formula: C8H11NO3
• Mol. Mass : 169.18 g/mol

Properties:
It is a white or brownish-White, crystalline powder, slightly soluble in
ethanol and soluble in water.
Mechanism of action:
Potent at α- receptor.(Less potent adrenalins).
Also effect on β1- receptor but no effect on β2- receptor.

Uses :
Strong Vasoconstriction properties. So it is used in local anaesthetic
solutions for dental use.
Reduced the absorption and to localize the effects of local anastetics.
Intravenous infusion for the treatment of hypotension.
Its principle use is to support blood in various acute hypotensive
states, especially in myocardial shock.

Storage:
It becomes colored on exposure to air and light. It should be
stored in well-closed airtight containers, under an inert gas and
protected from light.

2. Epinephrine
Adrenaline is a catecholamine and belongs to the family of
biogenic amines.
Chemical formula: C9H13NO3
Mol. Mass : 183.204 g/mol

Properties:
It is a white or creamy white, sphaero-crystalline powder.
It dissolves in solutions of mineral acids, potassium hydroxide, and of
sodium hydroxide, but sparingly soluble in water, insoluble in ethanol and
ether.
It directly bind with α1 and β1 and β2 receptor.(Potent for all)
It given by oral route in the form of pro-drug (Pivalic acid) to prevent
first pass metabolism.

Uses :
It is used as a sympathomimetic, broncholytic, and anti-asthmatic.
It is used to prevent bleeding during surgery or in case of inner organ
bleeding. Because adrenaline leads to constriction of blood vessel.
It is administered in combination with local anesthetics.
In this combination, anesthetics have long-lasting effect and can be
administered in smaller doses.

It is used in the treatment of heart block or circulatory collapse and
open-angle glaucoma.
It is usually the drug of choice in acute allergic disorders and histamine
reactions.
In emergency treatment of anaphylaxis and anaphylactic shock in the
cardio pulmonary disease.

Storage:
Epinephrine is light sensitive and easily oxidized on exposure to air
because of the catechol ring system.
The development of a pink to brown colour indicates oxidative
breakdown.
To minimize oxidation, solutions of the drug are stabilized by the
addition of a reducing agent. Ex- sodium bisulphite.
Adrenaline should be stored in well-closed airtight containers, which is
preferably filled with nitrogen, and protected from light.

3. Phenylephrine
Phenylephrine is available as hydrochloride salt.
Molecular formula: C9H14NO2CL
Molecular Weight: 203.67

Properties:
It is a white, odorless, bitter taste, crystalline powder.
It is soluble in water, alcohol, and glycerol.
Bind at α1 receptor.
No action on β receptor
Storage:
It should be stored in airtight container to protect from light

Synthesis:
Phenol with 2-chloro acetyl chloride gives 2-chloro -1[3-hydroxy
phenyl]ethanone.(M-Chloroacetylphenol)
2-chloro -1[3-hydroxy phenyl] ethanone react with NH2CH3 it gives
1-(3- hydroxyphenyl)2- (methyl amino) ethanone.
1-(3-hydroxyphenyl)2- (methyl amino) ethanone under go reduction
reactions (addition of hydrogen) to form Phenylephrine.

Uses:
Phenylephrine is a selective α1-receptor agonist. Oral absorption is not
reliable and so it is given parenterally or topically as eye or nasal drops.
Phenylephrine predominantly acts on peripheral arterioles results in a
rise in systolic and diastolic pressures accompanied by a marked reflex
bradycardia.
Phenylephrine is used as a nasal decongestant, mydriatric and as a
vaso-pressor agent.
Vasoconstriction of arterioes, Iris and constriction of Uterus.
Increase blood pressure in acute hypotension.

4. Dopamine
It is a neurotransmitter that helps to regulate movement And emotional
response.

Properties:
It is a white or almost white crystalline powder, soluble in alcohol,
sparingly soluble in acetone and methylene chloride, but freely soluble in
water.
It is directly stimulate β1 and α1 receptor.(Dual acting Drug)
Storage:
It should be stored in well- closed airtight containers, protected from
light.

Uses:
It is used in the treatment of shock.
It increases blood flow to the Kidneys
Dopamine exerts the CVS effects by interacting with D1-dopaminergic
receptors especially in the renal, mesenteric, and coronary beds.
It is also used in heart attack ,trauma, surgery and other serious
medical condition.

5. Methyldopa

Properties:
Methyldopa is a white to yellowish white, odorless fine powder,
and is soluble in water.
Methyldopa is converted into α- methyl nor-epinephrine by enzyme
dopamine beta hydroxylase and bind with α2.

Uses:
This medication is used alone or with other medications to treat high
blood pressure.(Hypertension)
Lowering blood pressure helps to prevent strokes, heart attacks and
kidney problems.
Storage: It should be stored in well- closed airtight containers, protected
from light.

6. Clonidine
Molecular weight: 0.093 g/mol
Chemical Formula: C9H9Cl2N3

Properties:
Clonidine is an imidazole derivate that acts as an agonist of
alpha-2 adreno receptors.
It is centrally acting on α2 receptor.

Uses:
It is used in the treatment of hypertension, nasal decongestant, open
eye glaucoma.
It is a potent sedative-hypnotic drug and can prevent post-operative
shivering.

7. Dobutamine
It is a synthetic catecholamine.
Molecular Formula: C22H29NO9
Molecular Weight: 451.5 mol

Properties:
It is a white or almost white crystalline powder, sparingly soluble
in water and alcohol and soluble in methanol.
It directly stimulate β1 as well as α1 receptor.(Dual acting drug)

Uses:
It is used in ICU for the treatment of congestive Heart failure,
Cardiogenic shock, pulmonary oedema and to increase cardiac output.
Storage:
It should be stored in well-closed airtight containers, protected from
light.

8. Isoproterenol (Isoprenaline)
Isoproterenol hydrochloride is a recent compound. It is a non selective and
synthetic catecholamine.
Molecular Formula: C11H17NO3.ClH or C11H18ClNO3

Properties:
It is a white or almost white crystalline powder, freely soluble in
water, sparingly soluble in alcohol, practically insoluble in methylene
chloride.
It is a nonselective β agonist and has strong β1 and β2 agonist
activity.
β1- Increase cardiac output
β2- Increase bronchodilation.

Uses:
Its primary use is in the treatment of bronchial asthma.
It is used as an antiarrhythmic agent and in the treatment of shock to
increase heart rate.
It is a CNS stimulant and peripheral vasodilator.
Storage:
light.

9. Terbutaline
Terbutaline is a non- catecholamine therefore is resistant to COMT.
Molecular Weight: 225.288 g·mol−1

Properties:
It exists as a gray-white crystalline powder, odorless and with a bitter
taste, soluble in water and alcohol.
It bind with β2 receptor.
It is better than Isoprenaline drug.
Storage:
light.

Uses:
Terbutaline is a brochodialator medicine that is used to treat
symptoms such as Wheezing, shortness of breath, chest tightness,
breathing difficulties, coughing etc. associated with asthma.
It is used to treat an acute attack of asthma as well as for prevention
of futher asthma attacks.

10. Salbutamol

Directly bind with β2 receptor.(Selective β2 agonist)
Properties:
It is a white or almost white crystalline powder, sparingly soluble in
water, but freely soluble in ethanol.

Uses:
It is useful in the treatment of acute myocardial infarction, severe left
ventricular failure.
It has been used to arrest premature labor and is effective in ocular
hypotension by topical application.
It is used only as a bronchodilator and is the drug of choice in the
treatment of bronchial asthma.
It is also used to treat emphysema.(A condition that involves damage
to the walls of the air sacs i.e alveoli of lungs)

Storage:
light.
Dose:
By oral inhalation the adult dose is 100 microgram, followed by a
second dose after 5 min, if required.

11. Bitolterol
It is a new β2 adrenergic agonist.
Molecular formula: C28H31NO5
Molecular mass: 461.558 g·mol−1

Properties:
Bitolterol is consider as a pro drug for colterol.
Directly bind with β2 receptor.(Selective β2 agonist)

Uses:
Bitolterol is used as its methane sulfonate salt for relief of
bronchospasm in conditions such as asthma, chronic bronchitis and
emphysema.
Storage:
light.

12. Naphazoline
It is a rapid and direct acting sympathomimetic drug and exist in
an ionised form.
Chemically it is 2-(1- naphthylmethyl)-2- imidazoline and an
imidazoline derivatives.
Molecular Formula: C14H14N2
Molar Mass: 210.28 g/mol.

Properties:
It is a white crystalline, odourless, and bitter compound.
The salt is soluble in water and in alcohol.
They essentially exist in an ionized form at physiological pH because
of the very basic nature of the imidazoline ring (pKa 9 to 10).
It is a powerful α – receptor stimulant.(Both α1 and α2)

Uses:
Mostly used as a local vaso - constrictor for the relief of nasal
congestion due to allergic or infarction manifestations.
It is also employed as an ophthalmic solution for the relief of ocular
congestion(swollen eyelids and eyes sensitive to bright light) and
blepharospasm(Eye twitching).

Storage:
light.
Dose:
For nasal mucosa, 2 drops of 0.05% solution; for conjunctivitis, 1 to
2 drops of a 0.1% solution after every 3 to 4 hours.

13. Oxymethazoline
It is a direct acting sympathomimetic drug.
Chemically it is 3-(4,5-dihydroxy-1H-imidazol-2-yl methyl)-
2,4- Dimethyl-6-tert-butyl Phenol.
Chemical Formula: C16H24N2O
Molecular Weight: 260.37456 g/mol

It is bind with both α1 and selective α2 Receptor.(It stimulates the
blood vessels of nose)
Uses:
It act as a decongestant during the allergy or infection of the nasal
passage.
Dose: By intranasal, 1 drop of a 0.1% solution in adult; or a spray of
0.05% solution.

14. Xylomethazoline
It is a direct acting sympathomimetic drug.
Chemically it is 2-[(4-tert-butyl-2,6-dimethyl phenyl)methyl]-4,5
dihydro-lH-imidazole.
Molecular Formula: C16H24N2

It is partially agonist at α 2 and selective agonist at α1 Receptor.
Dose: By intranasal, 1 drop of a 0.1% solution in adult; or a spray of
0.05% solution .

Uses:
It is found to act as a vasoconstrictor, when applied topically to
mucous membranes particularly.
It is frequently employed as a local vaso-constrictor for nasal
congestion caused by sinusitis or rhinitis.(Otrivin)

INDIRECT ACTING
Indirect acting sympathomimetic drugs are those that act indirectly
to increase the concentration of endogenous neurotransmitter by
release of endogenous NE.
These drugs enter the nerve ending by active uptake and displace NE
from its storage granules.

1. Hydroxyamphetamine
 Hydroxyamphetamine is indirect acting sympathomimetic agents
and derivatives of Amphetamines.
 It is chemically 4-(2- amino propyl)Phenol.
Chemical formula: C9H13NO

Properties:
It is a white powder freely soluble in water.
Indirectly acting sympathomimetics agent which causes the release
of nor epinephrine from adrenergic nerve terminals.

Uses:
It is asympathomimetic and anticholinergic combination and relaxes
muscles of the eye by dilating the pupil(mydriasis).
In narcolepsy (sudden attack of sleep in completely inappropriate
situations).
It is used in children with hyperkinetic syndrome.
It act an anorexiant(Drug that act on the brain to suppress appetite) in
the treatment of obesity.

2. Pseudoephedrine
It is an optically active isomer of Ephidrine.

It is stimulates both α and β receptors.
It stimulates CNS.
Uses:
It is used as vasoconstrictor to treat nasal and sinus congestion of
tubes that drain fluid from your inner ears.
It increases the blood pressure(Hypertension) by increasing cardiac
output and by causing vasoconstrictor.

3. Propylhexedrine
It is chemically (±)- 1- cyclohexyl-N-methypropan-2-amine.
Chemical formula: C10H21N

It is stimulates α-receptors in the mucosa of respiratory tract.
Same action shown as epinephrine and nor-epinephrine.
Uses:
It is used for the relief of congestion due to cold, allergies and allergic
rhinitis(Inflammation of mucous membrane of nose) and its euphoric
effects.

MIXED ACTING DRUG
Mixed acting sympathomimetic drugs are those causes activation of
adrenergic receptors by both direct binding as well as endogenously
stored nor-epinephrine from pre-synaptic terminals.

1. Ephedrine
It is chemically 4-(2- amino propyl)Phenol.
It occurs naturally. It has two asymmetric carbon atoms, so it has
four isomers.

It act both directly and Indirectly.
It stimulates both α and β receptor.

Uses:
It is used as bronchodialator, nasal decongestant,orthostatic
hypotension(condition in which your blood quickly drops when you
stand up from a sitting or lying position) or mysthenia gravis(a
neuromuscular disorder that causes weakness in the skeletal muscles).
It used in various allergic disease like hay fever (an allergic reaction
to pollen) and urticaria (A skin rash triggered by a reaction to food,
medicine or other irritants)

2. Metaraminol
Chemically it is 3-(-2-amino-1- hydroxy -propyl) phenol.

Properties:
It is a white crystalline powder and freely Soluble in water.
It act on both α and β receptor stimulates noradrenaline.
Uses:
It can be used parenterally as vasopressor in prevention of acute
hypertension state occurring with spinal anaesthesia.

Chapter -4
Adrenergic Antagonists

 DEFINITION:
Drugs that inhibits the functions of adrenergic receptors by blocking
the active site of receptors. This type of drugs prevent the interaction of
endogenous catecholamines like epinephrine, norepinephrine and
dopamine or sympathomimetics with the adrenergic receptors either α or
β are called as adrenergic antagonists.
Adrenergic antagonists are also called as sympatholytics or anti-
adrenergics or adrenolytic drugs or adrenergic blockers.

• An adrenergic antagonist is a drug that inhibits the function of
adrenergic receptors. There are five adrenergic receptors, which are
divided into two groups.
• The first group of receptors are the beta (β) adrenergic receptors.
There are β1, β2, and β3 receptors. The second group contains the
alpha (α) adrenoreceptors. There are only α1 and α2 receptors.
• Adrenergic receptors are located near the heart, kidneys, lungs, and
gastrointestinal tract. There are also α-adreno receptors that are
located on vascular smooth muscle.

• Mechanism of action
Adrenergic antagonists have inhibitory or opposing effects on the
receptors in the adrenergic system. Administration of an adrenergic
antagonist that specifically targets the beta receptors, results in this
decrease in blood pressure by slowing or reducing cardiac output.

 CLASSIFICATION
Adrenergic antagonists are classified as :
1.Alpha adrenergic blockers:
Drugs which will bind to α receptor and block the stimulation activity.
Eg: Tolazoline, Phentolamine, Phenoxybenzamine, Prazosin,
Dihydroergotamine, Methysergide.

2. Beta adrenergic blockers: Drugs which will bind to β receptor and
block the stimulation activity.
Eg: Propranolol ,Metipranolol, Atenolol, Betaxolol, Esmolol, Metaprolol,
Labetolol, Carvedilol

Chapter -5
Alpha adrenergic blockers:
Tolazoline*, Phentolamine,
Phenoxybenzamine, Prazosin,
Dihydroergotamine,
Methylsergide

1. Tolazoline
Molecular mass: 196.67 mol
Molecular Formula: C10H13ClN2
ALPHAADRENERGIC BLOCKERS
1. Non-selective alpha - adrenergic antagonists

2. Phentolamine
Molecular mass: 281.352 g/mol
Molecular Formula: C17H19N3O

Tolazoline and phentolamine have both alpha 1 and alpha 2 blocking
activity and produce tachycardia. The blocking action of these agents at
presynaptic alpha 2 - receptors, contributes to their cardiac stimulatory
effects by enhancing release of NE.

 SAR:
1. The agents in this class are structurally similar to the imidazoline
alpha - agonist and the type of group attached to the imidazoline ring
dictates whether it is agonist or antagonist.
2. For alpha 1 - agonists SAR studies extensive molecular modelling
studies have been provided.
3. Phentolamine is more effective alpha- antagonists while the
antagonistic action of tolazoline relatively weak.

Therapeutic uses:
Tolazoline is used to increase blood flow in peripheral vasospastic
condition like Raynaud's syndrome. Tolazoline used in persistent
pulmonary hypertension of the newborn. Phentalomine is used to
prevent or control hypertensive episodes.
Adverse reaction:
Tachycardia increased gastrointestinal motility and hyperchlorhydria.

3. Phenoxybenzamine
Phenoxybenzamine is the only haloalkylamine in clinical use at present.
Molecular mass: C18H22ClNO
Molecular Formula: 303.83 g·mol−1

• They are irreversible blockers of alpha - adrenergic receptors.
Chemically it is a Beta - haloalkylamine produce a long lasting,
irreversible a - adrenergic blockade.
• Initial step involves the formation of an intermediate aziridinium ion
which will form reversible complex with the receptor.
• The positively charge aziridinium ion electrophile then reacts with a
nucleophilic group on the receptor resulting in the formation of
covalent bond between the drug receptor which will lead to alkylated
receptor.

Metabolism:
Phenoxybenzamine is very lipid soluble. It is metabolized (dealkylated)
in the liver and excreted in bile and urine. It causes local irritation and
therefore can only be administered intravenously or orally.
Therapeutic Uses:
Phenoxybenzamine is used to treat peripheral vasospastic conditions like
Raynaud's disease, used in treatment of hypertension.

Adverse Reaction: Side effects include nasal congestion,
bronchoconstriction and miosis, reflex tachycardia, congestive heart
failure, cerebral stroke or kidney failure.

2. Selective a- blockers
1. Prazosin
Prazosin is quinazoline alpha 1 - blocker. As a result of its greater alpha
1 - receptor selectively, the quinazoline class of a-blockers exhibits
greater clinical utility.
Molecular mass: C19H21N5O4
Molecular Formula: 383.401 g/mol

It has potent alpha 1 - adrenoreceptor blocking activity. It is potent and
effective antihypertensive agent and maybe usefully combined with the
beta- adrenoreceptor blockers, and thiazide diuretics.
Metabolism:
Prazosin is extensively metabolised by the liver and has high first-pass
metabolism and low oral bioavailability.

Therapeutic Uses:
Used in treatment of hypertension and heart attack. Also help to improve
urination flow rate.
Adverse Reactions:
Side effects of prazosin are nasal congestion, dizziness, tiredness, nausea,
drowsiness, blurred vision, orthostatic hypotension

2. Dihydroergotamine
Ergot is a parasitic fungus on rye and certain grains. Two major actions
of ergot alkaloids are : to stimulate smooth muscles and to block alpha-
adrenoceptors.
Molecular formula: C33H37N5O5
Molecular mass: 583.689 g·mol−1.

Dihydroergotamine increases the a - blocking potency and reduces the
smooth muscle stimulant activity.
Metabolism:
Metabolism of dihydroergotamine by a cytochrome P-450 similar to that
involved in the metabolism of macrolide antibiotics.

Therapeutic uses:
Dihydroergotamine used to treat migraine. The pain of migraine and
vascular headache is associated with vasodilation, odema,
hydroergotamine is effective due to its action on vascular smooth
muscle and should be given during vasoconstriction phase.

Adverse reaction:
Nausea is a common side effect of IV administration and less common
in other modes. Antiemetics can be given prior to DHE to counteract
the nausea. Risks and contraindications are similar to the triptans. DHE
and triptans should never be taken within 24 hours of each other due to
the potential for coronary artery vasospasm. DHE produces no
dependence. Vomiting blurred vision, nasal stiffness.

3. Methylsergide
It is structurally identical to methyl ergonovine except methyl group to
indole nitrogen. All ergot alkaloids are amide derivative of lysergic acid
but diethyl amine lysergic acid produce profound hallucinatory effect.
Molecular formula: C21H27N3O2

Methylsergide interacts with serotonin (5-HT) receptors. Its therapeutic
effect in migraine prophylaxis has been associated with its antagonism at
the 5-HT2B receptor. It is an antagonist at the 5-HT2C receptor, while at
the 5-HTIA receptor it serves as a partial agonist. It is known to have partial
agonist effects on some of the other 5-HT receptors as well.
It antagonizes the effects of serotonin in blood vessels and gastrointestinal,
smooth muscle, but has few of the properties of other ergot alkaloids.

Metabolism:
Methylsergide is metabolized into methylergometrine in humans, which
is responsible for its psychedelic effects. The systemic availability of
Methylsergide was only 13%, most probably due to a high degree of
first-pass metabolism to methylergometrine
Therapeutic uses:
It is used to treat headache, carcinoid syndrome and serotonin syndrome.

Chapter -6
Beta adrenergic blockers : SAR of beta
blockers,
Propranolol*, Metibranolol, Atenolol,
Betazolol, Bisoprolol, Esmolol,
Metoprolol, Labetolol, Carvedilol

 BETA-ADRENERGIC BLOCKERS
Beta - blockers are among the most widely employed antihypertensive
and are also considered the first line treatment for glaucoma. Most of
the B-blockers are in the chemical class of aryloxypropanolamines. The
first B- blocker, dichloroisoproterenol was reported in 1958.

SAR of Beta-blocker
1. Dichloroisoproterenol differs from isoproterenol in that the agonist
directing 3'4-diOH groups have been replaced by two chloro groups but
DC1 is not a pure antagonist but partial agonist.
2. Propranolol is the standard against which all other B-blockers
compared. It consists of OCH2 group which incorporated between the
aromatic ring & the ethylamine side chain
3. OCH2 group is responsible for the antagonistic property of the
molecules.

4. The aryl group also affects the absorption, excretion & metabolism of
B-blockers.
5. The nature of the aromatic ring is also a determinant in their Beta 1
selectivity.
6. One common structural feature of many cardioselective Beta-blocker
is the presence of a para substitution of sufficient size on the aromatic
ring along the absence of meta substituents e.g. Proctolol
7. For B-blockers, the B-OH substituted carbon must be in the S
absolute configuration for maximal B-blocking activity.

8. Propranolol & most other B-blockers are used clinically as racemic
mixtures. The only exceptions are levobunolol, timolol & penbutolol with
which the (S) enantiomer is used.
9. The branched & bulky N-alkyl functional moieties such as ter-butyl,
iso-propyl etc. proved to be extremely vital for B-antagonistic activity.
10. The alcoholic function on side chain is an absolute necessary
requirement for its activity.
11. Isosteric replacement of the ethereal linkage (-O-) with moieties such
as CH, S or NCH3 found to be more or less detrimental.

1. Non Selective blockers
1. Propranolol
Molecular formula: C16H22ClNO2

It is prototypical & non selective p-blockers. It blocks the beta 1 & Beta
2 receptors with equal affinity
SAR:
1. Lengthening of side chain prevent appropriate binding of required
functional group to same receptor site
2. Propranolol is the most lipophilic drug among the available B-
blockers.

Metabolism:
It undergoes extensive first pass metabolism one of the major
metabolite of propranolol is mephthoxylactic acid. It is formed by
metabolic reactions involving N- dealkylation, deamination &
oxidation of the resultant aldehyde.

Therapeutic uses:
Propranolol approved for use in angina pectoris, past myocardia
infarction, hypertension, cardiac, migraine prophylaxis & essential
tremor also used in CNS disorders.
Adverse reactions: Sleep disturbance like insomnia and nightmares.
Propranolol should be used with caution in people with:
Diabetes mellitus or hyperthyroidism since and symptoms of
hypoglycemia may be masked.

2. Metibranolol
Molecular Formula: CH3OH
Molecular Mass: 32.04 g/mol

Uses:
• It is used in polymers after getting converted to formaldehyde.
• It is used to produce hydrocarbons.
• It is used as a precursor for methyl ethers, methylamines, and methyl
halides.
• It is used as a fuel for internal combustion engines.
• It is an excellent energy carrier.
• It is used in wastewater plants.

• Although it is known that metipranolol binds the beta1 and beta2
adrenergic receptors, the mechanism of metipranolol's action is not
known.
• It has no significant intrinsic sympathomimetic activity, and has only
weak local anesthetic (membrane-stabilizing) and myocardial
depressant activity.
• It appears that the ophthalmic beta-adrenergic blocking agents reduce
aqueous humor production, as demonstrated by tonography and
fluorophotometry.

3. Atenolol
Molecular Formula: C14H22N2O3
Molecular Mass: 266.341 g·mol−1

It is a type of selective B1 receptors antagonist, a drug belonging to the
group of ß blocker used in treatment of cardiovascular diseases &
hypertension.
Metabolism:
Atenolol undergoes little or no metabolism by the liver and the absorbed
portion is eliminated by renal excretion Over 85% of intravenous dose is
excreted in urine within 24 hours compared with 50% for an oral dose.

Therapeutic uses:
Atenolol is used for a number of conditions including hypertension,
angina, long QT syndrome, acute myocardial infarction,
supraventricular tachycardia, ventricular tachycardia, and the symptoms
of alcohol withdrawal.
Adverse reactions:
Atenolol was the main B-blocker identified as carrying a higher risk of
provoking type 2 diabetes, leading to its downgrading in the United
Kingdom in June 2006 to fourth-line agent in the management of
hypertension.

4. Metoprolol

Metoprolol blocks Beta 1 adrenergic receptors in heart muscle cells,
thereby decreasing the slope of phase 4 in the nodal action potential
(reducing Na+ uptake) and prolonging repolarization of phase 3
(slowing down K+ release). It also suppresses the norepinephrine-
induced increase in the sarcoplasmic reticulum (SR) Ca2+ leak and the
spontaneous SR Ca2+ release, which are the major triggers for atrial
fibrillation

Metabolism:
It undergoes a-hydroxylation and O-demethylation as a substrate of the
cytochrome liver enzymes CYP2D6 and a small percentage by
CYP3A4, resulting in inactive metabolites.
Therapeutic uses:
It is used in treatment of hypertension, acute myocardial infarction,
angina supraventricular & ventricular tachycardia. It is also used in
treatment of migraine headaches & congestive heart failure.

Adverse reactions:
• Side effects, especially with higher doses, include dizziness,
drowsiness, fatigue, diarrhea, unusual dreams, trouble sleeping,
depression, and vision problems.
• Metoprolol may also reduce blood flow to the hands or feet, causing
them to feel numb and cold; smoking may worsen this effect. Due to
the high penetration across the blood-brain barrier, lipophilic beta
blockers such as propranolol and metoprolol are more likely than
other less lipophilic beta blockers to cause sleep disturbances such
insomnia and vivid dreams and nightmares.

2. Mixed alpha/beta Adrenergic Antagonist
5. Carvedilol
Molecular Mass: 406.482 g·mol−1.

6. Labetalol
Molecular Mass: 328.412 g·mol−1

Mechanism of action: Both drugs are antihypertensive with al, B1 & B2
blocking activity.
SAR
1. If we replace t-butyl or isopropyl group of alpha 1 -receptor agonist by
larger groups the agonistic activity decreases and antagonistic activity
increases.
2. Carvedilol has an estimated Beta blocking activity 10-100 times it's a-
blocking activity.
3. Labetalol has more potent Beta-antagonist than alpha-agonist & it has
two asymmetric carbon atoms & it exists as a mixture of four isomers.

Metabolism:
• Carvedilol is about 25% to 35% bioavailable following oral
administration due to extensive first-pass metabolism. The
compound is metabolized by liver enzymes CYP2D6 and CYP2C9
via aromatic ring oxidation and glucuronidation, and then further
conjugated by glucuronidation and sulfation.
• The three active metabolites exhibit only one tenth of the
vasodilating effect of the parent compound.

Therapeutic uses:
They are used in the treatment of hypertension, angina pectoris, cardiac
arrhythmia, glaucoma, congestive heart failure.
Adverse reactions:
Neurologic Headache, Dizziness
Gastrointestinal: Nausea, Dyspepsia
Cholinergic Nasal congestion
Respiratory: Dyspnea

7. Betazolol

Betaxolol selectively blocks catecholamine stimulation of beta (1)-
adrenergie receptors in the heart and vascular smooth muscle. These
results in a reduction of heart rate, cardiac output, systolic and diastolic
blood pressure, and possibly reflex orthostatic hypotension. Betaxolol
can also competitively block beta (2)-adrenergic responses in the
bronchial and vascular smooth muscles, causing bronchospasm.

Therapeutic uses:
This medication is used to treat high blood pressure. Lowering high
blood pressure helps prevent strokes, heart attacks, and kidney
problems. Betaxolol belongs to a class of drugs known as beta blockers.
It works by blocking the action of certain natural chemicals in your
body such as epinephrine that affect the heart and blood vessels.

8. Bisoprolol
Molar Mass: 441.51g/mol

• Bisoprolol is cardioprotective because it selectively and competitively
blocks catecholamine (adrenalin) stimulation of Beta 1 adrenergic
receptors (adrenoreceptors), which are mainly found in the heart
muscle cells and heart conduction tissue (cardiospecific), but also
found in juxtaglomerular cells in the kidney.
• Normally, adrenalin and noradrenalin stimulation of the Beta 1
adrenoreceptor activates a signalling cascade (Gs protein and cAMP)
which ultimately leads to increased contractility and increased heart
rate of the heart muscle and heart pacemaker,

Metabolism:
Bisoprolol exhibits a high absolute bioavailability (90%) because of its
nearly complete absorption (greater than 90%) and small first-pass effect
(10%). Bioavailability is independent of food intake.
Therapeutic Uses:
Bisoprolol is beneficial in treatment for high blood pressure
(hypertension), reduced blood flow to the heart (cardiac ischemia);
congestive heart failure, and preventive treatment before and primary
treatment after heart attacks, decreasing the chances of recurrence.
Bisoprolol targets hypertension (elevated blood pressure).

9. Esmolol
Chemical Formula: C16H25NO4

Mechanism of action
• Similar to other beta-blockers, esmolol blocks the agonistic effect of
the sympathetic neurotransmitters by competing for receptor binding
sites.
• Because it predominantly blocks the beta-1 receptors in cardiac
tissue, it is said to be cardioselective. In general, so-called
cardioselective beta-blockers are relatively cardioselective;
• at lower doses they block beta-1 receptors only but begin to block
beta-2 receptors as the dose increases.

Metabolism:
Esmolol is rapidly metabolized by hydrolysis of the ester linkage, chiefly
by cytosol of red blood cells and not by plasma cholinesterase or red cell
membrane acetylcholinesterase.
Therapeutic Uses:
To terminate supraventricular tachycardia, episodic atrial fibrillation or
flutter, arrhythmia during anaesthesia. To reduce HR and BP during and
after cardiac surgery and in early treatment of myocardial infarction.

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