Salbutamol, Phenylephrine, Clonidine & ANS

• Drugs Act on the Autonomic Nervous System

Adrenergic Neurotransmitters

• Includes biosynthesis and catabolism of catecholamine

Adrenergic Receptors

• Alpha and Beta receptors and their distribution are included in this category.

Sympathomimetic Agents

• SAR of Sympathomimetic agents are included

Direct-Acting Agents

• The following are examples:
  • Nor-epinephrine
  • Epinephrine
  • Phenylephrine*
  • Dopamine
  • Methyldopa
  • Clonidine
  • Dobutamine
  • Isoproterenol
  • Terbutaline
  • Salbutamol*
  • Bitolterol
  • Naphazoline
  • Oxymetazoline
  • Xylometazoline

Indirect Acting Agents

• The following are examples:
  • Hydroxyamphetamine
  • Pseudoephedrine
  • Propylhexedrine

Agents with Mixed Mechanism

• The following are examples:
  • Ephedrine
  • Metaraminol

Adrenergic Antagonists

• Alpha-adrenergic blockers examples:
  • Tolazoline*
  • Phentolamine
  • Phenoxybenzamine
  • Prazosin
  • Dihydroergotamine
  • Methysergide
• Beta-adrenergic blockers include SAR of beta-blockers with the following examples:
  • Propranolol*
  • Metibranolol
  • Atenolol
  • Betazolol
  • Bisoprolol
  • Esmolol
  • Metoprolol
  • Labetolol
  • Carvedilol

Additional Information

• Study of the development of drug classes is required
• Include Classification and mechanism of action
• List uses of drugs mentioned in the course
• Structural activity relationship of selective drug classes are required (as specified)
• Synthesis of drugs superscripted with (*)
• The nervous system coordinates actions and sensory information by transmitting electrical/chemical signals.
• Central Nervous System (CNS) consists of the brain and spinal cord, functioning as integrative and control centers.
• The Peripheral Nervous System (PNS) includes cranial and signal nerves, serving as communication lines between the CNS and the rest of the body.
• Sensory (afferent) division transmits impulses from receptors to the CNS via somatic and visceral sensory nerve fibers.
• Motor (efferent) division conducts impulses from the CNS to effectors (muscles and glands) via motor nerve fibers.

Autonomic Divisions

• Sympathetic Division mobilizes body systems during activity, often known as "fight or flight"
• Parasympathetic conserves energy and promotes "housekeeping" functions during rest.
• Autonomic NS has visceral (involuntary) motor function; conducts impulses from the CNS to cardiac muscles, smooth muscles and glands.
• Somatic NS has somatic (voluntary) motor function; conducts impulses from the CNS to skeletal muscles
• A neurotransmitter is a chemical messenger that transmits signals across a synapse from a neuron to a target cell
• The autonomic nervous system (ANS) is previously known as the vegetative nervous system or also called visceral nervous system
• The ANS is a division of the peripheral nervous system supplying smooth muscle and glands to influence internal organ functions
• The ANS control system largely acts unconsciously and regulates bodily functions, such as heart rate, digestion, respiratory rate etc.
• The ANS is the primary fight-or-flight response controller
• The ANS is regulated through reflexes via the brainstem, spinal cord, and organs
• Most autonomous functions are involuntary, working with the somatic system for voluntary control
• Autonomic functions include respiration, cardiac activity, vasomotor activity, in addition to some reflex actions
• The sympathetic nervous system is fight or flight
• The parasympathetic is rest and digest, or feed and breed
• The enteric nervous system is an intrinsic system
• SNS and PNS have opposite actions, Sympathetic is a quick mobilizing system
• The parasympathetic is a slow dampening system
• The enteric system of neurons controls the gastrointestinal tract

Adrenergic Neurotransmitters

• Includes catecholamine organic compounds
• It contains a catechol and a side-chain amine
• Catecholamines come from tyrosine or dietary sources/synthesis from phenylalanine
• Adrenaline (epinephrine), Noradrenaline, and Dopamine form catecholamine neurotransmitters released from adrenergic nerves
• Neurotransmitters bind to receptor sites on the dendrite after being released from the axon
• Adrenergic nerve terminals are in the secondary neurons of the sympathetic nervous system, responsible for the fight/flight response

Norepinephrine Biosynthesis

• Norepinephrine biosynthesis happens near the terminus of the axon and the effector cell junction in adrenergic neurons
• The biosynthetic pathway starts when the amino acid L-tyrosine is transported into the adrenergic neuron cell
• The tyrosine hydroxylase enzyme oxidizes tyrosine's 3' position to form L-dihydroxyphenylalanine (L-DOPA)
• L-DOPA is decarboxylated to dopamine by aromatic L-amino acid decarboxylase in a second step

Catabolism of norepinephrine

• It diffuses through the intercellular space and attaches to α or β-adrenoceptors on the effector cells
• Mechanisms to get rid of norepinephrine from the synapse and terminating the adrenergic impulse happens after release and various receptor stimulation
• Metabolism to 3,4-dihydroxyphenylglycolaldehyde (DOPGAL) by mitochondrial monoamine oxidase (MAO) occurs with norepinephrine taken into the presynaptic neuron by uptake-1
• Another part is sequestered as a neurotransmitter in storage vesicles
• It is metabolized extra-neuronally by catechol-O-methyltransferase (COMT) and uptake-2
• COMT methylates the meta hydroxyl group of norepinephrine, forming normetanephrine

Adrenergic Receptors

• G protein-coupled receptors targeted by catecholamines like norepinephrine and epinephrine
• There are molecular structures in or on effector cells which catecholamines/sympathomimetic drugs react with
• Adrenergic drugs is a class of medications that bind to adrenergic receptors
• These receptors include alpha-1, alpha-2, beta-1, beta-2, and beta-3
• Adrenergic drugs bind directly to one (or more) these receptors to impact physiology

Distribution

• Adrenergic receptors sub-classified into alpha and beta adrenoceptor classes in 1948 by Ahlquist
• Basis relies on responses to agonists; norepinephrine, epinephrine, and isoproterenol

Sympathomimetic Agents

• mimic effects of endogenous agonists and act on the sympathetic nervous system are stimulants
• They partially or completely simulate action

Classification

• Classification is based on mechanism of action
  • Direct-acting agonists (e.g. epinephrine, dopamine)
  • Indirect-acting agonists (e.g. amphetamine, cocaine)
  • Mixed-action agonists (e.g. ephedrine, meta-araminol)
• Classification is based on the chemical structure (presence/absence)
  • Catecholamines: catechol ring present
    • Rapid MAO enzyme metabolization, quick, and act directly on the receptor
  • Non-catecholamines absence of catechol ring
    • Prolonged action, resistant to MAO, CNS-related side effects, direct or indirect action on the receptor

SAR Sympathomimetic Agents

• The parent structure for many sympathomimetic drugs is B-phenylethylamine
• Phenyl ring substitution, substitutions at nitrogen, and substitutions on the carbon side chain can happen
• Substitution on the meta and para positions influences the mechanism and receptor selectivity
• Drugs such as metaproterenol show selective B2 receptor activity
• Replacement of the catechol moiety is an important step
• In another approach, a hydroxymethyl group afforded Salbutamol, which shows selectivity to the B2 receptor.
• Naturally occurring noradrenaline has a 3,4-dihydroxy benzene ring, active at both a, and B receptors
  • Due to resistance from metabolism it provides selectivity for B2 receptors.
• Having an amino group in phenylethylamines results in direct agonist activity
• There should be separation of the amino group from the aromatic ring by two carbon atoms in the potent direct-acting agonists.
• Bulkier nitrogen substituents decrease α-receptor agonistic activity and increase β-receptor activity.
• As size increases from hydrogen in Noradrenaline to methyl in adrenaline, the activity of the receptors fluctuates
• Primary and secondary amines are more potent direct-acting agonists.
• For substitution on the carbon side chain:
  • Methyl or ethyl substitution on the α-carbon of the ethylamine chain reduces direct receptor agonist activity at both alpha and beta receptors
  • α-alkyl groups increase the duration of action of phenylethylamine agonists by increasing resistance to deamination.
  • α-substitution significantly affects receptor selectivity and stereochemistry.

Direct-Acting Sympathomimetic Agents

• It includes Nor-epinephrine:
  • Works by constricting blood vessels, increasing blood pressure and blood glucose levels
  • It shares a similar mechanism of action to epinephrine
• It includes epinephrine:
  • Used to tx serious allergic emergencies
  • Rapidly improves breathing, stimulates the heart, reduces swelling of the face,lips and throat
• It includes Salbutamol:
  • Its a short-acting beta 2-adrenergic receptor agonist
  • It will Opens the airways and relaxes the muscles on the lungs
  • Treat asthma, chronic bronchitis, emphysema and prevent exercise-related asthma
  • The most common adverse effects are:
    • Fine tremor
    • Anxiety
    • Headache
    • Muscle cramps
    • Dry mouth
    • Palpitation
  • Route 1:
    • Methyl 2-hydroxybenzoate + 2-Bromoacetyl chloride, resulting in
    • Bn (t-Bu) then LiAlH4
    • The last step in the reaction is hydrolization ( H2 / Pd-C) – Route 2:
    • 1-(4 hydroxyphenyl)ethan-1-one + (CH2O / HCl) then
    • AcONa/ Ac2O, then Br2
    • Then tBu / Bn resulting in
    • NaBH4 HOCH2 / H2/ Pd-C
• It includes Phenylephrine:
  • A selective α-adrenergic receptor activator
    • Causes constriction of both arteries and veins
      • Used as a decongestant, to dilate the pupil, to increase blood pressure, and to relieve hemorrhoids
    • Side effects include Nausea, Headache & Anxiety
  • IUPAC Name: (R)-3-[-1-hydroxy-2-(methylamino)ethyl]phenol
    • The reaction 3(benxyloxyloxy benzaldehyde) includes:
      • Ethyl bromoacetate
      • Then NH2NH2
      • Followed by HNO2
      • Then an Oxaxolidone reaction is produced
• It includes Clonidine:
  • It works by stimulating 2 adrenergic receptors on the brain stem,
  • Decreases vascular resistance, lowers BP
• Includes Dopamine:
  • Mechanism of Action includes Improves the pumping strength of the heart and improves blood flow to the kidneys.
  • Uses includes Treats shock caused by heart attack, trauma, surgery, heart failure, kidney failure
• It includes Methyldopa: - It is used alone for high bp or with other medication to treat high bp - Can help to improve kidney problems or treat high blood pressure - It functions by relaxing blood vessels and improving blood flow
  • It includes Dobutamine:
    • treatment for cardiogenetic shock and severe heart failure
    • Works through stimulation of beta 1 receptors
• It includes lsoproterenol:
  • treatment for bradycardia and sometimes for asthma.
  • alpha and beta 2 andrenergic receptor agonist
• It includes Terbutaline:
  • As a fast asthma bronchodilator and tocolytic to delay premature labor
  • Selective beta 2 receptors and non-catechol

Indirect-Acting Sympathomimetic Agents

• Hydroxyamphetamine: acts as an indirect receptor releasing nor-epinephrine causing pupil dilation
• Pseudoephedrine (PSE) will relieve congestion by releasing more nor-epinephrine from the nerve synapses
• Propylhexedrine - acts as nasal decongestant and appetite suppressant with caution
• Can cause hypertensions if they're on medication
• It is never used in combination with MOA drug

Mixed-Action Sympathomimetic Agents

• Ephedrine increases the activation of cand Beta adrenergic receptors to suppress activity
• This will then lead to an increase in high blood pressure
• It is a weight loss drug if combined with a well-balanced exercise program.

Direct-Acting Sympathomimetic Agents

• Bitolterol: a prodrug that converts to colterol
  • Mechanism/ Uses: relaxes smooth muscles, relieving relief of bronchospasm from asthma and COPD.

Naphazoline:

• Has a vasoconstrictor that reduces swelling
• Treat decreased congestion resulting
• Extended use has negative nasal effects
• Oxymetazoline:
  • It is Over the counter medicine for eyelids or nose bleeds
  • And is also linked to Redness due to minor irritation
• Xylometazoline:
  • Alleviates congestions as well as runny noses and allergic rhinitis
• Can reduce effect of the nose and reduce effects of the nerve
• Long-term use causes Rebound side effects

Adrenergic Antagonists or Blockers

• These drugs inhibit adrenoreceptors, reducing stimulation
• Known as sympatholytic agents
• Two classes of drug exist:
  • selective alpha-adrenergic/beta-adrenergic antagonists or blockers
  • Mechanisms of action includes competitive, non-competitive, and uncompetitive
• Competitive antagonists: binds to receptors to antagonize it
  • Short lasting due to reversibly binding: Propanolol, Phentolamine are examples
• Non-competitive antagonists:
  • Irreversible antagonist action to binding on/off receptors to deactivate the cell

Classification of Adrenergic Antagonists

• Alpha and Beta
  • Alpha: Tolazoline, Phentolamine, Prazosin
  • Beta: Propranolol, Metipranolol, Atenolol, Nebivolol
• Mixed-action:
  • Labetalol, Carvedilol, alpha/beta blockers or non-selective adrenergic antagonists/blockers

Alpha Adrenergic Antagonists or Blockers

• Tolazoline:
  • It is a non-selective a receptor antagonist: treats vasodilation
  • And it treats peripheral blood vessels spams
  • Can reverse side effect associated with agonist overuse
    • However it is used to reverse Veterinarian xylene Sedation
  • Route of action includes (benzyl cyanide + ethyl 2phenylacet)
• Phentolamine:
  • Has reversible non selective alpha andrenergic effects
  • Vasodilator with hypertensive effects for medical
  • Phenoxybenzamine:
    • It is a long lasting a agonist for receptors: treats hypoplastic left heart syndrome with (CRPS)
• Prazosin:
  • It is selective and treats enlarged prostates
  • It is usually used to lower Bp
• Dihydroergotamine: - Used for migraines and it also binds with serotonin receptors
• Methysergide:
  • it is a agonist treatment for episodic and chronic migraines

Beta Adrenergic Antagonist or Blockers

• beta antagonists that block the beta adrenal receptors of the nervous system.
  • Ex include epinephrine, atenoprol and various others.
• Beta adrenergic Blocker year 1958:
  • Dichloroisuprenialine then in the early 1960's
    • Propranoldol was created: the first blocker with no agonistic capabilities and used to black boat beta 1 and beta 2 adrenergic receptors and B3
• 1. Nonselective: beta 1 and 2
  • Ex propranaldol, timeolol and socialtol is used for B1, and with additional alpha is used for curvedilol

SAR beta blockers

• Essential features: H bond and secondary amine.
  • Bulky branch is also needed for antagonist purposes.
  • Additional beta 1 selectivity can also be used.
• Propanalol: - Carbon chiral has been introduced
  • it is able to decrease heart rate, the force of contraction and it will reduce cardiac output
  • Synthesis: ( Naphth-1-ol + Epichorohydrin+ with 1-H2N)

Other beta one selective blockers include

- atenolol
- acebutolol

• Timolol:
  • used as an ocular hypertension for glaucoma
• Pindolol:
• Has agonist and antagonist effects for seratonin
• Atenolol
  • Select beta one blocker has a racemic form and for chest.

Acebutolol

• It is a Selective blocker and racemic
• Other beta 1 exclusive include
  • esmolol
  • nebivolol
• Labetalol
  • A non selective blockers

Carvedilol:

• It is a B blocker
• It has some a1 receptor effects

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