SCMED 3010 Pharmacology and Toxicology Assignment Sample

Adrenergic Drugs

1. Summary: adrenergic drugs are a diverse class of drug which antagonize the signalling of sympathetic nerves by directly mimicking the function of norepinephrine and epinephrine or by indirectly inducing the release of norepinephrine. These neurotransmitters are also known as adrenaline or noradrenaline, therefore referred to as adrenergic. Adrenergic drugs can either induce or inhibit the norepinephrine or epinephrine activity in different tissues. This type of drugs generally bind directly to the adrenergic receptors of the body, which are of different types such as, alpha 1 and 2, beta 1, 2 and 3. The drugs can be classified based on the type of receptor it binds to. The primary clinical uses of these drugs include increasing blood pressure by stimulating the rate of heart muscle contractions to combat life-threatening health issues like cardiac arrests, acute bronchial asthma attack, sudden severe allergic reactions, and many other cardiovascular and respiratory disorders.

2. Drug Class: Adrenergic drugs are of different types depending upon the targeted receptors to which they bind. . The adrenergic receptors are of two different types i.e. alpha and beta. Alpha receptors are subdivided into α1, α2 and beta receptors are subdivided into β1, β2, β3. Their mode of action also may be direct by binding to the receptor or indirect by acting as a messenger or a signalling molecule (Ciccarelli et al. 2017). Some drugs may stimulate the response known as adrenergic agonists or sympathomimetic agents and the ones that suppresse the response are known as adrenergic antagonists or sympatholytic agents. Direct acting adrenergic drugs are classified depending upon their selectivity towards target receptor (Furchgott, 1972).

Examples of sympathomimetic that only bind to α1 adrenoceptors are phenylephrine, oxymetazoline and and sympatholytic drugs are doxazocin, tetrazocin, prazocin, indoramin etc. Agonist drugs only selective to α2 adrenoceptors includes alpha-methylnoradrenaline, clenbuterol, clonidine (Manzon et al. 2019), dexmedetomidine and antagonistic α2 selective drugs are yohimbine, rauwolscine, atipamezole, idazoxan, efaroxan etc (Antipov et al. 2020). One of the key agonist and antagonist drugs that bind selectively on β1 is dobutamine and atenolol respectively (Ruiz et al. 2018).

Some examples of β2 selective sympathomimetic drugs are bronchodilators (salbutamol, salmeterol, albuterol, terbutaline and key antagonist agent is butoxamine (Brodde, 2008). Adrenergic drugs can also be acting non-selectively or mixed acting by binding to different combinations of receptors. Such as, epinephrine binds to all adrenergic receptors α1, α2, β1, β2 and norepinephrine and dopamine to α1, α2, β1 receptors. Isoprinaline acts on β1, β2 receptors. Some indirectly acting adrenergic releasing drugs are ephedrine, amphetamine and some inhibitory drugs are cocaine, selegiline, entacapone, etc (Furchgott, 1972).

3. History: Adrenaline was first extracted from adrenal glands in animal tissues in early 1901 by Takamine. This natural hormone gave rise to the concepts of synthetic adrenergic drug agents over time. In the 1940’s different classes of β-receptor drugs were initially reported and the isopropyl analogue of natural norepinephrine was first synthesized as beta receptor selective agonist drug isoproterenol and first used in Germany. β1 selective dobutamine was approved in 1978 and β2 selective terbutaline was approved in 1970 in UK.

4. Indications: Adrenergic drugs are used to treat many medical conditions such as cardiovascular disorders like cardiac arrest, partial or complete heart blockage, congestive heart failure, respiratory problems like bronchial asthma, COPD (Chronic obstructive pulmonary disease ), allergic reactions (Brooks, 2016). Adrenaline is commonly used as cardiac stimulants by increasing blood pressure, also added with local anesthetics because of their vasoconstriction of blood vessels increase the action of local anesthetics, anaphylactic shok, epistaxis, glaucoma etc (Delbarre & Schmitt, 1971, Nocentini & Supuran, 2019).

Noradrenaline, ephedrine,phenylephrine, dopamine acts as pressor agents in managing cardiogenic shock by increasing vascular contractility (Larson, 2019). Isoprenaline, salbutamol, terbutaline act as bronchodilator in acute bronchial asthma. Phenylephrine, phenylpropanolamine act as nasal decongestants, amphetamine, methamphetamine, cocaine act as CNS stimulants. Ritodrine, isoxsuprine, salbutamol, terbutaline helps in direct uterine muscle relaxation and smoothens vascular muscles (Britannica).

5. Chemical structure and Synthesis of adrenergics:

Adrenergic agents like dopamine, norepinephrine, epinephrine are syntheisized by a biochemical pathway that involves 5 enzymes as shown in the figure below. Tyrosine is commonly considered as the initiation point, though phenylalanine hydroxylase can convert phenylalanine to tyrosine when there is deficiency of tyrosine. Tyrosine hydroxylase is the rate-limiting enzyme in this pathway. It adds to the 3’OH producing L–DOPA (L-3, 4-dihydroxyphenylalanine). This step requires oxygen, tetrahydropteridine, and Fe2+ as cofactors.

One of the oxygen atoms in the oxygen molecule is incorporated into an organic substrate and the other atom is reduced to water. Inhibition of tyrosine hydroxylase normally can reduce dopamine, norepinephrine, epinephrine levels significantly being the rate-limiting enzyme. Then DOPA is converted by the enzyme DOPA decarboxylase into dopamine. The aldehyde analogue of vitamin B6, i.e. pyridoxal is used as a cofactor for this reaction. Then dopamine is converted norepinephrine by a copper-containing enzyme dopamine-beta-monooxygenase and at the end of the pathway, norepinephrine N-methyltransferase converts norepinephrine to epinephrine (Ophardt, 2003).

adrenergic drug synthesis pathway (Ophardt, 2003)

6. Available forms of the drug: liquid for injection

7. Mechanism of action:

Adrenergic receptors, also known as adreno-receptors, are classified into two types i.e.alpha or beta receptors. These two classes are subdivided into alpha-1, alpha-2, beta-1, beta-2, and beta-3. Alpha-1 and alpha-2 both receptors have three subclasses. These are all G-protein-coupled receptors (Farzam & Lakhkar, 2018).

Alpha-1 receptors - Gq coupled-receptor

alpha-2 receptors - Gi coupled-receptor

Beta-2 and beta-3- Gi coupled-receptors

All beta adrenergic receptors are Gs coupled-receptors to

When agonist adrenergic drugs bind to receptors, following cellular mechanisms are induced:

α1 Receptor

Phospholipase C is activated, which promotes the induction of IP3 (inositol triphosphate) and diacylglycero. Therefore, calcium level rises.

α2 Receptor

Adenylate cyclase is inactivated, which results in a decrease in cyclic adenosine monophosphate (cAMP).

β1 Receptor

Adenylate cyclase is activated leading to increase in cAMP.

β2 Receptor

Adenylate cycle gets activated by the Gs-protein-coupled receptors, resulting in an increase of the cAMP in cell. Gi protein-coupled receptors are also activated, which decrease the cAMP level (Choi et al. 2018).

Norepinephrine (NE) is secreted from the nerve at the synapse in response to a electric impulse or drug. NE binds to the alpha and beta receptor site. Its receptor action is inactivated by an enzyme like chloropheniramine, an antihistamine drug, inhibits the mechanism of norepinephrine (Nickerson, 2017). Norepinephrine activates alpha receptors and epinephrine activates beta receptors primarily (Creveling, 2017). Stimulation of alpha receptors is associated with constriction of small blood vessels in the bronchial mucosa and relaxation of smooth muscles of the intestinal tract (Dean & Reddivari, 2019). Beta receptor activation relaxes bronchial smooth muscles which cause the bronchi of the lungs to dilate (Ophardt, 2003). Stimulation of beta receptor also increases the force and rate of heart muscle contractions resulting in increased blood flow to all body organs and muscles that actively participate in the body's mechanism to combat stress (Fowler, 2019).

8. Side effects: Adrenergic drugs have many adverse effects. Selective binding to alpha and beta receptors can cause different side effects such as follows:

• Hypertension, which can lead to cerebral hemorrhage.

• Bradycardia, Tachycardia

• Palpitations

• Restlessness

• Tremors

• Headache

• Dizziness

• Insomnia

• Euphoria

• Loss of energy and appetite, dry mouth

• Nausea, vomiting

• Anorexia

• Cold hands and feet

• Sexual distress in men

• Altered lipid profile

• Urinary retention

• Mydriasis

• Angina and arrhythmias

9. Toxicity: All adrenergic receptors have antagonists. Alpha-blockers are generally not indicated for the treatment of overdoses of alpha-agonists. Beta-blockers may be used to treat acute adverse effects resulting from adrenergic receptor agonists. Beta-blockers can also treat the tachycardia and hypertension that may be caused from vasopressors (Farzam & Lakhkar, 2018).

References:

1. Antipov, A., Brizuela, M., Blessing, W. W., & Ootsuka, Y. (2020). Alpha2-adrenergic receptor agonists prevent emotional hyperthermia. Brain Research, 1732, 146678.

2. Brodde, O. E. (2008). β-1 and β-2 adrenoceptor polymorphisms: functional importance, impact on cardiovascular diseases and drug responses. Pharmacology & Therapeutics, 117(1), 1-29.

3. Brooks, C. M. (2016). A. The Effects of Adrenergic Drugs on the Heart. The Nervous System: Autonomic Nervous System Drugs, 1.

4. Choi, M., Staus, D. P., Wingler, L. M., Ahn, S., Pani, B., Capel, W. D., & Lefkowitz, R. J. (2018). G protein–coupled receptor kinases (GRKs) orchestrate biased agonism at the β2-adrenergic receptor. Sci. Signal., 11(544), eaar7084.

5. Ciccarelli, M., Sorriento, D., Coscioni, E., Iaccarino, G., & Santulli, G. (2017). Adrenergic receptors. In Endocrinology of the Heart in Health and Disease (pp. 285-315). Academic Press.

6. Creveling, C. R. (2017). Drugs interfering with the formation of adrenergic transmitters. Pharmacology of Cholinergic and Adrenergic Transmission. Eds. Koelle, GB, Douglas, WW, Carlsson, A, 185-204.

7. Dean II, J. S., & Reddivari, A. K. R. (2019). Alpha 1 Receptor Agonists. In StatPearls [Internet]. StatPearls Publishing.

8. Delbarre, B., & Schmitt, H. (1971). Sedative effects of α-sympathomimetic drugs and their antagonism by adrenergic and cholinergic blocking drugs. European Journal of Pharmacology, 13(3), 356-363.

9. Farzam, K., & Lakhkar, A. D. (2018). Adrenergic Drugs.

10. Fowler, M. (2019). Beta-adrenergic blocking drugs in severe heart failure. Reviews in Cardiovascular Medicine, 3(S3), 20-26.

11. Furchgott, R. F. (1972). The classification of adrenoceptors (adrenergic receptors). An evaluation from the standpoint of receptor theory. In Catecholamines (pp. 283-335). Springer, Berlin, Heidelberg. 12. https://www.britannica.com/science/adrenergic-drug

13. Larson, P. O. (2019). Vasoconstrictors: Chemistry, Mode of Action, and Dosage. In Anesthesia and Analgesia in Dermatologic Surgery (pp. 43-74). CRC Press.

14. Laurent, S. (2017). Antihypertensive drugs. Pharmacological research, 124, 116-125.

15. Manzon, L., Nappe, T. M., & Maguire, N. J. (2019). Clonidine Toxicity. In StatPearls [Internet]. StatPearls Publishing.

16. Nickerson, M. (2017). Adrenergic receptor mechanisms. Pharmacology of Cholinergic and Adrenergic transmission, 3, 303-315.

17. Nocentini, A., & Supuran, C. T. (2019). Adrenergic agonists and antagonists as antiglaucoma agents: a literature and patent review (2013–2019). Expert Opinion on Therapeutic Patents, 29(10), 805-815.

18. Ophardt, C. E. (2003). Virtual chembook. Elmhurst College, 121-125.

19. Ruiz-Medina, B. E., Cadena-Medina, D. A., Esparza, E., Arrieta, A. J., & Kirken, R. A. (2018). Isoproterenol-induced beta-2 adrenergic receptor activation negatively regulates interleukin-2 signaling. Biochemical Journal, 475(18), 2907-2923. 20. NCBI (https://pubchem.ncbi.nlm.nih.gov/)

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