Understanding the Drug-Target Interaction - Report Example

Understanding the Drug-Target Interaction: β2-adrenergic as a target for the drug Propranolol Most drugs are small organic molecules with low molecular weights. These drugs often interact with much larger molecules, like proteins and other biomolecules in the body to produce dramatic effects on human health and well-being. Even small changes to a drug structure can have dramatic results on how well that drug functions in vivo, or in the body, because the exact shape of a molecule is often what allows a certain drug to interact with a certain target site. Many different receptors exist, so the potential for discovering and creating new drugs is limitless. Many new drugs are developed from natural products or synthesized in a lab by studying drugs that already exist to try to make those drugs have stronger affects, higher efficacy, or see how they interact when used with other drugs at the same time. In order to understand drug and target interactions better, a detailed review of the drug Propranolol and its target, the β2-adrenergic receptor will be done in this paper. Propranolol is a versatile drug that is from a class of drugs that are called beta blockers and it is many times used to treat conditions such as hypertension, but it also can be used to treat the outward symptoms of anxiety, such as high heart rates, perfuse sweating, and the tremours that can happen when someone has stage fright (Oransky, 2009). Other beta blockers that are commonly avalaible include drugs like acebutolol, betaxolol, bisoprolol, esmolol, atenolol, labetalol, carvedilol, metoprolol, and nebivolol. Many of these drugs are often used after cases of heart attack to prevent the patient from having another heart attack or putting him or herself at risk for one. The drug also treats hyperthyroidism, akathisia (inability to sit still for normal periods of time), and sometimes glaucoma symptoms (Ogbru, 2010). All beta blocker drugs are more correctly described as beta-adrenergic blocking agents. That means that these drugs can stop epinephrine, which is also called adrenaline, and norepinephrine from binding to the beta adrenergic receptors that are found on nerves. The three types of beta receptors are β1, β2, β3 and these are all located on different parts of the body and they all have different purposes in the body. Most beta blocker drugs block β1 and β2 receptors. Propranolol is a type of beta blocker that is called non-selective. That means that the drug does not specific which type of receptor it blocks, blocking both β1 and β2 receptors. It does not block β3 receptors, which are the receptors located in fat cells. It blocks the β2 receptors that are located in the gastrointestinal tract (GI tract), the lining of the lungs, the tissue of the uterus, the blood vessel walls, and the skeletal muscles, and it blocks the β1 receptors that are in the heart, kidneys, and eyes (Ogbru, 2010). Because β1 and β2 receptors are very common in the body, Propranolol is an important drug for blocking them. Propranolol is sold under the commercial name Inderal as propranolol hydrochloride, a white, crystalline solid that is stable and soluble n both water and ethanol with a molecular weight of 295.80. It comes in 10 mg, 20 mg, 40 mg, 60 mg, and 80 mg tablets for oral administration and is available for inderal injection in severe cases. Its chemical forumal is 2-Propanol, 1-[(1-methylethyl)amino]-3-(1-naphthalenyloxy)-, hydrochloride,(±)- (Inderal, 2007). Propranolol has interactions with many other drugs, including Warfarin, several alpha blockers, other beta blockers, tricyclic antidepressants, reserpine, several nonsteroidal anti-inflammatory drugs, digoxin, clonidine, haloperidol, monoamine oxidase inhibitors, certain arrhythmia medications, calcium channel blockers, and alcohol. Most of these interactions occur because the drugs interfere with each others’ elimination from the body (Monson, K. & Schoenstadt, 2010). Lowered blood pressure (a condition called hypotension) and unusual heart rhythms can be caused when the drug propranolol interacts with some other drugs, such as thioridazine (marketed as Mellaril) or chlorpromazine (marketed as Thorazine) because when these drugs are together in the body, they make the other drug stay in the body a longer time which increases the effect of the interacting drugs (Ogbru, 2010). The mechanism of propranolol action means that it must be carefully administered in order to keep from making bad interactions and harming the patient. Propranolol is given both orally and through inderal injections in life threatening cases to block actions of epinephrine and norepinephrine on both β1 and β2 adrenergic receptors in the body. When the beta-adrenergic receptor sites are blocked by the drug, the inotropic, chronotropic, and vasodilator responses to beta-adrenergic stimulation are decreased in proportion to the amount they are blocked (Long, 2005). According to Canadian physician Phillip Long M.D. (2005), the chemical mechanisms of many of the effects of propranol have not been fully explaned, including its effect on hypertension, though overall decreased cardiac output may be a big factor in this effect. Also, the drug has a strong membrane stabilizing activity in high concentrations (such as in overdose) and very little intrinsic sympathomimetic activity (ISA) (Glennon, 2009). ISA refers to the partial beta-adrenergic agonist responses caused by a series of beta-adrenergic antagonists all together. In some cases, the structural specific of the drug will allow competitive binding to the receptor site as an antagonist and some interaction at the receptors activator site as an agonist (Black & Mann, 1984). This rarely occurs in propranolol use. New research has lead scientists to believe that propranolol can also inhibit norepinephrine transporters and even stimulate the release of norepinephrine in the synapse (Glennon, 2009). Though the mechanism of propranolol is not fully understood, its unique structure lets it interact with both β1 and β2 adrenergic receptors to make big results in the human body that can help with several different conditions. Adrenergic receptors in general are sometimes called adrenoceptors. These receptors are a special type of G protein-coupled receptors that are fixed into the plasma membrane of certain cells that are the targets of catecholamines in the nervous system, except for dopamine that has different receptors that follow totally different rules (Chen-Izu et al., 2000). The β1 and β2 receptors that propranolol targets are all linked to Gs proteins. The β2 receptors are special in that they also get to link to Gi proteins. Both receptors are then linked to adenylate cyclase. Normally, epinephrine or norepinephrine will bind onto the receptor that is associated with a heterotrimeric G protein. The G protein then will then be able to associate with adenylate cyclase that converts ATP to cAMP inside of the cell. This causes the signal to spread across the cell (Goodsell, 2004). This means that when the agonist binds onto the receptor, the cAMP (cyclic adenosine monophosphate) second messenger inside the cell will become more concentrated. cAMP is a common second messenger in cells and it is very important in hormone binding to receptors because it means that one hormone molecule can amplify to many, many cAMP molecules inside the cell (Goodsell, 2004). This keeps the body from having to make too many messenger molecules like hormones, which might interfere with other systems in the body, like blood pH and metabolism. The drug Propranolol blocks the receptors needed for catecholamines through a process of competitive inhibition, but does not actually change the concentration levels of catecholamines in the blood (Vandongen et al., 1981). This means that the drug must be given in amounts large enough to beat all most of the catecholamines in the blood to receptor sites, so more sites end up blocked than activated. Because the drug does not cause the normal effect of releasing more cAMP into the cell, the cell thinks no catecholamine is there and does not change in response. This is how propranolol works. Though no mechanism of action is known precisely for how propranolol blocks receptors, possibly because there are so many different sites in the body where it acts, propranolol is still a very useful drug. The drug is very lipophilic, which means that most of the drug dissolves better in cell membranes in the GI tract than water and so it gets mostly absorbed when a patient is given an oral pill. A total of 25% makes it past the first-pass system in the liver and gets into the blood so that it can actually reach the receptors (Propranolol, 2010). In order to reach the receptor in the first place, the drug has to attach to proteins in the blood plasma or it cannot get there. Because the drug propranolol is not a pure drug but actually a mix of two enantiomers that are like mirror images, some of the propranolol (the S(-)-enantiomer) binds better to the blood protein alpha 1-acid glycoprotein and some binds better to the protein albumin (the R(+)-enantiomer). Since it is bound to both of these proteins and it is very small, the drug propranolol can pass through the blood-brain barrier and the placenta. It also can be sent to a baby through breast milk is the mother is lactating, so special care must be taken if it is prescribed to a breast-feeding mother. In the blood it gets to a volume distribution of up to 4 liters/kg (Propranolol, 2010). Like many beta blockers available, propranolol has the ability to competitively inhibit normal catecholamines from binding to the adrenergic receptors in certain cells in the nervous system. It is unique because it is not selective for a certain type of receptor, and can bind to β1 or β2 adrenergic receptors. Β adrenergic receptors themselves are a type of G protein-coupled receptors that have been well studied in research since their discovery in the middle of the twentieth century. Understanding the drug propranolol and how it relates to its target receptors helps to understand an important class of drug-target interactions. References Oransky, Ivan. (2009, August 15). Why would an Olympics shooter take propranolol? Scientific America. Accessed 11 August 2010. Retrieved from http://www.scientificamerican.com/article.cfm?id=olympics-shooter-doping-propranolol Ogbru, Omudhome PharmD. (2010). Medication and Drugs: Beta Blockers. MedicineNet. Accessed 11 August 2010. Retrieved from http://www.medicinenet.com/beta_blockers/article.htm Monson, K., and Schoenstadt, A. 2010. Drug Interactions With Propranolol. MedTV. http://heart-disease.emedtv.com/propranolol/drug-interactions-with-propranolol.html Young R, Glennon. (2009 April). S(-)Propranolol as a discriminative stimulus and its comparison to the stimulus effects of cocaine in rats. Psychopharmacology (Berl.), 203 (2), 369-382. Long, Phillip. (2005). Propranolol. Internet Mental Health. Accessed 11 August 2010. Retrieved from http://www.mentalhealth.com/drug/p30-i02.html Inderal (propranolol hydrochloride) Tablets Description. 2007. RX List. Accessed 11 August 2010. Retrieved from http://www.rxlist.com/inderal-drug.htm Black, CD and Mann HJ. (1984). Intrinsic sympathomimetic activity: physiological reality or marketing phenomenon. Drug Intelligence & Clinical Pharmacy, vol. 18 (7), 554-559. Chen-Izu Y, Xiao RP, Izu LT, Cheng H, Kuschel M, Spurgeon H, Lakatta EG. (2000 November). G(i)-dependent localization of beta(2)-adrenergic receptor signaling to L-type Ca(2+) channels. Biophysics, vol. 79 (5), 2547–2556. Goodsell, David S. (2004 October). G Protiens: Molecule of the Month. Protein Data Bank. Accessed 11 August 2010. Retrieved from http://www.pdb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb58_1.html Propranolol. (2010). Drugs Website. Par Pharmaceutical, Inc. Accessed 11 August 2010. Retrieved from http://www.drugs.com/pro/propranolol.html Vandongen, R., Davidson, L., Beilin, L.J., and Barden, A.E. (1981 September). Effect of beta-adrenergic receptor blockade with propranolol on the response of plasma catecholamines and renin activity to upright tilting in normal subjects. Journal of Clinical Pharmacol,vol. 12 (3), 369–374. Read More