Drugs are chemicals and they owe their activity to the contribution of each chemical group in their structure. For instance, a drug that has an organic acid group like acetylsalicylic acid (aspirin), is well absorbed in the acidic medium of the stomach, and the acidic group is also important for its anti-inflammatory activity. The purpose of this paper is twofold: first, to discuss the structure-activity relationship (SAR) of doxazocin, nadolol, and nitroglycerine, and secondly to determine the best drug for a 72-year-old patient called HP who has high blood pressure. HP is already taking other drugs such as saw palmetto, sildenafil, and Symbicort for the management of prostatic hypertrophy, erectile dysfunction, and chronic bronchitis respectively.
Structure-Activity Relationship
Doxazocin
Doxazocin is a derivative of prazosin. Figure 1 shows the chemical structure of doxazocin.
Figure 1: 2D structure of doxazocin
The antihypertensive action of the drug is the result of peripheral vasodilation caused by postjunctional blockade of α1-adrenoceptors. To achieve optimum activity and minimize the side effects, the drug must have high selectivity for α1-adrenoceptors.
The quinazoline ring is essential for receptor selectivity. For doxazocin, the 4-amino-6,7-dimethoxyquinazoline group ensures high affinity and selectivity for α1 adrenergic receptors. Additionally, the 4-amino-6,7-dimethoxyquinazoline imparts favorable effects on plasma lipids. It reduces triglycerides, and total cholesterol, improving the levels of HDL which is good cholesterol.
The piperazine ring of doxazocin is not essential for adrenoceptor blockade activity because alfuzocin in which the piperazine ring is open still has almost equal selectivity for α1 receptor as does doxazosin and prazosin.
Nadolol
Nadolol is a non-selective β receptor blocker. The chemical structure is shown in figure 2. The drug inhibits both β1 receptors and β2 receptors. This blockade causes negative inotropic effect and negative chronotropic effect. It also prevents release of renin and blocks sympathetic innervation.
Figure 2: 2D structure of Nadolol
The compound has a tertbutyl group attached to the amino-terminal. The tertbutyl group makes it selective against alpha receptors and gives it a very high affinity for beta receptors. The tertbutyl group also makes nadolol highly hydrophilic, increasing its half-life. Lipophilicity also reduces CNS side effects of the drug since it cannot cross the BBB.
The –OCH2 group increases the antimuscarinic potency of the compound. Lengthening the side chains attached to this group does not interfere with the folding of the molecule which is important for receptor binding.
Nadolol has short substituents on the para position which makes it mixed-acting. Replacing these substituents with longer chains would make it selective to β1.
Nitroglycerine
Nitroglycerine is mainly used for the management of angina. It also lowers blood pressure. It has the chemical structure shown in figure 3.
Figure 3: 2D structure of Nitroglycerine
The action of nitroglycerine depends on denitration which releases NO in the smooth muscles. NO causes smooth muscle relaxation through increased cGMP levels. The activity of the drug depends entirely on its metabolism to NO which implies that nitroglycerine itself is a prodrug whose active form is nitric oxide.
As the drug interacts with sulfhydryl groups and glutathione groups of tissues and erythrocytes it produces nitric oxide through an intermediate called S-nitrosothiol. Another action of NO is to increase the concentration of potassium ions in the blood, leading to hyperpolarization.
Drug Choice.
Doxazosin is the best drug to administer to HP for the management of hypertension. The rationale for this choice is that doxazosin has high specificity for α1 adrenergic receptors compared to nitroglycerin which produces mild relaxation. Doxazosin synergizes sildenafil activity on benign prostate hyperplasia. At the same time, Sildenafil potentiates the anti-hypertensive effect of doxazosin. Given that HP is very elderly, administration of Doxazosin will also help to check on his plasma lipid profile, further minimizing his hypertension.
Why the other Drugs are not appropriate
Nitroglycerine is not appropriate for the patient despite the fact that it can cause the desired hypotension. This is because the patient already takes sildenafil. A combination of sildenafil and nitroglycerine can cause severe hypotension which, for such an elderly patient, can result in sudden death. Furthermore, nitroglycerine is more effective in angina pectoris, yet the patient does not have angina.
Nadolol is also not appropriate because it is a mixed beta blocker. The patient already ha emphysema and bronchitis. So, blocking β2 receptors would worsen the respiratory problems that the patient already has.
