The Effects of Different Drugs on Cardiovascular System

Introduction

Background

Many drugs can affect the cardiovascular system and its functions. This experiment focused mainly on Propranolol, Salbutamol, and Glyceryl Trinitrate. Propranolol is a non-selective beta-adrenergic receptor antagonist that can affect the cardiovascular system and alter its function. It can be used to treat a variety of diseases such as, high blood pressure or hypertension, different circulatory conditions and also to reduce the chances of getting a heart attack. It works by blocking the action of adrenaline on beta1- and beta2-adrenergic receptors, (Viera et al., 2009). An experiment was done by Prichard and Gillam (1964), where 16 hypertensive patients have been given the drug for seven months. The results showed that Propranolol can be used to treat hypertension by lowering Heartrate (HR) and Mean Arterial Pressure (MAP), as some patients have shown low blood-pressure levels after taking the drug. Although most subjects showed no side-effects, one patient developed heart failure after two days of taking the drug. Therefore, it is said that Propranolol has no side-effects when taking the recommended dosage, (Prichard and Gillam, 1964).

Salbutamol is a beta-adrenoceptive receptor that is used in the treatment of different medical conditions such as, bronchial asthma and chronic obstructive pulmonary disorder (COPD), (CULLUM et al., 1969). Nakpheng et al. (2017) suggested that it relaxes the bronchial muscles via the activation of adenylate cyclase and the increase in the synthesizes of cAMP which leads to an increase in heart rate. An experiment in Edgell et al., (2016) article was done to test the cardiovascular effects of Salbutamol. The drug is known to have the ability to affect the cardiovascular system by increasing the atrial wall thickness. It usually used in the treatment of Asthma that can give rise to some diseases in the cardiovascular system. This drug can also cause a rise in the activity of the sympathetic nerves. The outcomes of the experiment showed an increase in HR and no acute effects on mean atrial pressure(MAP), blood pressure or heart rate variability (HRV), (Edgell et al., 2016).

Glyceryl Trinitrate (GTN) is a vasodilator drug that causes a widening of the blood vessels by relaxing the muscles in the walls, (Little et al., 2018). It is used for the treatment of chest pain and high blood pressure. In a study done with 140 subjects (80 hypertensive patients and 60 controls), the effects of two different doses of this drug on HR, sympathetic nerve activity and arteries diameter were compared, (Ghiadoni et al., 2019). Ghiadoni et al. (2019) suggested that a reduction occurred in MAP, which was clearer in when the subjects took the higher dose, there was a greater increase in the HR with the higher dose.

Aims

This experiment aimed to study the effects and the ability of Propranolol, Salbutamol and Glyceryl Trinitrate to modify heart rate. Also, to create an experiment with human volunteers to test those effects.

Hypothesis

• If Propranolol blocks the actions of beta-adrenergic receptors, then it will lower HR and MAP. The aim of the exercise is reaching a higher heart rate and to exaggerate the effects of the drug on the cardiovascular system.
• Salbutamol is usually used to treat Asthma. If the drug can relax the bronchial muscles, then it will help in delivering more blood to the heart and will increases HR but will not have any effect on the MAP.
• GTN is known to have effects on widening blood vessels. Therefore, if the drug relaxes the smooth muscles on the vessels, then it will make the blood move in low pressure and heart rate will drop as well as the MAP

Participants

87 healthy participants (males and females, aged 19-21) participated in the study (Subjects A had been given Propranolol, subjects B inhaled Salbutamol, and subjects C took GTN). All reported being in good health and free of any known heart disease or hypertension. All volunteers gave their informed written consent. The study was approved by the Faculty Research Ethics Committee. The chosen drugs have been approved that they have a little risk in healthy volunteers. The medical demonstrator decided whether or not the subjects fit the criteria for each drug.

Materials and Methods

Propranolol

The experiment started by taking a control recordings of the subject's A heart rate (HR) by Polar a1 Heart Rate Monitor, Polar Electro Oy, Fin-9-440, Kempele, Finland, systolic blood pressure (SBP) and diastolic blood pressure (DBP) by Omron M5-I Blood Pressure Monitor, Omron Healthcare, Kruiseg 577, 2130AA Hoofddorp, Netherlands and Peak Expiratory Flow Rate (PEFR) by Mini-Wright Peak Flow Meter, Clement Clark International Ltd,Edinburgh Way, Harlow, CM20277. Then Pulse Pressure (PP) and mean atrial pressure (MAP) were calculated from the recordings every 3 minutes for 9 minutes before exercising. Then the height and the load of the cycle (Monark Ergometer 828E, 50 Vansbro)were adjusted depending on the participant sex and fitness. The exercise was carried out for 2 minutes while recording the HR every 15 seconds. After 2 minutes the subject was asked to step off the cycle and the recordings were measured again for 5 minutes. The medic gave the subject 4 10mg tablets of Propranolol- (TEVA UK Ltd. Eastbourne, BN22 9AG) and the participant was seated for 50 minutes to allow the absorption of it. All measurements of subject A were taken again after 50 minutes as at the beginning of the experiment, following that, the subject was asked to repeat the exercise by repeating the same recordings.

Salbutamol

During the 50 minutes, the control recordings and measurements of subject B were taken and then the same exercise was repeated as subject A. The subject inhaled 2 separate doses of 100 mcg Salbutamol- ((Ventolin Evohaler) Allen & Hanburys, Stockley Park, Middlesex UB11 1BT)and the measurements were done every 3 minutes for 9 minutes. The exercise was repeated under the same conditions with HR being recorded every 15 seconds. After 2 minutes of exercising, all measurements were taken again.

Glyceryl Trinitrate (GTN)

The control measurement and calculations were repeated for subject C except for the PEFR. The subject was given one tablet of GTN (500 microgram)- (Actavis, Barnstaple, EX32,8NS) and sked to administer it sublingually. All readings kept recorded every 3 minutes for 30 minutes after taking the drug. All volunteers had their HR and BP checked by the medical demonstrator before they left the laboratory.

Statistical analysis

Values are presented as means ± standard deviations. Differences between groups were tested for using paired t-test, using IBM SPSS Statistics 26 (IBM, Armonk, New York, USA). Significance level was set at 0.05.

Results

All three drugs showed different effects on HR(beats/min) and MAP(mmHg).

Propranolol

The significant changes were a decrease in HR, which was recorded after administering Propranolol ( 144.00 ± 5.00 beats/min) after it rose to ( 121.00 ± 3.17 beats/min), a decrease in MAP to ( 89.92 ± 2.00 mmHg) from ( 106.00 ± 4.00 mmHg). The effects before taking the drug and the effects after the administration of propranolol are shown in table 1.

Propranolol

Initial studies with smaller doses of propranolol in humans produced a significant drop in HR and MAP, as concluded in Prichard and Gillam (1964). Their practical examined the effects of the drug on the cardiovascular system, the suggested that propranolol lowers HR as well as MAP. This agrees with the outcomes of this practical. As a Beta-adrenergic blocker, propranolol slows HR by blocking the action of beta 1 receptors on the heart. Beta 1 receptors are coupled to Gs-proteins, that activate adenylyl cyclase to form cAMP from ATP. High levels of cAMP activate protein kinase (PK-A) which phosphorylates L-type calcium channels and causes increased calcium entry into the cells. Increased calcium influx during action potentials results in enhanced release of calcium by the sarcoplasmic reticulum in the heart; these actions increase contractility. Gs-protein activation also increases heart rate by opening ion channels responsible for pacemaker currents in the SA node. PK-A phosphorylates sites on the sarcoplasmic reticulum, which raises the release of calcium through the receptors associated with the sarcoplasmic reticulum. This provides more calcium for binding the troponin-C, which enhances the contraction action. Therefore, propranolol stops the action of these receptors which slows HR and decreases the force of blood being pumped to the systemic circulation. This prevention of calcium ions also leads to a decrease in MAP after taking the drug. Thus, propranolol is used to treat hypertension because of its effects on the responses of the heart to nerve stimuli.

Salbutamol

Salbutamol is a β2-agonist that activates the β-adrenergic receptors on the airway smooth muscles. In this practical, it was observed that the inhalation of salbutamol had no significant changes in HR and MAP after exercise because its primary function is on the respiratory system. This drug works by relaxing bronchial smooth muscle. After the binding of the drug to the receptor, it forms a complex that activates the Gs-proteins that then binds to GTP and causes activation of adenylate cyclase and increased levels of cAMP, which in turn activates PKA. Salbutamol is a bronchodilator; therefore, it increases the flow of air to the lungs. Inhaled salbutamol may have limited absorption and therefore will not have clear systematic effects. Goubault (2001) studied the effects of inhaled salbutamol on healthy subjects. The outcomes of the experiments showed that salbutamol had a slight effects on blood pressure and heart rate that were not considered beneficial during exercise. This suggested that the salbutamol administration can be safe and does not affect exercise intensity in healthy people.

Glyceryl Trinitrate

Glyceryl Trinitrate is a vasodilating agent. Its pharmacological action is a direct relaxation of vascular smooth muscle. It produces a dilation of both arterial and venous beds, which improves oxygen supply to the heart. Myocardial oxygen consumption is decreased by both the arterial and venous effects of Glyceryl Trinitrate. This drug is an organic nitrate that is commonly used to treat angina. The effects are due to a stimulation of soluble guanylate cyclase by nitric oxide derived from GTN through metabolization catalysed by enzymes. The cyclic GMP produced by the guanylate cyclase acts via cGMP-dependent protein kinase. The effects observed in the present practical were lowering of MAP and increasing of HR when administering GTN. A study of the effects of GTN on ten subjects was done, all the effects on the cardiovascular system said to be a result of the known vasodilatory effect of GTN, (YAGINUMA et al., 1986).

The study had some limitations that must be highlighted. One is the subjects, males and females subjects who participated in this practical. All data was obtained from both genders. It would have been ideal to have gender-matched criteria, in order to do more investigations on the effects of the drugs in men and women. Another factor is the sample size, the observed effects on the cardiovascular system were very small, therefore, a greater sample size may be needed in future studies to detect any further effects of the drugs and to get more information of the changes may occur in the cardiovascular system. Further, the time might also affect the validity of the outcomes as the measurements were repeated on different subjects for four days. Future changes in the duration of the experiment will help in measuring the results more accurately. Also, this experiment focused on healthy subjects, so testing the effects of the drugs on subjects with medical conditions like Asthma, Angina or Anxiety will give a chance to do more studying on the physiological changes of HR and MAP.

Conclusion

To sum up, all three drugs that have been used in this study had the ability to alter HR via their action on the receptors on the heart. Propranolol decreased HR and GTN increased it, whereas, salbutamol only increased it slightly. Although the administration of propranolol and GTN led to low levels of MAP, salbutamol did not affect MAP. Therefore, one of the current medical uses of propranolol is in the treatment of high blood pressure, due to the pharmacological effects of the drug on both beta 1 and beta 2 adrenergic receptors. The drug is a beta-blocker that reduces the contractility of the heart by inhibiting the increase of the levels of intracellular calcium ions. This effect also helps with patients with anxiety, because it lowers the force of pumping blood and heartbeats. Short-term inhaled doses of salbutamol showed no effects on MAP and smaller effects on HR than the other two drugs used in this study.

The main effect was on PEFR and more air was delivered to the heart. salbutamol is used to Asthma by relaxing airflow pathways which may have some systemic and coronary side-effects such as effects on HR. salbutamol in most cases has the opposite effects of propranolol, as it is a beta-agonist that activates beta receptors. In this study, the effects of the drug were no clear and showed no significant changes. GTN is known as a vasodilator, it causes widening of blood vessels. On one hand, it leads to a change in the strength of pumping blood to the circulation. On the other hand, an increase in HR was observed during the practical. GTN is used to treat angina, the pain associated with this disease is due to the narrowing of the blood vessels. Thus, taking GTN will relax the vessels and make the flow of blood from and to heart muscle easier.