Lesson 13 Flashcards
What are sympatholitics? What drugs of this kind do you know who act on adrenergic receptors?
Sympatholytic drugs, sometimes called antiadrenergic agents, are a class of drugs that inhibit the postganglionic function of the sympathetic nervous system. They reduce the actions of the sympathetic nervous system by various mechanisms, such as blocking adrenergic receptors or inhibiting the release of neurotransmitters like norepinephrine. These drugs are used to treat conditions such as hypertension, anxiety, and some types of cardiac arrhythmias. They address hypertension through two primary mechanisms: reducing systemic vascular resistance and decreasing cardiac output. These actions are mediated by different receptors, with alpha1 receptors regulating the vascular system and beta1 receptors mainly influencing the heart. Sympatholytics are both adrenoreceptor antagonists and central sympatholytics, the latter acting on presynaptic receptors like alpha2. Presynaptic receptors, normally have the function of reducing the release of neurotransmitters so they are involved in the reduction of the adrenergic flow and thus we have a reduction of the adrenergic receptors. So all these compounds acting to the pre synaptic regions are called sympatholytics.
Let’s start from Beta1 adrenoreceptor antagonists, such as propranolol, they impact the heart rate and contraction. Propranolol, though a beta-aspecific receptor, antagonizes both beta1 and beta2 receptors, leading to bronchoconstriction and a hypertensive effect in prolonged therapies. Since it acts on beta2 receptors as well, propranolol causes creating bronchoconstriction, and beta2 receptors are also involved in the relaxation of smooth muscles of the vessels, thus we have an hypertense effect achieved with longer therapies. Reduction on vasomotor tone may seem paradoxical, infact beta2 normally causes vasodilation, but we have beta1 receptors on the kidneys leading to the secretion of renin which is the first step in the production of angiotensin II which is a potent vasoconstrictor. so anyway we have a decreased vasomotor tone,
Newer-generation drugs like metoprolol, atenolol, and nebivolol focus on beta1 receptors to achieve a more specific effect. Administering beta1 antagonists to individuals with normal blood pressure does not alter their baseline values, making them effective in cases where hypertension results from adrenergic overstimulation due to stress. However, they may present side effects such as elevated triglycerides, reduced HDL, hyperglycemia, sedation, impotence, depression, and bronchoconstriction.
There are also combined alpha1-beta1 antagonists: combining alpha1 and beta1 antagonists, as seen in labetalol, provides a potent action on reducing vascular resistance and cardiac output. Labetalol is available in oral and parenteral formulations, with the latter being utilized in emergencies. These mixed antagonists offer efficacy with lower dosages and fewer side effects, making them suitable for younger individuals with pump-based hypertension. These drugs are less used then diuretics or inhibitors of RAAS (we will see it later). however the mixed ones are very effective in younger people who have pump based hypertension because of the less amount of side effects.
Hypertension agents trigger compensatory responses, leading to sodium and water retention and tachycardia. Combining two different drugs, such as beta antagonists and diuretics from the beginning of therapy, helps prevent the loss of efficacy due to compensatory effects, providing a more potent impact on blood pressure
Alpha1 receptor antagonists like prazosin, terazosin, and doxazosin selectively impact arterial smooth muscles without affecting the heart. Notably, these compounds do not alter lipid profiles, mitigating the risk of cardiovascular diseases. However, there are still debates due to claims of manipulated critical trials influencing the perceived side effects of alpha1 antagonists. It’s important to note that alpha adrenergic antagonists are not typically employed for long-term hypertension treatment.
Central sympatholytic agents operate by activating alpha2 receptors, which are presynaptic and reduce the stimulation of target receptors. However, due to significant side effects and the importance of sympathetic tone, the use of alpha2 adrenergic agonists is no longer prevalent. Among these compounds we find ganglionic blockers like trimethaphan and hexamethonium which inhibit nicotinic cholinergic activity at sympathetic ganglia, effectively lowering blood pressure. However, these agents are no longer employed due to severe adverse effects, including constipation, blurred vision, sexual dysfunction, and orthostatic hypotension.
what is reserpine?
Some sympatholytic agents like Reserpine, originally extracted from an herb used by Indian gurus, inhibit neurotransmitter transpiration, reducing the sympathetic tone. Reserpine is a drug that depletes stores of neurotransmitters from sympathetic nerve endings. However, its use is limited due to adverse effects such as depression, orthostatic hypotension, and sexual dysfunction. The side effects observed with reserpine contributed to the development of drugs for depression.
Speak about potassium channel openers and calcium channel blockers to stop hypertension
Vascular tone regulation involves calcium and potassium channels. Calcium influx is crucial for contraction, and drugs that reduce calcium entry induce relaxation. Additionally, compounds that open potassium channels hyperpolarize cells, reducing smooth muscle contraction.
Calcium channel blockers, there are three classes of calcium channel blockers: benzothiazepine, phenylalkylamine and dihydropyridines (e.g., nifedipine and amlodipine), reduce systemic vascular resistance and cardiac output. They are administered orally for chronic hypertension treatment. These blockers cause vasodilation, decreased contraction force, and reduced heart rate. Calcium channel blockers can cause vasodilation, reduction on the force of contraction and a decreased rhythm of the heart. So we mainly have a vasodilating, so they act mainly on the smooth muscles while the other classes have mainly an effect on the heart. Nifedipine and amlodipine have dual effects on both smooth muscles and the heart. To minimize side effects, combination therapies with different mechanisms of action are often employed.
Potassium channel openers, specifically KATP channels since they open based on the amount of ATP in the cell, include minoxidil. These drugs induce vasodilation through hyperpolarization, reducing smooth muscle contraction. Minoxidil opens potassium channels leading to hyperpolarization and in muscular smooth cells we will have less contraction so this is why we have this vasodilator effect, but in some locations this excessive vasodilation can be also a problem because one of the causes of migraines. There are topic creams used on the head to reduce this problem. Hydralazine, although less commonly used because its mechanism of action is not clear yet, is another potassium channel opener weaker then minoxidil. These drugs are vasodilators but they are not first choice drugs and are used when all other drugs are not working.
How can we cure hypertension by modulating RAAS?
The Renin-Angiotensin-Aldosterone System (RAAS) is a complex network involving renin, angiotensin, and aldosterone. Angiotensinogen, produced by the liver, serves as a precursor, readily transformed into angiotensin I by renin, secreted by the kidneys in response to decreased blood pressure and renal perfusion. Angiotensin I is then converted into the potent vasoconstrictor angiotensin II by ACE, primarily located on pulmonary and renal endothelium. Angiotensin II increases blood pressure, stimulates ADH release, triggers aldosterone production for water and sodium reabsorption in the kidneys, and enhances sympathetic activity.
To modulate this system, drugs such as renin inhibitors, ACE inhibitors, and AT1 angiotensin receptor antagonists are employed, often preferred for hypertension management.
- Renin Inhibitors: Renin inhibitors for example Aliskiren, were initially considered a promising approach to block the entire cascade, effectively preventing high blood pressure. However, Aliskiren has become less common in practice and is the least utilized among the group.
- ACE Inhibitors: they target the enzyme responsible for converting angiotensin I to angiotensin II. By reducing the levels of angiotensin II, ACE inhibitors mitigate vasoconstriction, aldosterone secretion, and promote vasodilation through the bradykinin pathway. Despite a potential side effect of cough, ACE inhibitors are particularly beneficial for individuals with increased renin secretion, and their impact on kininase II makes them effective for those with normal renin levels. They do not affect kidney function, making them suitable for individuals with kidney problems, and have minimal impact on glucose and lipid levels. But we also have to consider that diuretics were found more effective in clinical trials for preventing cardiovascular diseases. These drugs have 3 patterns of metabolism. Captopril is the prototypical ACE inhibitor and is already active when administered but it is also metabolically transformed into an active metabolite, providing a dual-life effect. Enalapril and ramipril are prodrugs requiring metabolic activation. Lisinopril is administered in its active form and excreted unchanged by the kidneys. ACE inhibitors should be used cautiously in patients with renal artery stenosis to avoid intravascular volume depletion, where the RAAS system serves as a compensatory mechanism. However, they are recommended for hypertensive diabetic patients due to their kidney-friendly profile.
Aliskiren and ACE inhibitors are contraindicated during pregnancy due to teratogenic effects, meaning that they might cause developmental malformations or birth defects in an embryo or fetus.
To modulate RAAS we can also use Angiotensin II receptor antagonists, commonly known as Sartans. They stand as the primary choice for hypertension treatment. By antagonizing the AT1 receptor, these drugs inhibit the vasoconstrictive and aldosterone-promoting effects of angiotensin II, surpassing the efficacy of previous interventions. Unlike ACE inhibitors, Sartans do not impact bradykinin, resulting in a lower incidence of the cough side effect while maintaining effectiveness.
Sartans effectively block the AT1 receptors responsible for vasoconstriction and aldosterone secretion. Meanwhile, the AT2 receptors, associated with vasodilation, remain unaffected. This selectivity contributes to a reduced vasodilation effect compared to ACE inhibitors, making Sartans a well-tolerated alternative.
In cases of severe hypertension, where lifestyle modifications and a single drug may prove insufficient, a strategic approach involves combining agents with different mechanisms of action. Rather than escalating the dosage of a single drug, this combination strategy employs submaximal doses, thereby minimizing adverse effects.
