Antidepressants The Cheese Effect

ANTIDEPRESSANTS AND THE CHEESE EFFECT

According to Meyer & Quenzer (2019), dopamine, norepinephrine, and other similar substances such as epinephrine and serotonin constitute a small but significant group of neurotransmitters and hormones known as the catecholamine. The catecholamine is derived from the common chemical similarities shared by the members of this family of neurotransmitters. A pivotal structure of catechol and a nitrogen- containing moiety called an amine (Meyer & Quenzer, 2019). The catecholamines belong to an extensive group of transmitters called the monoamine or biogenic amines - compounds originating from living organisms. Epinephrine is often referred to as adrenaline.

Whereas norepinephrine is referred to as noradrenaline. The adjectives, adrenergic and noradrenergic are used to describe adrenal and noradrenaline activity respectively. In catecholamine synthesis, the enzyme, tyrosine hydroxylase catalyzes the rate-limiting process. There are several steps involved in this process. The synthetic pathway begins with the amino acid, tyrosine which is available in the food that we consume. Tyrosine is derived from dietary protein (Meyer& Quenzer, 2019).

There are two essential enzymes involved in the conversion of tyrosine to catecholamine, tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase (AADC). In the first and second synthetic processes, Dopamine is produced. The third process proceeding further with the aid of the third enzyme, dopamine. Meanwhile, dopamine B-Hydroxylase (DBH) converts dopamine to norepinephrine. Dopamine can also be synthesized by converting the precursor, L-DOPA to dopamine. Meanwhile, L-DOPA has been the therapeutic agent of choice in the treatment of Parkinson’s disease because it easily crosses the blood brain barrier with less adverse effects. Dopamine itself, is administered also as carbidopa in combination with levodopa to minimize side effects in the treatment of Parkinson’s disease. Drugs that inhibit catecholamine synthesis include the a-methyl-para-tyrosine (AMPT).

According to Meyer & Quenzer (2019), the metabolism of the catecholamine involves two enzymes, catechol-o-methyltransferase (COMT) and monoamine oxidase: MAO-A and MAO-B. The importance of each MAO subtype depends on the neurotransmitter that is being metabolized. Norepinephrine is metabolized by MAO-A in humans and rodents (Meyer & Quenzer, 2019). While dopamine is metabolized by MAO-B in humans. Dopamine is metabolized by MAO-A in rodents. The antidepressants, paroxetine and moclobemide work to elevate the concentrations of the neurotransmitter, serotonin (by inhibiting reuptake of serotonin). While moclobemide decreases the rate at which serotonin is metabolized by inhibiting MAO-A. Excessive combination of serotonergic agents results in what is known as serotonin crisis or serotonin syndrome.

The action of the two metabolizing enzymes, COMT and MAO of the catecholamine yields the catecholamine metabolites.

According to Meyer & Quenzer (2019), the metabolism of dopamine in humans yields the metabolite, homovanillic acid (HVA). While the metabolism of norepinephrine yields the metabolite, 3-methoxy-4-hydroxy-phenylglycol (MHPG) and Vanillylmandelic acid (VMA). Vanillylmandelic acid is eventually excreted in the urine.

The concentration of these metabolites in blood and urine provides approximate prediction of catecholaminergic activity in nervous system, and also used to determine the potential involvement of neurotransmitters in depression or schizophrenia. Drugs that inhibit the action of the catecholamine result in concentration of these neurotransmitters.

According to Meyer & Quenzer (2019), drugs such as phenelzine (nardil) and tranylcylcypomine (parnate) are non-selective MAO-inhibitors that inhibit both MAO-A and MAO-B used in the treatment of clinical depression. Selegiline and rasagiline are inhibitors of MAO-B. While moclobemide as mentioned earlier, is selective inhibitor of MAO-A. COMT inhibitors are used as adjuvant therapy to potentiate efficacy of L-DOPA in Parkinson’s disease treatment.

According to Finberg etal (1983), inhibitors of the enzyme, MAO has been used therapeutically for the treatment of affective disorders. However, their use falls out of favor due to reports of serious hypertensive reaction when patients treated with MAOI drugs consume foods rich in protein such as yellow cheese that is high in catecholamine derivative substance, tyramine. Tyramine or (4-hydroxyphenethylamine, para-tyramine) is commonly found in nature as it’s readily formed from its precursor amino acid, tyrosine by the action of the enzyme, aromatic amino acid decarboxylase (AAADC).

Tyramine oxidase is an MAO that acts on tyramine receptor or other MAO enzymes such as serotonin, catecholamine, benzylamine, and beta-phenylethylamine (Baker etal, 2011). Tyramine is a receptor for both isoforms of MAO, MAO-A and MAO-B. Tyramine stimulates alpha and beta adrenoceptors in the blood, producing vasodilation.

To elicit antidepressant effect using MAO inhibitor, it’s necessary to block MAO-A, the subtype of MAO involved in deamination of noradrenaline and serotonin (5-HT). However, the inhibition of MAO-A alone will elevate tyramine effects, also known as the cheese effect that includes acute hypertension well beyond 200 mmHg when engaged in various common endurance activities. Modest levels of physical endurance elevate the systolic blood pressure even higher, in excess of 400 mmHg.

According to Sandler (1981), it’s commonly accepted that the monoamine oxide (MAO) inhibiting moiety of drugs have a relevant role in the treatment of clinical depression. Intervention in cheese effect includes treating acutely elevated blood pressure only if there is evidence of end organ injury and only in supervised care setting (Finberg etal, 1983. In conclusion, according to Corn (1990), a new group of reversible selective inhibitors of MAO provide the benefit of antidepressant efficacy analogous to older irreversible non-selective drugs devoid of the cheese effect, and restrictive diet. This has played a significant role in the decline of the use of the MAOI antidepressants. Also, the availability of the newest class of antidepressants, including the paroxetine and fluoxetine provide more effective alternatives to the monoamine oxidase inhibitors, thereby eliminating the risk of tyramine effect.

References

Corn, T. H. (1990). Reversible Inhibitors of Monoamine Oxidase A: Antidepressants Without Cheese Effect? International Review of Psychiatry, 2(2), 187–192. https://doi.org/10.3109/09540269009028282

Finberg, J.P.M. & Gillman, K. (2011). Selective inhibitors of monoamine oxidase type B and the “cheese effect”, Douce, P. & Youdim, M.B.H. (eds.). International Review of Neurobiology, Academic Press, Volume 100, Pages 169-190https://doi.org/10.1016/B978-0-12-386467-3.00009-1 Get rights and content

Meyer, S.J. & Quenzer, L.F. (2019). Psychopharmacology: Drugs, the Brain, and Behavior. Oxford University Press. www.oup.com

Ramachandraih, Chaitra T.; Subramanyam, Narayana1; Bar, Kral Jurgen2; Baker, Glen3; Yeragani, Vikram K.4, Antidepressants: From MAOIs to SSRIs and more. Indian Journal of Psychiatry 53(2): p 180-182, Apr–Jun 2011. | DOI: 10.4103/0019-5545.82567

Sandler M. (1981). Monoamine oxidase inhibitor efficacy in depression and the ‘cheese effect.’ Psychological Medicine. 1981;11(3):455-458. doi:10.1017/S0033291700052764

ABCD APPROACH TO CARDIOVASCULAR INTERVENTION

A: ACE INHIBITORS

B: BETA BLOCKERS

C: CALCIUM CHANNEL BLOCKERS

D: DIURETICS

EXCERPT ONE:

ABCD APPROACH TO CARDIOVASCULAR INTERVENTION: ACE INHIBITORS

The ACE inhibitors are the Angiotensin converting enzyme inhibitors that inhibit the conversion of Angiotensin I to Angiotensin II thereby, terminating the process that usually results in the release of aldosterone, leading to vasoconstriction and thus, elevation of blood pressure.

According to Litch & Mazur (2019), the precursor for the release of aldosterone is the detection of the plummeting pressure of the blood-delivering kidney tissue, blood volume, and renal perfusion. In other words, the release of aldosterone is triggered by the sensing of decrease in blood pressure, including hypoperfusion in the renal arteries. In response, the kidneys release renin. Renin functions as a rate-limiting enzyme that splits angiotensinogen, a serum globulin secreted by the liver, to form Angiotensin I. Enzymes in the lungs known as Angiotensin converting enzymes convert Angiotensin I to Angiotensin II. Angiotensin II, a vasoconstrictor induces the release of aldosterone (Litch & Mazur, 2019).

Aldosterone is a sodium ions-retaining hormone that is followed by water thereby, elevating the blood volume and thus, increasing blood pressure. This process is a mechanism of cardiovascular regulation known as renin-Angiotensin-aldosterone system or RAAS, which plays a significant role in homeostatic control of blood pressure. Another side of sodium ions retention is increased excretion of potassium to maintain the electroneutrality or electrolyte balance of the blood. Pharmacotherapeutically, agents used in blood pressure intervention inhibit the release of rennin, the Angiotensin II converting enzyme, Angiotensin receptor, or aldosterone receptor. Excess RAAS activity contributes to vasoconstriction, endothelial dysfunction, and cardiac hypertrophy. RAAS inhibitors stimulate the production of rennin.

ANGIOTENSIN RECEPTOR BLOCKERS (ARBS LOSARTAN))

Meanwhile, based on the information above and other scientific evidence, selecting drugs for hypertension involves considering whether it’s a primary or secondary hypertension. Primary hypertension is idiopathic in etiology. Whereas secondary hypertension is iatrogenic, in this case, renal hypertension that is secondary to renal dysfunction. Thus, rennin inhibitor is not the appropriate drug. The appropriate drugs include ACE inhibitors and Angiotensin II type 1 (AT1) receptor blocker. The advantages of using ACE inhibitors and AT1 receptor blocker over renin inhibitor include avoiding tasking the kidney and the heart further, which can lead to cardiac hypertrophy and cardiomegaly. Also, these drugs inhibit aldosterone release thus, preventing vasoconstriction and increased blood volume. The disadvantages of using ACE inhibitors include the risk of plummeting blood volume, the risk of hypovolemic shock, and hypotension.

According to Corballis et al. (2022), recent findings indicate that the Angiotensin-converting enzyme II plays important role in the regulation of the RAAS system. It also plays important role in COVID-19 infection by facilitating the penetration of cells by COVID-19 virus. However, considering that Angiotensin II is a potent vasoconstrictor, inhibiting Angiotensin II converting enzyme prevents the activation of Angiotensin II. Nevertheless, irrespective of its implication in COVID-19 virus infection, Angiotensin II converting enzyme is important in cardiovascular function. The choice is to weigh between benefits and risks.

ABCD APPROACH TO CARDIOVASCULAR INTERVENTION: BETA BLOCKERS

Beta blockers block beta adrenergic receptors. Beta blockers or antagonists act on beta adrenergic receptors, inhibiting their expression. Beta receptors are GPCRs with different subtypes and isoforms. According to Gersh etal (2013), beta receptor is a part of adenylyl cyclase (AC) pathway. G-protein pathway links beta receptor to adenylyl cyclase when the G-protein is in excitatory state. When it’s in inhibitory state, the result is muscarinic stimulation following vagal stimulation. When stimulated, adenylyl cyclase produces cAMP from ATP.

According to Gersh etal (2013), the intracellular second messenger of beta receptor signaling is cAMP. This conformation leads to the opening of calcium ion channels thereby, increasing the rate and force of myocardial contraction and also, increase in reuptake of cytosolic calcium into the sarcoplasmic reticulum thereby, eliciting relaxing effect.

According to Gersh etal (2013), beta blockers are effective in antianginal intervention because their mechanism of action reduces the demand for oxygen induced by either strenuous exercise or other physical endurance that increases the demand for oxygen and increased heart contractility. They are also effective in antiarrhythmic intervention. Beta blockers are no longer approved as first-line of cardiovascular treatment for hypertension by the Joint National Council of the USA (JNC) (Gersh etal, 2013). The prototype beta blocker is propranolol which inhibits both B1 and B2-receptors (Gersh etal, 2013).

ANTI-ARTEROSCLEROTIC AND ANTI-ATHEROSCLEROTIC CONTROL OF CARDIOVASCULAR DISEASE

Atherosclerosis is formed by plaque formation and fat deposits in the blood vessels. The result is stenosis or narrowing of the blood vessels and often, leading to complete obstruction of blood vessel. The consequential hardening of the vessels is arteriosclerosis. This can lead to restricted blood flow, hypoxia, deprivation of oxygen and blood flow to the brain, leading to ischemic cardiovascular accident or stroke. Often the plaque deposits can breakaway to form a circulating bolus or clot known as thromboembolism or simply, embolus or static clot known as thrombolus or simply, thrombus.

Non-steroidal anti-inflammatory drugs prevent platelet adhesion, act as anti-coagulants, and anti-inflammatory agents that enhance blood flow by reducing the viscosity of the blood. They are commonly known as blood thinners. Some drugs used in routine treatment and in emergency as blood thinners and clot busters include aspirin (routine baby aspirin), warfarin, coumadin, and heparin.

EXCERPT TWO:

Novel oral anticoagulants or Non-vit K antagonist oral anticoagulants (NOACs) are the newest anticoagulants available. According to Hoffman & Monroe (2017), the properties that make NOACs unique and safer unrivalry as anticoagulants include their differences from the mechanism of action of Vit-K anticoagulants that include the dose-response relationship between NOAC and Vit-K anticoagulants skew slightly in favor of NOACs because NOACs bioavailability is more predictable than Vit-K anticoagulants. Also, because NOACs molecules are much smaller, they tend to reach targets where other anticoagulants cannot.

Also, the reversibility of NOACs protease activity makes them safer and easier to intervene in case of overdose. However, there is the possibility of rebound procoagulation if target concentration is interrupted, making continuous administration necessary. Also, it’s easier to upregulate or downregulate the effects of NOACs by manipulating the amount of substrate available for target protease. Hence, according to Hoffman & Monroe (2017), the biochemical properties of NOACs make them appropriate for use in conditions whereby predictable and manageable degree of anticoagulation is necessary. What I see as the future of oral anticoagulant therapy in terms of the use of NOACs and the classic anticoagulants such as warfarin is increased options to choose from when deciding on what generation of anticoagulants to select for the appropriate anticoagulation therapy. However, NOACs are more likely to be selected because their molecular properties, safety, and ease of use.

THE ENDTHELIAL CARDIOVASCULAR CONTROL APPROACH

The endothelium is a single cell layer lining the lumen of the vessel wall. It plays many important roles involved in maintain cardiovascular physiology. Healthy endothelium translates to healthy blood vessel, which in turn translates to unobstructed blood and nutrient perfusion in the body. In other words, damage to the endothelium can result in pathophysiological conditions such as hypoperfusion, inflammatory condition, auto-immune response, vasoconstriction, and stenosis. Eventually, interrupted perfusion and damage to the blood vessels can result in ischemic cerebrovascular accident.

It’s also important to note that the vascular endothelium can produce two potent vasodilators such as nitric oxide and prostaglandin. Vascular endothelium can also produce a very potent vasoconstrictor known as the peptide endothelium-1 thereby, reminding us of the bidirectional or reverse activities of the vascular endothelium.

Meanwhile, having the ability to activate two opposing functions within the endothelium can serve important pharmacotherapeutic purpose in maintaining optimum blood pressure as seen in the use of methyldopa in combination with the amiloride in controlling high blood pressure especially, in pulmonary arterial hypertension. Whereby, ET-1, a vasoconstrictor activates the ET-A receptor, leading to vasoconstriction. While the activation of ET-B receptor by ET-1 leads to the stimulation of nitric oxide release, a potent vasodilator, leading to equilibrium that maintains optimum blood pressure (Davenport & Maguire, 2015).

These opposing functions can be taken advantage of by skewing the mechanisms of action of the ET-1 to the direction we prefer either of by inhibiting the function of the ET-1 on ET-A receptor when trying to reduce blood pressure or stimulating the action of ET-1 on ET-A receptor when trying to mimic the action of digoxin, which is useful in improving myocardial contraction. According to Dienel et al. (2018), subarachnoid hemorrhage is a devastating sub-type of cerebrovascular accident caused by the rupture of the cerebral aneurysm. Vascular endothelial receptor subtype ET-A or Endothelium-A is responsible for the posthemorrhagic large artery spasms or vasospasms (Dieniel et al., 2018). However, it’s revealed that posthemorrhagic microcirculatory dysfunction that leads to hypoperfusion, thrombosis, and vasospasm is caused by the depletion of nitric oxide that counterbalances the effects of ET-1 that is released during subarachnoid hemorrhage.

Therefore, administering ET-1 antagonist or ET-A receptor antagonist is an appropriate intervention measure after cerebrovascular accident or subarachnoid hemorrhage. According to Gwozdz et al. (2000), factors involved in the development of protracted cerebral vasospasm after subarachnoid hemorrhage include damage to the endothelium and hypoxia as a result hypoperfusion, including spasmogenic substances such as ET-1. According to Gersh (2013), endothelial B-3 receptors mediate the vasodilation elicited by nitric oxide administration or nitrates in response to the vasodilating action of b-adrenergic blockers. Nitroglycerin, a nitric oxide is also a coronary vasodilator that acts by decreasing systemic resistance thus, lowering heart and reducing the demand for oxygen. Hence, nitroglycerin is also effective in anti-anginal intervention and stroke in which immediate restoration perfusion is necessary to minimize physiological and functional injury. Viagra (Sildenafil Citrate) is a nitric oxide that is used in men to treat erectile dysfunction because acts by facilitating vasodilation thereby, restoring blood flow.

ARRHYTHMIAL CARDIOVASCULAR CONTROL APPROACH

According to hopkinsmedicine.org (2023), Cardioversion is a procedure used to return irregular heartbeat to regular beat. Cardioversion is also used to resuscitate the heart in case of life-threatening emergency. In most cases, the goal is to restore the heart to normal or regular rhythm. Similarly, the goal or end-point of long-term management of patients with arrhythmia or irregular heartbeat using anti-arrhythmic drugs is to either prevent or terminate an arrhythmia in progress. However, according to Brunton et al. (2011), anti-arrhythmic drugs have bidirectional mechanisms of action. They can control arrhythmia as well as cause it especially, in long-term therapy.

Therefore, treating arrhythmia requires resolving the underlying factors (Brunton et al., 2011). Hence, it’s essential to determine the exact type of arrhythmia, whether atrial arrhythmia or ventricular arrhythmia for effective therapy. Therefore, my response to the question of what should be the end-point of long-term management of patients with arrhythmias and what should be done reflects the position of experts in this area that the type of arrhythmia be determined and treatment targets the root cause of the arrhythmias (Brunton et al., 2011).

ABCD APPROACH TO CARDIOVASCULAR INTERVENTION: CALCIUM CHANNEL BLOCKERS

Calcium channel blockers (CCBs) or calcium channel antagonists act by vasodilation and decreasing the peripheral vascular resistance (Gersh etal, 2013). Calcium channel blockers are classified into two major groups: Dihydropyridines (DHPs) and Non-Dihydropyridines (Non-DHPs).Nifedipineisthe first prototype of theDHPs, followed by Amlodipine. The non-DHPs include Verapamil and Diltiazem. The common pharmacological mechanism of action linking both members of the group is the selective inhibition of the L-Type channel opening in the vascular smooth muscle and in the myocardium.

Differences in DHPs and non-DHPs can be determined from their varying binding sites on the calcium channel openings and their increased vascular selectivity of the DHP drugs. Calcium channel blockers are contraindicated in heart failure. There are two pharmacologically identified calcium channel blocker subtypes namely: the L-Type and the T-Type. The long-acting subtype or the L-Type opening calcium channel is blocked by calcium channel blockers with increased activity by the catecholamines. The action of the L-Type subtype of the calcium channel blockers is to enhance the efflux of significant amount of calcium ions necessary for the transduction of contraction, through calcium-induced calcium reflux from the sarcoplasmic reticulum.

The T-Type, T for transient subtype of the calcium channel blockers opens at greater negative potentials than the L-Type. The T-Type calcium channel blockers play relevant role in the initial depolarization of the sinus and the atrioventricular node. Calcium channel blockers inhibit the efflux of calcium ions through the calcium channel thereby, restricting the amount of calcium ions available to innervate contraction. The result is vasodilation and negative inotropic effect, that is usually moderate in DHPs due to the unloading action of the peripheral vasodilation.

According to Gersh etal (2013), betablockers inhibit the renin-angiotensin pathway by reducing renin-release while antagonizing the hyperadrenergic conformation in heart failure, calcium channel blockers collectively, have no such inhibitory action. Thus, beta blockers, and not calcium channel blockers are the recommended agents in heart failure. Example of such beta blocker is dobutamine. Beta blockers are also effective as antianginals because they reduce the demand for oxygen induced by physical exercise or other strenuous physical endurance that increase heart contractility and the demand for oxygen.

EXCERPT THREE:

ABCD APPROACH TO CARDIOVASCULAR TREATMENT: DIURETICS

According to Ernst & Moser (2009), thiazides diuretics become available in the late 1950s and are the first effective oral antihypertensive drugs with acceptable side-effect history. Five decades later, thiazides still maintain important the role of invaluable medications for pharmacotherapeutic treatment of hypertension. Thiazides lower blood pressure when used alone and also when used in adjunct to other antihypertensive agents. The review article in this discussion focuses on thiazides as the diuretics used most often for prolonged antihypertensive therapy.

According to Ernst & Moser (2019), most thiazides have a half-life of approximately eight to twelve hours thereby, allowing for effective once daily dosing. Chlorthalidone is the most unrivalled long-acting thiazide with elimination half-life of fifty to sixty hours due to its large volume of distribution. Meanwhile, thiazides have significant residual effects after discontinuation. However, rapid volume expansion, weight gain, and decreased renin levels occur after withdrawing thiazides. But blood pressure rises gradually and does not immediately attain pretreatment levels. Whereas adherence to lifestyle changes such as weight loss, reduction in sodium and alcohol intake in nearly seventy percent of patients perhaps, leads to antihypertensive interval for up to one year after prolonged thiazide-based pharmacotherapy is discontinued.

According to the article, many physicians consider thiazides as the diuretics of choice for prolonged antihypertensive pharmacotherapy. The hypertension sensitive to thiazides is considered to be low-renin or salt-sensitive hypertension. Small studies have indicated thatthiazides can induce antihypertensive effect in patients with chronic kidney disease. However, the use of thiazides in severe renal deficit remains impractical.

Chlorothiazide is relatively insoluble in lipids thus, large doses are necessary to achieve levels adequate to reach site of action. While hydrochlorothiazide has relatively higher bioavailability that is approximately sixty to seventy percent absorbed that is enhanced by food intake. Nonetheless, hydrochlorothiazide and chlorthalidone are often erroneously described as equal in potency. However, analogous trials of the two drugs indicate that hydrochlorothiazide is approximately twice less potent than chlorthalidone. Irrespective of a long evidence of efficacy as antihypertensive agents, thiazides continue to attract debate. They are only utilized in one third of antihypertensive therapy for which they are more appropriate.

In conclusion, the take home message from this review article is that thiazides need to be utilized more in the treatment of hypertensive for which they are most appropriate. However, cost-effectiveness is also put into consideration when it comes to drug formulary and insurance network coverage. However, I think the authors’ message suggests that appropriate selection, dosing, and monitoring of patients on diuretics can immensely achieve the intended antihypertensive goals. But the authors neglect to address other reasons why diuretics are under prescribed even when most appropriate, such as formulary inventory and drug selection restriction within a health insurance network.

ANTIHYPERTENSIVE DRUGS AND PHARMACOGENETICS

There are different classes of cardiovascular drugs, including different approaches to treatment in different ethnic groups. It’s now well-documented that different ethnic groups respond to cardiovascular drugs differently thereby, giving credence and validation to the significance of pharmacogenetics. Available evidence indicates that black patients respond more effectively to treatment with some specific antihypertensive drugs especially, calcium channel blockers such as diltiazem. While white patients respond favorably to clonidine or the alpha 2 agonists.

Hence, as we learn from this different ethnicity response to different antihypertensive drugs; the specific area that I think should be an important focus for developing new drugs to improve the treatment of hypertension is through evaluating past research data and health records to determine what drugs have worked effectively in each ethnic group and expand research studies on those drugs targeting those ethnic groups by determining how the moiety of those evidence-based antihypertensive drugs can even be modified further for more efficacious antihypertensive drugs targeting those ethnic groups. That’s applied pharmacogenetic approach to developing new drugs to improve the treatment of hypertension.

References

Brunton, L., Chabner, B., & Knollman, B. (2011). The Pharmacological Basis of Therapeutics (12th ed.). The McGraw-Hill Companies, Inc.

Corballis, N., Tsampasian, V., & Vassilliou, V.S. (2022). Renin-Angiotensin-Aldosterone Inhibitors and COVID-19 Infection. Current Hypertension Reports, 24: 425 – 433. Hhttp://doi.org/10.1007/s11906-022-01207-3

Davenport, A.P. & Maguire, J.J. (2015). Endothelium Receptors and Their Antagonist. Seminars in Nephrology, Vol. 35, No. 2: 125 – 136.

Dienel, A., Liu, H., Nehrkorn, K., Plesnila, N., Scholler, K., Schwarzmaier, S.M, & Terpolilli, N.A. (2018). Microvasospasms After Experimental Subarachnoid Hemorrhage Do Not Depend on Endothelin A Receptors. American Heart Association, Inc. Doi: 10.1161/STROKEAHA.117.020028. Http://ahajournals.org

Dishy V, Sofowora G, Harris PA, Kandcer M, Zhan F, Wood AJ, Stein CM. The effect of sildenafil on nitric oxide-mediated vasodilation in healthy men. Clin Pharmacol Ther. 2001 Sep;70(3):270-9. doi: 10.1067/mcp.2001.117995. PMID: 11557915.

Ernst, E.M. & Moser, M. (2009). Use of Diuretics in Patients with Hypertension.

The New England Journal of Medicine, 361;22. WWW.NEJ.ORG

Gersh, B.J. & Opie, L.H. (2013). Drugs for the Heart (8th ed.). Elsevier Saunders. www.elsevier.com

Gwozdz, B., Harabin-Slowinska, M., Hendryk, S., Jedrzejowska-Szypulka, H., Josko, J., Lange, D. (2000). Effect of Endothelin-1 Receptor Antagonist BQ-123 On Basilar Artery Diameter After Subarachnoid Hemorrhage (SAH) In Rats. Journal of Physiology & Pharmacology, 51(2): 241 – 249.

Hopkinsmedicine.org (2023). What is Electrical Cardioversion? https://www.hopkinsmedicine.org/health/treatment-tests-and-therapies/electrical-cardioversion#:~:text=Cardioversion%20is%20a%20procedure%20used,and%20even%20sudden%20cardiac%20death

.Litch, N.A. & Mazur, E.E. (2019). Lutz’s Nutrition and Diet Therapy (7th ed.). F.A Davis Company. www.fadavis.com

Antidepressants The Cheese Effect

Antidepressants The Cheese Effect Antidepressants The Cheese Effect

Antidepressants The Cheese Effect