Antidepressants Alternative Complementary Therapies

INTRODUCTION

The theme of this discussion about antidepressant pharmacotherapy and other natural or alternative therapies in depression treatment includes evaluating behavioral health patients’ outcome in response to the use of psychotherapy alone, the use of pharmacotherapy alone, and the combination of psychotherapy and pharmacotherapy (psycho- pharmacotherapy), in addition to natural or alternative therapies for the treatment of depression. Evaluating the outcome of this combination of therapeutic interventions for the treatment of depression can provide the much-needed information for establishing evidenced-based standard for quality and effective clinical intervention for patients experiencing depression. After briefly reviewing the recent literature within the area of behavioral pharmacology, the question that needs to be addressed is whether the combination of pharmacotherapeutic response and cognitive behavioral response should become the endpoint in the treatment of depression.

DEPRESSION

In this discussion, there is no specific distinction between any form of depression. All forms of depression or depressive disorders are included. According to the American Psychiatric Association, depressive disorders include disruptive mood dysregulation disorder, major depressive disorder, persistent depressive disorder, substance or medication-induced depressive disorder etc. (American Psychiatric Association, 2022). With reference to gender as a predictor of the probability of depression, Coyle et al (2015) reports that the female to male ratio of predisposition to depression is 2 to 1.

PSYCHOTHERAPY

Psychotherapeutic response is derived from cognitive behavioral therapy or as a result of social exposure. In psychology, role or social modeling is a form of cognitive behavioral therapy. While cognitive behavioral therapy is categorized in psychology as a form of psychotherapy (Taylor, 2018).

PHARMACOTHERAPY:

EXCERPT ONE

Simply, treatment using antidepressant that induces therapeutic response. According to Johnson & Preston (2016), there are two classes of antidepressants that include typical and atypical antidepressants. The typical antidepressants are the older class of antidepressants that include the serotonin reuptake inhibitors such as the fluoxetine (Prozac) and paroxetine (Paxil). While the atypical antidepressants are the newer class of heterogenous compounds that are often referred to as second and third generation antidepressants (Crespo et al, 2010). They include maprotiline and nefazodone. This class of compounds selectively inhibit norepinephrine reuptake, also known as selective norepinephrine reuptake inhibitors (Crespo et al, 2010). The clinical decision of which class to select for intervention plan depends on symptomatic manifestations of the depressive disorder (Johnson & Preston, 2016).

Therapeutics guideline recommends SSRIs if symptomatic presentation includes anxiety and suicidal ideation (Johnson & Preston, 2016). While the atypical antidepressants are recommended in depressive symptoms including apathy and anhedonia (Johnson & Preston, 2016). There are also the alternative natural OTC antidepressants that include S-adenosylmethionine commonly known as SAM-e, 5-HT, and St. John’s Wort (Johnson & Preston, 2016).

PARAMETER FOR COMPARING EFFECTIVENESS AND THERAPEUTIC SUPERIORITY

EXCERPT TWO

The determinant of the effectiveness or superiority of the combination of antidepressant and psychotherapy over antidepressant monotherapy or psychotherapy alone for the treatment of simulated animal model of depression is the duration measured in minutes, of motility or agility when the animals are placed in water. To have a brief glimpse of what depression is, according to the American Psychiatric Association (2022) in its diagnostic and statistical manual fifth edition (DSM-V) definition of depression, which is used interchangeably with depressive disorder, depression involves sadness, feeling of emptiness, irritable mood with duration of episode, timing, and pathogenesis distinguishing each form of depressive disorder from another (American Psychiatric Association, 2022).Comer (2016) adds that depression or depressive disorder is a low, sad state that makes life seem pessimistic and overwhelming.

Meanwhile, Comer also reiterates that different manifestations of depression include emotional, behavioral, cognitive, motivational and physical manifestations (Comer, 2016). The emotional symptoms include feeling of sadness, loss of sense of humor, and in some cases, anhedonia (Comer, 2016). According to Comer (2016), depressed patients are not often interested in pursuing normal activities of daily living that are pertinent to maintaining quality of life due to depressed mood.

In terms of motivation, sometimes good hygiene is compromised due to amotivation and lack of interest again, in vocational or interpersonal relations. The behavioral symptoms manifest in less active and less productive living (Comer, 2016). The cognitive symptoms include low self-esteem, inferiority complex, indecision etc. (Comer, 2016). The physical symptoms can include psychosomatic feeling of malaise, headaches, indigestion, and constipation, loss of appetite etc. (Comer, 2016).

Castagne et al (2009) writes that the clinical diagnosis of depression requires the manifestation of various core symptoms such as depressed mood and decreased pleasure that are accompanied by other transient symptoms such as irritability, weight fluctuation, and sleep disruption. Karrouri et also echoes that depression is a common psychiatric disorder that usually results in poor quality of life (Karrouri et al, 2021).

According to Comer (2016), patients experiencing depressive disorders suffer solely from the depression subtype known as unipolar depression. This group of patients have no prior history of mania. Thus, there is the possibility of full recovery following treatment While contrary to depression, mania is a state of exhilarating euphoria coupled with a delusional sense of grandiosity. Manifestations of mania are the criteria for the diagnosis of two groups of disorders called depressive disorders and bipolar disorders (Comer, 2016).

Whereas bipolar disorder is marked by intervals of mania and depression, Comer (2016) describes major depressive disorder as a severe pattern of depression that disrupts activities of daily living not linked to drugs nor secondary to general medical conditions. Patients who experience major depression bouts devoid of previous history of mania are diagnosed with major depressive disorder (Comer, 2016). It can be further narrowed into seasonal if it alternates with seasons. Chronic unipolar depression is termed persistent depressive disorder. Cases of unipolar depression are often triggered by stressful experience especially, the month preceding the onset of the depression (Comer, 2016).

ETIOLOGY OF DEPRESSION AND THE ANTIDEPRESSANT LINK

EXCERPT THREE

Here the pathogenesis of depression is described in relation to the serotonergic pathway that is the basis for antidepressant prescription for the treatment of depression especially, the class of antidepressants known as selective serotonin reuptake inhibitors (SSRIs), the most frequently prescribed antidepressants. The conventional premises such as depression is a deficiency of neurotransmitters or that depression is a state of chemical imbalance in the brain thus, that antidepressants act by supplementing the deficient neurotransmitters to restore balance are incomplete, obsolete, or absolutely outdated (Andrade & Rao, 2010).

The most recent conventional explanation of the mechanisms of action of antidepressants reflecting the pathogenesis of depression is that antidepressants inhibit the reuptake or degradation of monoamine neurotransmitters such as serotonin, noradrenalin, and dopamine (Andrade & Rao, 2010).

Also, Andrade & Rao (2010) reaffirms that there is a vast body of evidence indicating that antidepressants act by stimulating neuroplastic alterations in the brain. A research study by Kreiss et al (1994) invigorates the clinical discoveries that drugs such as serotonin agonists induce 5-HT neurotransmission, either by inhibiting 5-HT uptake or by stimulating postsynaptic receptors directly to produce antidepressant effects.

Conventional antidepressant research evidence validates that drugs produce antidepressant effects by inhibiting reuptake or degradation of neurotransmitters such as serotonin. Meyer & Quenzer (2019) confirms that with the modulation of the 5-HT transporter, serotonergic neurotransmission ends with reuptake of 5-HT from the extracellular fluid, adding that 5-HT transporter is the target of some antidepressants. According to Meyer & Quenzer (2019), selective serotonin reuptake inhibitors act by inhibiting 5-HT. Serotonin reuptake is the process by which serotonin is eliminated from the extracellular fluid. 5-HT acts by binding to 5-HT receptors of which various subtypes have been discovered (Meyer & Quenzer, 2019). Also, it’s worth recalling that 5-HT is the end-product of serotonin synthesis from the amino acid, tryptophan that is derived from food. The process is regulated by enzymatic activity that is dependent on the availability of the intrinsic factor, tryptophan. Two steps are involved in the synthesis of serotonin.

The first step is the catalysis of tryptophan by the enzyme, tryptophan hydroxylase in which tryptophan is converted to 5-hydroxytryptophan (5-HTP). The second process involves the conversion of 5-HTP to 5-hydroxytryptomine (5-HT) catalyzed by the enzyme, aromatic amino acid decarboxylase (AADC). 5-HT is the serotonergic agonist that is transduced as neurotransmitter by serotonergic neurons that process serotonergic neurotransmitter.

There are two subtypes of tryptophan hydroxylase (TPH), TPH1 and TPH2. The TPH2 is the subtype of interest here because it’s expressed by serotonergic neurons that process 5-HT (Meyer & Quenzer, 2019). The drug, para-chlorophilalanine (PCPA) inhibits 5-HT synthesis by blocking the action of tryptophan hydroxylase.5-HT is available in drug stores as over the counter alternative to serotonergic antidepressant (John & Preston, 2016).

Taking some nutritional supplements with claimed potential health benefits doesn’t necessarily imply the delivery of those benefits. For example, taking 5-HTP supplements is not the same as taking 5-HT supplements as serotonin analog. Because while 5-HTP is a precursor to 5-HT, there is no guarantee that 5-HTP can be converted into 5-HT, a serotonin analog because there are other physiological processes competing for the converting enzyme. Thus, 5-HTP is not a guaranteed efficacious nutritional supplement for Serotonin supplementation. However, some suggest taking the 5-HTP in empty stomach for maximum benefit.

Pharmacotherapy (often antidepressants) is the most common treatment option for depression (Karrouri et al, 2021). Karrouri research team recommends the standardization of clinical interventions for the treatment of depression to facilitate informed and evidence-based clinical intervention decision. Thus, this discussion aims at contributing to fill that knowledge gap necessary for informed and evidence-based clinical decision for the treatment of depression.

A research study by Dekker et al (2008) comparing the efficacy of psychotherapy alone, pharmacotherapy alone, and combined pharmacotherapy and psychotherapy for the treatment of depression, using Hamilton Depression Rating Scale (HDRS), Clinical Global Impression of Severity and Improvement (CGI – S), THE Symptoms Checklist (SCL), and the Quality-of-Life Depression Scale (QLDS) etc. confirms that combination therapy is more effective than psychotherapy alone or pharmacotherapy alone.

According to Aaronson et al (2015), therapeutic wisdom and common understanding indicate that when treating major depression, two evidence-based effective treatments that include the combination of antidepressants and psychotherapy will improve the outcome better. In other words, the combination of psychotherapy and pharmacotherapy compared to pharmacotherapy alone or psychotherapy alone is more effective in improving patient outcome.

Bellino concurs with Aaronson’s team finding that the use of combined treatment with psychotherapy and pharmacotherapy is superior to the use of each therapy alone for the treatment of depression. In a systemic meta-analysis of ten randomized controlled trials comparing psychotherapy and pharmacotherapy in the treatment of depression, Bortolotti et al (2008) concludes that psychotherapy interventions can significantly supplement the conventional pharmacotherapy to improve patient outcome in depression treatment.

While the current standard of care for depression is usually drug prescription (Karrouri et al, 2021), what behavioral healthcare providers don’t inform patients before initiating drug treatment for depression is that most psychoactive drugs are addictive. And whereas antidepressants are not considered addictive, they are associated with withdrawal symptoms thereby, making complete discontinuation difficult (Haddad, 1999). Thus, weaning out of them is often difficult once initiated. Hence, pairing psychotherapy with antidepressants will facilitate earlier weaning from the drug while continuing with psychotherapy until behavioral health is fully restored.

Moreover, preponderance of evidence validates the superiority of the combination of psychotherapy and pharmacotherapy over either monotherapy alone. According to Ijaz et al (2018) research study, patients with treatment-resistant-depression can benefit from the inclusion of psychotherapy in combination with pharmacotherapy. While Balayan et al (2011) stresses that because the quality of life is negatively impacted during the course of major depression, numerous studies indicate that significant improvements are achieved using the combination of pharmacotherapy and psychotherapy compared to using either alone.

Blais et al (2013) adds that while depression is an ubiquitous and burdensome behavioral health disorder in the United States, there is substantial empirical evidence validating the superiority of combined psychotherapy and pharmacotherapy over either therapy alone. Also, Choi et al (2018) writes that current evidence validates that the combination of pharmacotherapy and psychotherapy is more effective than pharmacotherapy or psychotherapy alone. According to Cuijpers et al (2007), a meta-analysis of selected randomized trials indicates that the addition of psychotherapy to pharmacotherapy for the treatment of depression has added value compared to pharmacotherapy alone. Frank et al (1992) recalls from their research study that evaluates the rate of response to therapy indicating that the combination of pharmacotherapy and interpersonal psychotherapy for acute and chronic treatment of recurrent major depression in the elderly patients is associated with improved response.

Citing from the repertoire of information derived from the systemic review of ten randomized controlled trials that include seventeen comparisons between antidepressants, psychotherapy, or the combination of both therapies, Balkom et al (2013) concludes that the best evidence validates the superiority of combination over monotherapy.

From their network meta-analysis of the effectiveness of psychotherapies, pharmacotherapies, and the combination of both therapies in the treatment of depression, Cuijpers et al (2020) concludes that the combination of psychotherapy and pharmacotherapy is more effective than either alone in the treatment of depression.

Again, a two-year naturalistic, retroactive follow-up of patients treated with psychotherapy, pharmacotherapy, and the combination of both psychotherapy and pharmacotherapy indicates that the combination of both therapies is more effective in significantly reducing cases of relapse in patients treated for depression. Yet another meta-analysis of randomized research studies conducted by Cuijpers et al (2008) also indicates that the combination of pharmacotherapy and psychotherapy is more effective than psychological therapy alone.

With reference to their careful review of relevant literature retrieved from PubMed and other research literature databases, Li et al (2005) asserts that in comparison to control group that receives fluoxetine alone, the combination of fluoxetine and cognitive behavioral therapy achieves better result in depressed adolescents compared to those receiving antidepressants alone.

In his clinical assessment about the superiority of the combination of psychoactive drugs and psychotherapy over either therapy alone, Dr. Mintz (2006) writes that while we don’t know much about what is responsible for the superior effect of the combination of pharmacotherapy and psychotherapy over either therapy alone, some benefits of combination therapy can be attributed to simply the additive or cumulative effects of pharmacotherapy and psychotherapy.

Further, citing one hundred and fifteen research studies in validation of the declaration, Cuijpers et al (2013) reiterates that whereas without doubt that psychotherapy is an effective therapy for the treatment of adult depression, combined treatment with pharmacotherapy is more effective than either alone.

In his evidence-based applications of the combination of psychotherapy and pharmacotherapy for the treatment of depression, Dunlop (2016) argues that the combination of antidepressant pharmacotherapy and psychotherapy facilitates depressed patients’ recovery and also minimizes the risk of relapse

And according to Frank et al (2005), the review focusing on information reflecting antidepressant pharmacotherapy and psychotherapy for the treatment of depression in English literature, Frank et al (2005) reinvigorates the presumption that the use of combination therapy both from the outset and sequentially has a better health impact than either monotherapy alone, stressing the possible benefits of including a targeted psychotherapy to an incompletely effective pharmacotherapy and the addition of targeted pharmacotherapy to an incompletely effective psychotherapy for improved health outcome in depression patients. The American Psychiatric Association (2023) adds that psychotherapy is usually used in combination with drug for the treatment of behavioral health conditions.

However, in some cases, psychotherapy alone is the best option. While in other cases, the combination of psychotherapy and pharmacotherapy is the better choice than either alone. Hence, some researchers in this area of behavioral medicine suggest knowing the best option that can render the most improved result before settling for monotherapy or combined therapy.

Meanwhile, the conclusion is that the combination of both antidepressant pharmacotherapy and psychotherapy represents the most effective treatment than either alone. Belovicova et al (2017) declares from their animal behavioral study that to accurately predict animal behavior in a given test, it’s imperative to evaluate the animal’s behavior in its natural environment. Thus, it’s easy to expect that that when the test rodent is placed in water, its first instinct is to attempt to swim to safety, until it’s clear that such effort is futile, leading to the feeling of helplessness and surrender to fate.

According to Dekker et al (2001), patients treated concurrently with antidepressants combined with psychotherapy show significantly reduced episodes of depressive symptoms and relapse compared to those treated with antidepressants alone or placebo.

According to Fava & Guidi (2021), the combination of psychotherapy and pharmacotherapy reduces the risk of relapse in the treatment of patients with depression compared to those treated with psychotherapy or pharmacotherapy alone.

According to Ayuso-Mateos et al (2017), the combination of psychotherapy and pharmacotherapy yields significantly better results compared to psychotherapy or pharmacotherapy alone.

According to Devi et al. (2005), antidepressants are commonly used in the treatment of depression and anxiety. The effects of antidepressants following the initiation of treatment take weeks to begin to manifest. Depression is usually characterized by feelings of sadness, emotional withdrawal, inactivity, isolation, including anhedonia and nonchalance. Sometimes the symptoms of depression can deteriorate to suicidal ideation. Nonetheless, not all patients respond to antidepressant treatment.

Hence, the mechanisms of action of antidepressants are worth investigating to improve clinical benefits. In another instance, an article posted on the National Library of Medicine website reiterates that the main purpose of antidepressant intervention in depression is to mitigate the symptoms associated with it such as anxiety and feeling low; and also prevent relapse after the initiation of pharmacotherapy (InformedHealth.org, 2023).

According to Andrade & Rao (2010), there is a vast body of evidence indicating that antidepressants act by stimulating neuroplastic alterations in the brain. However, conventional premises such as depression is a deficiency of neurotransmitters or that depression is a state of chemical imbalance in the brain thus, that antidepressants act by supplementing the deficient neurotransmitters to restore balance are incomplete, obsolete, or absolutely outdated. The most recent conventional explanation of the mechanisms of action of antidepressants is that antidepressants inhibit the reuptake or degradation of monoamine neurotransmitters such as serotonin, noradrenalin, and dopamine thus, selective serotonin reuptake inhibitors or SSRIs are among the most common antidepressants in circulation today.

Also, the maladaptive response to depression pointed out by Chaudhury & Petkovic (2022) such as perceived inability to escape a situation can be altered by cognitive behavioral incentives that include environmental enrichment and role modeling. According to Fliugge & Fuchs (2006), another behavioral approach to simulate human depressive mood in animal models is the learned helplessness model, However, this model is beyond the scope of this paper because of its feasibility and ethical concerns.

his study by Cuijpers et al (2007) involves the activity scheduling of behavioral treatment of depression in which patients in this case, animal models are conditioned to pleasant stimuli and improved positive interactions with their environment that is analogous to cognitive behavioral therapy or psychotherapy in humans. This animal model of behavioral treatment without drugs is used to simulate psychotherapy in animal models of depression.

This is another research study by Kreiss et al (1994) focusing on the clinical discoveries that drugs such as serotonin agonists induce 5-HT neurotransmission, either by inhibiting 5-HT uptake or by stimulating postsynaptic receptors directly to produce antidepressant effects. Conventional antidepressant research evidence validates that drugs produce antidepressant effects by inhibiting reuptake or degradation of neurotransmitters such as serotonin.

Another research study by Dimascio et al (1979) testing the efficacy of tricyclic antidepressants alone, various psychotherapies alone, and the combination of pharmacotherapy and psychotherapy in a completely randomized clinical trials validates the superiority of combination therapy over either alone.

Castagne et al (2008) writes that the clinical diagnosis of depression requires the manifestation of various core symptoms such as depressed mood and decreased pleasure that are accompanied by other transient symptoms such as irritability, weight fluctuation, and sleep disruption.

In another meta-analytic research study, Cuijpers et al (2023) examines the relevance of cognitive behavioral therapy (CBT) intervention and its recommendation in common treatment guidelines, comparing psychotherapies, pharmacotherapies, and their combination for the treatment of depression. The research team reveals that combined treatment is more effective than pharmacotherapy alone.

Meanwhile, according to Ijaz et al (2018) research study, patients with treatment-resistant-depression can benefit from the inclusion of psychotherapy in combination with pharmacotherapy.

While Blayan et al (2011) stresses that because the quality of life is negatively impacted during the course of major depression, numerous studies indicate that significant improvements are achieved using the combination of pharmacotherapy and psychotherapy compared to using either alone.

Blais et al (2013) adds that while depression is an ubiquitous burdensome behavioral health disorder in the United States, there is substantial empirical evidence validating the superiority of combined psychotherapy and pharmacotherapy over either therapy alone.

DISCUSSION AND CONCLUSION

EXCERPT FOUR

The American Psychiatric Association (2023) adds that psychotherapy is usually used in combination with drug for the treatment of behavioral health conditions. However, in some cases, psychotherapy alone is the best option. While in other cases, the combination of psychotherapy and pharmacotherapy is the better choice than either alone. Hence, some researchers in this area of behavioral medicine suggest knowing the best option that can render the most improved result before settling for monotherapy or combined therapy. Frank et al (2005) writes that cognitive therapy focuses on cognitive remediation of negative thoughts and beliefs that influence behavior and pessimistic feeling of helplessness about a situation resulting in amotivation and failure to act or attempt to act. The conclusion is that the combination of both antidepressant pharmacotherapy and psychotherapy represents the most effective treatment than either alone.

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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.

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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

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