Journal of Pain & Relief
Open Access

Pain Control; Drugs; Epidemics; Therapy; Analgesics; Opioids;

Introduction

Calcium channels are functional pores in membranes through which calcium flows down an electrochemical gradient when the channels are open. Calcium channels exist in cardiac muscle, smooth muscle, and probably many other cellular membranes. These channels are also present in cellular organelle membranes such as the sarcoplasmic reticulum and mitochondria. Calcium functions as a primary generator of the cardiac action potential and an intracellular second messenger to regulate various intracellular events [1]. Calcium enters cellular membranes through voltage-dependent channels or receptor-operated channels. The voltage-dependent channels depend on a trans-membrane potential for activation. Receptor-operated channels either are linked to a voltage-dependent channel after receptor stimulation or directly allow calcium passage through cell or organelle membranes independent of trans-membrane potentials [2]. There are three types of voltage-dependent channels: the T, L, and N channels. The T and L channels are located in cardiac and smooth muscle tissue, whereas the N channels are located only in neural tissue. The T channel is activated at low voltages in cardiac tissue, plays a major role in cardiac depolarization, and is not blocked by calcium antagonists. The L channels are the classic “slow” channels, are activated at higher voltages, and are responsible for phase II of the cardiac action potential. These channels are blocked by calcium antagonists. Calcium channel blockers interact with the L-type calcium channel and are composed of drugs from four different classes: the dihydropyridine derivatives, the phenylalkyl amines, the benzothiazepines, and diarylaminopropylamine ether. The L-type calcium channel has specific receptors, which bind to each of the different chemical classes of calcium channel blockers. Systemic hemodynamic effects of calcium channel blockers represent a complex interaction among myocardial depression, vasodilation, and reflex activation of the autonomic nervous system. Nifedipine, like all dihydropyridines, is a potent arterial dilator with few veno dilating effects. Reflex activation of the sympathetic nervous system may increase HR. The intrinsic negative inotropic effect of nifedipine is offset by potent arterial dilation, which results in lowering of BP and increase in CO in patients. Dihydropyridines are excellent antihypertensive agents, owing to their arterial vasodilatory effects. Antianginal effects result from reduced myocardial oxygen requirements secondary to the afterload-reducing effect and to coronary vascular dilation resulting in improved myocardial oxygen delivery [3].

Discussion

Verapamil is a less potent arterial dilator than the dihydropyridines within minutes. Protein binding is and elimination half-life is approximately in hours. Nifedipine is available for oral administration in capsular form. The compound degenerates in the presence of light and moisture, preventing commercially available intravenous preparations. Puncture of the capsule and sublingual administration provide an onset of effects in minutes. Nicardipine is a dihydropyridine agent with a longer half-life than nifedipine and with vascular selectivity for coronary and cerebrovascular beds [7]. Nicardipine may be the most potent overall relaxant of vascular smooth muscle among the dihydropyridines. Peak plasma levels are reached 1 hour after oral administration, with bioavailability. Plasma half-life is of hours. Although the drug undergoes extensive hepatic metabolism with less than the drug excreted renally, greater renal elimination occurs in some patients. Plasma levels may increase in patients with renal failure; reduction of the dose is recommended in these patients. Verapamil’s structure is similar to that of papaverine. Verapamil exhibits significant first-pass hepatic metabolism, with a bioavailability [8]. One hepatic metabolite, norverapamil, is active and has a potency approximately that of verapamil. Peak plasma levels are reached within 30 minutes. Bioavailability markedly increases in hepatic insufficiency, mandating reduced doses. Intravenous verapamil achieves hemodynamic and dromotropic effects within minutes, peaking at few minutes and lasting up to few hours. Accumulation of the drug occurs with prolonged half-life during long-term oral administration. After oral dosing, the bioavailability of diltiazem is greater than that of verapamil. As with verapamil, hepatic clearance is flow dependent and major hepatic metabolism occurs with metabolites having 40% of the clinical activity of diltiazem. Hepatic disease may require decreased dosing, whereas renal failure does not affect dosing. Most significant adverse hemodynamic effects can be predicted from the calcium channel blockers’ primary effects of vasodilation and negative inotropy, chronotropy, and dromotropy. Hypotension, heart failure, bradycardia and asystole, and AV nodal block have occurred with calcium channel blockers. These side effects are more likely to occur with combination therapy with β-blockers or digoxin, in the presence of hypokalemia [9]. Calcium antagonists provide excellent symptom control in patients with unstable angina. In the absence of β-drenergic blockade, the shortacting dihydropyridine nifedipine may increase the risk of myocardial infarction or recurrent angina. When β-adrenergic blockers cannot be used, and HR slowing is indicated, verapamil and diltiazem may offer an alternative. Systemic hypertension, long recognized as a leading cause of cardiovascular morbidity and mortality, accounts for enormous health-related expenditures. Nearly a fourth of the U.S. population has hypertensive vascular disease; however, these individuals are unaware of their condition and another are inadequately treated. On a worldwide basis, nearly billion individuals are hypertensive. Hypertension management comprises the most common reason underlying adult visits to primary care physicians, and antihypertensive drugs are the most prescribed medication class. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure defined systolic BPs exceeding Hg and diastolic BPs Hg as stage hypertension. BPs less than were defined as normal and those in between as consistent with prehypertension. Risk for cardiovascular disease appears to increase at BPs exceeding, with a doubling in risk associated increment in systemic pressure. Thus, the most recent JNC report recommends drug therapy for prehypertensive disease in patients with compelling indications, such as chronic renal disease or diabetes. Antihypertensive therapy generally is targeted to achieve systemic BPs; however, for high-risk patients such as those with diabetes or renal or cardiovascular disease, lower BP targets are suggested, typically less. More than distinct medications are marketed for treatment of hypertension. Often, combined therapy with two or more classes of antihypertensive medications may be needed to achieve treatment goals. Although the specific drug selected for initial therapy now has been deemed less important than in the past, recognition that specific antihypertensive drug classes alleviate end-organ damage, beyond that simply associated with reductions in systemic BP, has led to targeted selection of antihypertensive drug combinations on the basis of coexisting risk factors such as recent myocardial infarction, chronic renal insufficiency, or diabetes [10]. For purposes of characterizing treatment urgency, severe hypertension is characterized as either a hypertensive emergency with target organ injury or hypertensive urgency with severe elevations in BP not yet associated with target organ damage. Chronic elevations in BP, even when of a severe nature, do not necessarily require urgent intervention and often may be managed with oral antihypertensive therapy on an outpatient basis. In the most extreme cases of malignant hypertension, severe elevations in BP may be associated with retinal haemorrhages, papilledema, and evidence of encephalopathy, which may include headache, vomiting, seizure, and/or coma.

Conclusion

Progressive renal failure and cardiac decompensating are additional clinical features characteristic of the most severe hypertensive emergencies.

Acknowledgement

None

Conflict of Interest

None

1. Cesa SL, Tamburin S, Tugnoli V, Sandrini G , Lacerenza M, et al. (2015) How to diagnose neuropathic pain? The contribution from clinical examination, pain questionnaires and diagnostic tests. Neurol Sci EU 36: 2169-2175.

Indexed at, Google Scholar, Crossref

2. Hush JM, Stanton TR, Siddall P, Marcuzzi A, Attal N, et al. (2013) Untangling nociceptive, neuropathic and neuroplastic mechanisms underlying the biological domain of back pain. Pain Manag NY 3: 223-236.

Indexed at, Google Scholar, Crossref

3. Seaman DR, Cleveland C (1999) Spinal pain syndromes: nociceptive, neuropathic, and psychologic mechanisms. J Manipulative Physiol Ther US 22: 458-472.

Indexed at, Google Scholar, Crossref

4. Zundert JV (2007) Clinical research in interventional pain management techniques: the clinician's point of view. Pain Practice US 7: 221-229.

Indexed at, Google Scholar, Crossref

5. Oaklander AL (2008) Mechanisms of pain and itch caused by herpes zoster (shingles). J Pain EU 9: 10-18.

Indexed at, Google Scholar, Crossref

6. Downar J, Crawley AP, Mikulis DJ (2002) A cortical network sensitive to stimulus salience in a neutral behavioral context across multiple sensory modalities. J Neurophysiol US 87: 615-620.

Indexed at, Google Scholar, Crossref

7. Jubeau M, Sartorio A, Marinone PG, Agosti F, Hoecke JV, et al. (2008) Comparison between voluntary and stimulated contractions of the quadriceps femoris for growth hormone response and muscle damage. J Appl Physiol US 104: 75-81.

Indexed at, Google Scholar, Crossref

8. Martin PG, Gandevia SC, Taylor JL (2006) Output of human motoneuron pools to corticospinal inputs during voluntary contractions. J Neurophysiol US 95: 3512-3518.

Indexed at, Google Scholar, Crossref

9. Lauritzen F, Paulsen G, Raastad T, Bergersen LH, Owe SG, et al. (2009) Gross ultra-structural changes and necrotic fiber segments in elbow flexor muscles after maximal voluntary eccentric action in humans. J Appl Physiol US 107: 1923-1934.

Indexed at, Google Scholar, Crossref

10. Bittar RG, Purkayastha IK, Owen SL, Bear RE, Wang S, et al. (2005) Deep brain stimulation for pain relief: a meta-analysis. J Clin Neurosci UK 12: 515-519.

Indexed at, Google Scholar, Crossref