Calcium Channel Blockers
 |
Calcium-Channel Blockers Commonly Used Brand Names in the United States: Adalat (nifedipine), Calan (verapamil), Cardene (nicardipine), Cardizem (diltiazem), Cardizem CD (diltiazem), Cardizem SR diltiazem), Covera-HS (verapamil), Dilacor XR (diltiazem), Diltia XT (diltiazem), DynaCirc (isradipine), Isoptin (verapamil), Nimotop (nimodipine), Norvasc (amlodipine), Plendil (felodipine), Procardia (nifedipine), Procardia XL (nifedipine), Sular (nisoldipine), Tiamate (diltiazem),Tiazac (diltiazem), Vascor (bepridil), Verelan (verapamil) Commonly Used Brand Names in Canada: Adalat (nifedipine), Apo-Diltiaz (diltiazem), Apo-Nifed (nifedipine), Apo-Verap (verapamil), Cardene (nicardipine), Cardizem (diltiazem), Cardizem SR (diltiazem), Isoptin (verapamil), Nimotop (nimodipine), Novo-Diltazem (diltiazem), Novo-Nifedin (nifedipine), Novo-Veramil (verapamil), Nu-Diltiaz (diltiazem), Nu-Nifed (nifedipine), Nu-Verap (verapamil), Plendil (felodipine), Renedil (felodipine), Sibelium (flunarizine), Syn-Diltiazem (diltiazem), Verelan (verapamil) Disclaimer The information in this section has been taken from a number of sources. It is meant to give you information about certain medicines, but it does not cover all of the possible uses, warnings, side effects, or interactions with other medicines and vitamin or herbal supplements. This page should not be used as medical advice for individual problems. Please talk to your doctor and/or your pharmacist for full prescription information. Why do I need to take a calcium-channel blocker? Calcium-channel blockers are used to control high blood pressure (hypertension), chest pain (angina), and irregular heartbeats (arrhythmia). How do calcium-channel blockers work? Calcium-channel blockers slow the rate at which calcium passes into the heart muscle and into the vessel walls. This relaxes the vessels. The relaxed vessels let blood flow more easily through them, thereby lowering blood pressure. How much do I take? There are many different kinds of calcium-channel blockers. The amount of medicine you need to take may vary. Talk to your doctor or pharmacist for more information about how and when to take this medicine. If you are taking an "extended-release" calcium-channel blocker (any that end in XL, XR, XT), do not chew or crush the pills. What if I am taking other medicines? Other medicines that you may be taking can increase or decrease the effect of calcium-channel blockers. These effects are called an interaction. Be sure to tell your doctor about every medicine and vitamin or herbal supplement that you are taking, so he or she can make you aware of any interactions. The following are categories of medicines that can increase or decrease the effects of calcium-channel blockers. Because there are so many kinds of medicines within each category, not every type of medicine is listed by name. Tell your doctor about every medicine that you are taking, even if they are not listed below.
While on calcium-channel blockers, you should also avoid smoking. Smoking while you are on calcium-channel blockers may cause a rapid heartbeat (tachycardia). Also, some studies have shown that grapefruit juice interferes with your body's absorption of this medicine. If you are going to drink grapefruit juice, you should wait at least 4 hours after having taken your medicine. What else should I tell my doctor? Talk to your doctor about your medical history before you start taking calcium-channel blockers. The risks of taking the medicine need to be weighed against the good it will do. Here are some things to consider if you and your doctor are deciding whether you should take a calcium-channel blocker.
What are the side effects? Sometimes a medicine causes unwanted effects. These are called side effects. Not all of the side effects for calcium-channel blockers are listed here. If you feel these or any other effects, you should check with your doctor. Common side effects:
Less common side effects:
Rare side effects:
Again, tell your doctor right away if you have any of these side effects. Do not stop taking your medicine unless your doctor tells you to. If you stop taking your medicine without checking with your doctor, it can make your condition worse. See on other sites:
American Heart Association
MEDLINEplus Updated March 2002 |
Source
Calcium Channel Blocker Acts As Male Contraceptive; Produces Reversible Male Infertility
Procardia (Nifedipine) appears to have contraceptive potential, and the calcium channel blocker also appears to cause reversible male infertility. The research stemmed from earlier observations that men who presented to infertility clinics were often taking a calcium channel blocker. Investigators noted the cholesterol content of the membrane was significantly reduced. Cholesterol synthesis significantly increased in sperm treated with nifedipine. The team subsequently determined that these drugs act by changing the cholesterol content of the membrane. If you load sperm with cholesterol, you can make them nonfunctional, and that is what these drugs are doing. The idea of regulating sperm through cholesterol metabolism is not an idea that has been previously pursued. The researchers noted that if physicians have a male patient on a calcium channel blocker and they are experiencing difficulties with infertility, it is reasonable to try a different antihypertensive. Men should then wait approximately 3 months before attempting to impregnate their partner in order for new sperm to generate that have been unaffected by the calcium channel blocker.
Joint Annual Meeting of the American Society for Reproductive Medicine and the Canadian Fertility and Andrology Society September 1999 Toronto, Canada
COMMENT: An interesting side effect of a commonly used drug. There seems to be far better alternatives to calcium channel blockers for most people. One should consider seeking an alternative if they are taking one of these drugs.
 |
Epidemiologic Review of the Calcium Channel Blocker Drugs An Up-to-date Perspective on the Proposed Hazards  Jorge
R. Kizer, MD, MSc; Stephen E. Kimmel, MD,
MSCE In the setting of soaring popularity,
postmarketing studies of calcium channel
blockers came to suggest an increase in a
variety of major adverse end points. The
evidence, however, was largely
observational, and large-scale trials
capable of addressing the concerns were
wanting. Clinical trials now support the
safety and efficacy of the long-acting
dihydropyridines for patients with both
uncomplicated and diabetic hypertension,
although conventional therapies and, in
the latter case, angiotensin-converting
enzyme inhibitors have superior proof of
benefit. By contrast, short-acting
dihydropyridines should be avoided. In
the acute coronary syndromes,
Arch Intern Med. 2001;161:1145-1158 |
-blockers
remain the treatment of choice; the
evidence for nondihydropyridines remains
inconclusive. Stable angina calls for
Source
calcium-channel blocker calcium-channel blocker,any of a class of drugs used in treating hypertension, angina pectoris, and certain arrhythmias. They prevent the calcium ions needed for muscle contraction from entering the cells of smooth and cardiac muscle. This causes blood vessel walls to relax and blood to flow more freely to the heart, ...
Source
CALCIUM CHANNEL BLOCKING DRUGS
DRUGS INCLUDED IN THIS CATEGORY
There are three types of calcium antagonists in common use. These three types are from three distinct chemical classes.
-
The phenyl alkylamines, e.g. verapamil
-
The benzothiazepines, e.g. diltiazem
-
The dihydropyridine derivatives, e.g. nifedipine, felodipine, nimodipine and amlodipine
OVERVIEW
Self poisoning from calcium channel blockers (CCBs) is the most common cause of in-hospital death from self poisonings in Australia (Buckley et al 1995). Morbidity and mortality is generally due to cardiovascular collapse resulting from a combination of extreme peripheral vasodilation, myocardial depression and impaired myocardial conduction. Extra-cardiac toxicity such as hyperglycaemia, lactic acidosis, seizures and non-cardiogenic pulmonary oedema are less common but imply a poorer prognosis.
Sustained release preparations are available and produce both delayed and prolonged toxicity.
Individuals vary considerably in their response to CCBs dependent on underlying diseases and other medication. However, doses only 2-3 times the normal dose may cause profound toxicity in susceptible individuals.
MECHANISM OF TOXIC EFFECTS
All act by preventing the opening of voltage-gated calcium channels (the L type). The major actions are vasodilation (inhibiting contraction of vascular smooth muscle) and block of cardiac conduction, particularly the SA and AV nodes where there are no sodium gated channels and conduction is totally dependent on calcium flux.
Binding of the various calcium antagonists to these channels may be both use dependent and voltage dependent.
KINETICS IN OVERDOSE
Absorption:
All calcium antagonists are rapidly absorbed from the small intestine. Peak levels of standard formulations of these drugs occur in therapeutic use within 1-2 hours. All of these drugs have a significant first pass effect with bioavailability being as low as 10-40% for verapamil and diltiazem. The bioavailability is likely to increase in overdose as the first pass effect is saturable.
Verapamil has two enantiomers with different kinetics and activity. The S isomer is more active but has a shorter half life and lower bioavailability than the R isomer. The higher proportion of S isomer that is available is the major reason why IV verapamil has more cardiac effects for a given serum concentration than oral verapamil.
Distribution:
All CCBs have large volumes of distribution and moderate CNS penetration
Metabolism & Elimination:
All CCBs are metabolised in the liver to less active or inactive metabolites.
The half life of nifedipine, verapamil and diltiazem in therapeutic use is short (3-8 hours). Newer dihydropyridine drugs have considerably longer half lives. There is no data on the half life in overdose.
There may be significant enterohepatic circulation.
Controlled Release Medication
Due to their short half lives, the older CCBs (verapamil, diltiazem and nifedipine) are frequently sold in controlled release preparations. The kinetics of drugs in these preparations are quite different and alter in overdose. This also alters the clinical presentation (i.e. cause delayed presentation and toxicity) and the optimal method of gastrointestinal decontamination.
(See also Controlled release drugs in overdose)
CLINICAL EFFECTS
Cardiac
Hypotension, due to a combination of vasodilation (relative volume depletion), heart block and myocardial depression develops over the first few hours if a standard preparation has been ingested or may be delayed in onset for up to 24 hours if a controlled release preparation has been ingested. Intractable hypotension and/or asystole is the usual mode of death.
Increasing heart block typically occurs in a sequence from sinus bradycardia to 1st degree heart block to junctional bradycardia (with absent p waves) to a slow idioventricular rhythm to asystole. This may occur with any CCB but higher degrees of block are much more common with verapamil and diltiazem.
Gastrointestinal
Nausea and vomiting are common. The effect of CCBs on the gut can lead to an ileus which may significantly interfere with gastrointestinal decontamination of controlled release preparations.
Other effects are rarely life-threatening but include hyperglycaemia, lactic acidosis, seizures and non-cardiogenic pulmonary oedema (may be delayed in onset). These are less common and occur only in poisonings with significant cardiac effects.
Late presentation
This is most likely to occur with sustained release preparations and the clinical effects will be similar. If the patient is asymptomatic, and more than 24 hours have elapsed, then no treatment is indicated. In all other circumstances the treatment, including gastrointestinal decontamination, should be done as usual.
INVESTIGATIONS
Blood levels:
These are unhelpful in management.
ECG:
Repeated measures of the ECG, with continuous monitoring if available, serves as a measure of severity and is the best guide to the need for specific treatment.
DIFFERENTIAL DIAGNOSIS
There are a number of drugs that can lead to a patient presenting with profound hypotension and bradycardia. Correct diagnosis is important as these drugs have different specific treatments.
DIFFERENCES IN TOXICITY WITHIN THIS DRUG CLASS
In therapeutic use, verapamil is relatively cardio-selective with more significant effects on cardiac conduction while the dihydropyridines are predominantly selective for smooth muscle and lead primarily to peripheral vasodilation. Diltiazem's effects lie between these two groups.
In overdose all these drugs have both cardiac and vasodilating actions. However the cardiac effects of verapamil and diltiazem appear to be generally more profound and few deaths have been reported from dihydropyridine overdose alone.
DETERMINATION OF SEVERITY
Prognosis correlates best with the degree of heart block. Hypotension due to vasodilation without heart block usual responds to fluid loading and is rarely life threatening. Other factors that increase the severity of the overdose are:
-
patients with underlying heart disease
-
late presentation/ ineffective gastrointestinal decontamination
-
coingestion/regular treatment with beta blockers or digoxin (antidotes to these drugs may also be considered in this case)
-
old age
TREATMENT
Supportive:
IV access with normal saline fluids should be secured as soon as possible. ECG monitoring in intensive care is indicated for all but the most trivial poisonings.
GI Decontamination:
Gastric lavage should be used in sustained release verapamil or diltiazem poisonings and patients presenting within an hour of ingestion. Atropine should be given prior to lavage and in any patient who is vomiting. The aim is to prevent worsening bradycardia due to enhanced vagal tone associated with nausea and gastrointestinal decontamination.
Oral activated charcoal should be given to all patients ingesting any overdose of a CCB.
This should be followed by repeated doses of activated charcoal
Patients who have taken sustained release preparations require whole bowel irrigation .
Generous fluid replacement to counteract the volume depletion associated with gastrointestinal decontamination is important in overdose with vasodilating drugs.
Specific Antidotes:
The following large number of drugs/treatments have been claimed to act as antidotes for CCB poisoning. Many of these are supported only by occasional case reports. Our belief is that calcium is the most effective and logical agent to use. Atropine, isoprenaline, Insulin Dextrose Euglycaemia and glucagon are probably the best adjunctive treatments.
-
Calcium loading
-
Glucagon
-
Atropine
-
Isoprenaline
-
Cardiac pacing
-
Bay K 8644 (calcium channel agonist)
This is primarily indicated in patients with heart block (who have usually taken verapamil or diltiazem).
The patient should be given initially 10 mls of 10% calcium gluconate or calcium chloride (1 gram) and this can then be followed by a further gram every 3 to 5 minutes if there is no response in blood pressure or pulse rate. Large doses may be required (up to 10 grams as initial treatment and 30 grams in total).
Patients may require continuous infusion. Serum calcium should be measured but it should be noted that hypercalcaemia is the aim of treatment. In a number of our patients a response has only been seen with measurements of serum calcium between 4.0 & 5.0 mEq/L.
The treatment of hypotension without heart block should not usually require calcium or any cardioactive medication. It is possible that calcium will be cardiotoxic in patients in this situation (particularly those who have ingested dihydropyridines (eg nifedipine)) and may induce ventricular arrhythmias. Hypotension alone should initially be treated with volume expansion & pressor agents.
This is a well accepted antidote for beta-blocker poisoning. The rationale for its use in CCB poisoning is that it activates myosin kinase independent of calcium flux.
This appears to be a vary promising technique and has been effective in animal work as well as humans.
This should be tried in all patients with bradycardia. The aim is to reverse enhanced vagal tone associated with nausea and gastrointestinal decontamination. A response may only occur after calcium loading.
This is given to increase the heart rate. However it will generally be ineffective if there is a high degree of conduction block as its action is predominantly through increasing the frequency of impulses originating in the SA node.
This can be done to increase heart rate. Ventricular rather than atrial pacing should be performed as the AV node is usually blocked. However, in severe poisoning the heart may fail to capture and therefore this is not a substitute for pharmacological therapy.
Bay K 8644 (calcium channel agonist)
This is a logical antidote but it is not commercially available or licensed for use in humans for any indication. Animal studies using calcium channel agonists have not been very promising.
Elimination Enhancement:
This is unlikely to be useful.
LATE COMPLICATIONS, PROGNOSIS & FOLLOW UP:
Late complications/deterioration have been reported with controlled release preparations of verapamil and diltiazem. These may occur as late as 24 hours in asymptomatic patients and life threatening cardiovascular collapse and death can occur as late as two to three days post ingestion.
Long term sequelae have not been reported and no follow up is required after resolution of the clinical signs & ECG findings unless the patient has been profoundly hypotensive.
REFERENCES & FURTHER READING
-
Buckley NA, Dawson AH, Whyte IM, McManus P & Ferguson N. Six years of self-poisoning in Newcastle: 1987-1992. Med J Aust 1995;162:190-193.
-
Buckley NA, Dawson AH, Howarth DM, Whyte IM. Slow release verapamil poisoning. Use of polyethylene glycol whole-bowel lavage and high-dose calcium. Med J Aust 1993;158:202-204.
-
Howarth DM, Dawson AH, Smith AJ, Buckley NA, Whyte IM. Calcium Channel blocking drugs in overdose: an Australian series. Hum Exp Toxicol 1994;13:161-6.
-
Doyon S, Roberts JR. The use of glucagon in a case of calcium channel blocker overdose. Ann Emerg Med 1993;22(7):1229-33.
-
Pearigen P, Benowitz N. Poisoning due to calcium antagonists. Drug Safety 1991;6(6):408-30.
20/12/99 11:11:31
Copyright to Meditox Pty Ltd 1999,2000
Mechanism of Ca++-channel blocker action
-
Normally, an increase in the intracellular Ca++ concentration causes cardiac and smooth muscle cells to contract.
-
In cardiac muscle, Ca++ binding to troponin C relieves troponin inhibition of actin-myosin interactions. (see fig. 2 & fig. 4)
-
In smooth muscle, Ca++ binding to calmodulin activates myosin light chain kinase which in turn phosphorylates the P-light chain of myosin. This triggers contraction (i.e. actin-myosin interactions), but there appear to be additional Ca++ regulatory mechanisms. (see fig. 1 & fig. 3)
-
-
Channel blockers bind to the L-type channels ("slow channels"), which are abundant in cardiac and smooth muscle (see regulation of intracellular calcium). This may partially explain their rather selective effects on the cardiovascular system.
-
Different classes of Ca++ channel blockers bind to different sites on the a1-subunit, which is the major channel-forming subunit (a2, b, g, and d subunits are also present). See fig. 6
-
Different sub-classes of L-channels exist which may contribute to tissue selectivity.
| Why Nimotop? | |||
|
Pharmacology Nimodipineis a 1,4-dihydropyridine calcium channel blocker that binds to the a1 subunit of the L-type calcium channel (Alborch et al. 1995). Several properties may distinguish nimodipine from other members of this drug class.
Nimodipineis lipophilic, which enables it to cross the blood-brain barrier and achieve effective drug concentrations (Scriabine et al. 1988). Pharmacological Properties The underlying mechanism of the beneficial effects of nimodipine on neurological outcomes, as observed in clinical trials, remains unclear. However, this area is under extensive investigation, using normal animals as well as preclinical models of subarachnoid hemorrhage and cerebral ischemia. These studies have collected large amounts of data identifying several pharmacological properties that may be relevant to the drug’s clinical efficacy in patients with aneurysmal SAH. Increased cerebral blood flow Nimodipine increased cerebral blood flow following oral, intravenous, or intraarterial administration to dogs, cats, rabbits, goats, and monkeys (Scriabine et al. 1988). In most studies, the increases in cerebral blood flow were accompanied by only minor decreases in systemic blood pressure (Wadworth et al. 1992). Inhibition of cerebral vasoconstriction Nimodipine reduced vasoconstriction in pial arteries in response to hypertension, hypocapnia, or sympathetic nerve stimulation in anesthetized cats (Haws et al. 1984). Hypocapnia-induced cerebral vasoconstriction was blocked by nimodipine in rabbits and monkeys (Scriabine et al. 1988). Neuronal effects
Calcium influx is postulated to be the
final common pathway for irreversible
neuronal injury (Siesjö
1988).
Pisani et al. recently provided additional evidence supporting the importance of L-type calcium channels in the mechanism of cerebral ischemia (Pisani et al. 1998). By depriving slices of rat brain of oxygen and glucose and then monitoring levels of intracellular calcium and membrane potential, they were able to study the effects of nimodipine and other calcium channel blockers in an in vitro model of ischemia. Their results suggest that L-type calcium channels are the major gateway for calcium influx under these conditions, entering toward the late stage of membrane depolarization. Nimodipine was found to significantly reduce both the rise in intracellular calcium and membrane depolarization. Nevertheless, neuronal injury may also develop via pathways that are initially independent of voltage-sensitive L-type calcium channels. Excitatory amino acids released during periods of ischemia can produce early and delayed neuronal damage. Early neuronal damage appears due to influx of sodium, chloride, and water leading to osmolysis, whereas delayed neuronal injury appears due to calcium influx, which triggers a series of degradative changes leading to cell death (Siesjö 1988). Nimodipine may prevent delayed neuronal deficit by reducing this calcium influx. For example, nimodipine prevented hippocampal cell death induced by exposure to the excitatory amino acid glutamate (Krieglstein 1997). Reduced ischemic deficits Nimodipine was effective in animal models of global and focal ischemia (Scriabine et al. 1988). In these models, the arterial blood supply to the brain was interrupted for varying periods and then reperfused. Nimodipine improved cerebral circulation and reduced infarct size following middle cerebral artery occlusion in rats. Nimodipine reduced the increase in cytosolic free calcium measured directly in the cat cortex in response to middle cerebral artery occlusion and reperfusion (Uematsu et al. 1989). Furthermore, nimodipine improved neurologic recovery in pigtail monkeys subjected to a period of global ischemia when it was administered after the insult (Steen et al. 1985). Mechanism of Action The precise mechanism of action in humans is unknown. Although the clinical studies described demonstrate a favorable effect of nimodipine on the severity of neurological deficits caused by cerebral vasospasm following SAH, there is no arteriographic evidence that the drug either prevents or relieves the spasm of these arteries. However, whether or not the arteriographic methodology utilized was adequate to detect a clinically meaningful effect, if any, on vasospasm is unknown. Nimodipine is a calcium channel blocker. The contractile processes of smooth muscle cells are dependent upon calcium ions, which enter these cells during depolarization as slow ionic transmembrane currents. Nimodipine inhibits calcium ion transfer and thus inhibits contractions of vascular smooth muscle. Extracellular calcium levels are maintained at concentrations that are 10,000 times greater than the free calcium concentration present inside the cell. Cytoplasmic calcium concentrations may be increased in a number of different ways, including calcium influx via one of several calcium channels or by calcium release from intracellular binding sites. Nimodipine and other dihydropyridine calcium channel blockers primarily inhibit calcium influx through voltage-sensitive L-type calcium channels. Other pathways leading to elevated cytoplasmic calcium levels are insensitive to these drugs. Vasospasm
Vasospasm reduces cerebral blood flow;
severe reductions to 15–18 mL/100 g brain
tissue/min lead to loss of neuronal
electrical activity, whereas metabolic
functions are lost when cerebral blood
flow falls to 10–12 mL/100 g brain
tissue/min (Meyer
1990).
In the range between these thresholds,
low-level metabolism is still able to
maintain ionic homeostasis.
Isolated cerebral arteries undergo vasoconstriction when exposed to blood or post-hemorrhagic CSF; nimodipine blocks this in vitro vasospasm. Whereas nimodipine reduces vasospasm produced in animal models by injections of small volumes of blood, it does not block vasospasm induced by larger blood volumes (Meyer 1990). Angiographic results in patients with aneurysmal SAH indicate that the magnitude of vasospasm is unaffected by nimodipine treatment. Furthermore, clinical studies indicate that nimodipine does not increase overall cerebral blood flow in patients with aneurysmal SAH. Therefore, if nimodipine improves blood flow to some degree, it may occur in small arteries that are not visualized by angiography. The preferential dilation of small pial arteries by nimodipine is consistent with this mechanism.
|
|||
Furthermore,
nimodipine is very potent, with in vitro
nanomolar concentrations being effective
on human cerebral vessels. In 16 patients
who underwent extracranial-intracranial
bypass surgery for cerebral infarcts,
nimodipine administered intravenously was
also more effective in dilating small
pial arteries (<70 µ) than those larger
in size. Nimodipine did not dilate pial
veins (
Ischemia
develops when vasospasm leads to a
profound reduction in cerebral blood
flow. In the absence of sufficient
oxygen, neurons are no longer able to
maintain ionic homeostasis. One
consequence is that neurons depolarize,
which leads to an opening of
voltage-sensitive calcium channels and an
influx of calcium. Nimodipine may limit
this calcium influx and there by prevent
the neuron from sustaining irreversible
damage. For example, in rat hippocampal
neurons, nimodipine inhibited the
increase in intracellular calcium
produced by depolarization, and it
normalized calcium levels under
persisting depolarizing conditions.
The
brain may tolerate these severe
reductions in cerebral blood flow for
short periods; however, irreversible
brain damage may develop when low blood
flow is maintained for significant
periods of time. Neuronal function
recovers with increases in blood flow,
and even patients with delayed ischemic
deficits recover when blood flow is
increased slightly above these
thresholds. 
|
I promise to answer your message -- click here to send me a personal message
|
SUBSCRIBE: The Wednesday Letter is a free electronic monthly newsletter written and published by Karl Loren. You can view more than 50 back issues of this publication by clicking here. The Wednesday Letter subscription list is maintained on a secure server, no name is ever given or sold to anyone, and it is never used except for this Newsletter. It is automatically published on the Tuesday night just before the first Wednesday of every month. You can subscribe to this free monthly electronic letter by entering your eMail address and name below. You will then automatically receive a request for confirmation, sent to whatever address you have entered. If you do NOT receive this confirmation request, then you will not be subscribed. There may have been an error with your address and you should resubmit. The letter is never sent twice to the same address -- so you do not have to worry about a duplicate subscription. When you receive this confirmation request you must reply to it, or your subscription will not become active. No one can subscribe your name, and address, without you being notified, and if you get an unwanted notice of subscription you only need to DO NOTHING and the subscription will NOT be active.
REMOVAL: You can remove yourself from the subscription list in several different ways. Click here to read about this entire newsletter system. Every edition of The Wednesday Letter is delivered to your address with YOUR name and address in view on the letter, with a link that allows you to remove THAT name from the subscription list. If you try to send this removal message from an address different from the one you used to send in your original confirmation, then you will get a warning notice first, sent to the subscription address, asking you to confirm that you want to be removed from the list -- by replying to THAT request for confirmation, you will then be automatically removed. Thus, no one else can unsubscribe you, from some other computer, without your knowledge. But, if you send in the unsubscribe notice from the same machine used to receive the Letter, then the removal from the subscription list is automatic.
Personal Message: When you send a personal message to Karl Loren, you will receive a personal reply as per his instructions. Karl pledges that every personal message will get a personal answer. When you provide your mail address, we will send you free information including our free catalog and a cassette tape lecture by Karl Loren about heart disease, no charge, by mail, even if outside the US. You can select particular information you would like to receive, along with the free cassette tape and catalog.
You can reach Vibrant Life in many ways, including by mail to Vibrant Life, 2808 N. Naomi St., Burbank, CA 91504. Within the US and Canada, use the toll free number: (800) 523-4521, the local number: (818) 558-1799, the FAX: (818) 558-7299, eMail to kimberly@oralchelation.com or any one of the hundreds of message forms throughout the 50 web sites. Vibrant Life normally ships the same day we get an order. There are message forms on each of the 100,000+ pages on this and other sites where you can communicate with Vibrant Life. Check out our companion site, at: http://www.oralchelation.net where Karl's 2000 page book is published. Karl Loren is the author and webmaster for this BOOK, as well as for another web site about ORAL CHELATION. His personal philosophical articles are at PHILOSOPHY.
Copyright © April 25, 2008 2:38 AM by Karl Loren on behalf of Vibrant Life, ALL RIGHTS RESERVED. Permission is granted for non-commercial downloading, copying, distribution or redistribution on two conditions: One, that some form of copyright notice is included in every copy distributed or copied, showing the copyright belonging to Vibrant Life, Burbank, CA, at www.oralchelation.com . The second condition is that the material is not to be used for any purpose contrary to the purposes and objectives of this site. This permission does not extend to materials on this site which are copyrighted by others.