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Old 02-10-2008, 11:26 PM   #1
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Toxic and therapeutic effects of medications

It may be hard to believe, but much of the toxicity of drugs is just an extension of their therapeutic actions. No drug can be deemed completely safe for humans. They are all toxic at certain dosage. In some cases, toxicity can be avoided by managing the dose and close monitoring. In others, by not administering it in the first place, especially if the indications for it are not very strong. In treating hypertension, for instance, a drug which is necessary and beneficial is also toxic when given in doses large enough for optimal benefit. Adding a second drug with different toxicity allows for a reduced dose and toxicity of the first one. Some drugs act on single receptors in different tissues. To mitigate their toxicity, they should always be given in lowest therapeutic doses. Another way to lower toxicity is by manipulating the concentration of the drug in different parts of body, thus increasing the drugs' selectivity (asthma meds for instance).

Interestingly, many drugs (including thiazide diuretics) were discovered by experimenting with toxic or therapeutic effects of other similar drugs (in a clinical setting, of course).
Before drugs can be clinically tested, toxicity studies must be done. Pre-clinical toxicity studies determine potential human toxicities, design tests for toxic mechanisms and predict specific toxicities which must be monitored in clinical trials. There are some limitations. These toxicity studies can cost 41 million or more per successful drug and take up to five years. The information needed for clinical trials (supplied by the toxicity studies) includes the "no effect" dose (max. dose at which a specific toxic effect is not seen), minimum lethal dose and median lethal dose. These are used to calculate the intial dose of the drug to be tried in people.
I wonder if the same process is used here and how much of the R&D is actually done here since it is so costly. There is much more information but I have to stop for now. It's bedtime.

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Old 02-11-2008, 05:26 AM   #2
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Re: Toxic and therapeutic effects of medications

Quote:
Originally Posted by flowergirl2day View Post
...
I wonder if the same process is used here and how much of the R&D is actually done here since it is so costly.
flowergirl
Thanks so much for the info, FG. Will be anxious to hear what else you learn.

The cost of testing is expensive and it is one of the (many) reasons testing isn't done with alternative medicines. Only the rich can afford to test...

Bethsheba

 
Old 02-17-2008, 11:03 AM   #3
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Re: Toxic and therapeutic effects of medications

I did some reading about beta blockers again. It seems that everytime I do, I learn something new.

There are three generations of beta blockers. The drugs belonging to the 1st generation are used mostly for treating portal hypertension, arrhythmia and thyroid conditions.
The 2nd generation of beta blockers is used in people with CAD, arterial hypertension, arrhythmia and heart failure. The drugs in the 3rd generation of beta blockers have additional vasodilating effects and are used in treating arterial hypertension and heart failure. Nebivolol, the new drug we've been hearing about, is in this group of beta blockers. The third generation of beta blockers is said to have a reduced incidence of new onset of diabetes mellitus, and fewer or no metabolic side effects.

There are many differences between individual beta blockers and they should not be considered interchangable. Some of these differences include selectivity, lipid solubility, partial agonist activity, bioavailability, local anesthetic action, and the very important elimination half-life. The half-life ranges from 10 minutes (Esmolol) to 14-24 hours (Nadolol). My beta blocker, Bisoprolol, has a half life of 9-12 hours. Bioavailability, which is dose-dependent, ranges from 0 (Esmolol) to >90 with Penbutolol. Atenolols' bioavailability is 40, Propranolol 30, Bisoprolol 80, Labetalol 30 according to my drug book.

The low bioavailability of Propranolol and other drugs means that the oral administration leads to a much lower drug concentration than would be achieved with the same dose intravenously. Due to the differences between individual people, the plasma concentrations of the same dose of a drug vary. Some people are poor metabolizers and their plasma concentrations are very high after administration (up to ten times higher) than of those people who are good metabolizers. This is seen especially with metoprolol. I wonder what symptoms such person experiences with the plasma concentration ten times the normal. Severe side effects, maybe? I'll have to look into it further.(I am still looking for the reasons behind my severe breathing problems.) Most of the beta-receptor antagonists are absorbed well with peak concentration in 1-3 hours.

Lipid solulibility makes a difference also. The more lipid soluble beta blockers are taken up and metabolized rapidly by the liver (Metoprolol). The less lipid soluble ones (Nadolol) are not metabolized in the liver and are mostly excreted by the kidneys unchanged. The result is that plasma half-life and duration of action is much longer.

The reason beta blockers should not be used in people with asthma is that no agent is purely cardioselective, especially in large doses. The beta1 blockers antagonize mainly cardiac beta1 receptors in the heart BUT the degree of beta2 blockade varies in other tissues. No tissue has just one group of receptors - all tissues have both with one predominating - for instance beta1 in the heart, beta2 in bronchioles. Thus, during an asthma attack, even a minimal degree of beta2 blockade from cardioselective beta1 Bisoprolol can cause big trouble. Pre-existing asthma and other forms of airway obstruction worsen with beta blocker use. Even a very mild asthma can become SEVERE after a beta receptor blockade. Beta blockers should not be used at all in people with reactive airways. If they are, it must be with great caution. I am on a low dose of a beta blocker with 20% decrease in pulmonary function when tested last year. Probably should not be on it at all.
Good place to stop for now.

flowergirl

 
Old 02-17-2008, 02:09 PM   #4
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Re: Toxic and therapeutic effects of medications

[The reason beta blockers should not be used in people with asthma is that no agent is purely cardioselective, especially in large doses. The beta1 blockers antagonize mainly cardiac beta1 receptors in the heart BUT the degree of beta2 blockade varies in other tissues. No tissue has just one group of receptors - all tissues have both with one predominating - for instance beta1 in the heart, beta2 in bronchioles. Thus, during an asthma attack, even a minimal degree of beta2 blockade from cardioselective beta1 Bisoprolol can cause big trouble. Pre-existing asthma and other forms of airway obstruction worsen with beta blocker use. Even a very mild asthma can become SEVERE after a beta receptor blockade. Beta blockers should not be used at all in people with reactive airways. If they are, it must be with great caution. I am on a low dose of a beta blocker with 20% decrease in pulmonary function when tested last year. Probably should not be on it at all.
Good place to stop for now.

Thank you Fower - thank you thank you thank you....

This is the EXACT information that I needed -- I have had mild asthma EXTREMELY well controlled for the past 5 years. Once I was switched from the rgular Torpol to the generic and then back again - my breathing problems started with a vengence - and have continued for (4) months.

My Dr. did not BELIEVE that such a low dose (the 25mg Toprol XL that I take) would interfere or affect my breathing at all -- THIS PROVES THAT is not always true. Thank you SO MUCH... I will print this out and bring it to him

flowergirl[/QUOTE]

 
Old 02-17-2008, 05:04 PM   #5
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Re: Toxic and therapeutic effects of medications

Hi Vanessa,

I am glad you're finding this information helpful. The fact that beta blockers cause bronchospasms and breathing problems in people with asthma and other pulmonary conditions has been throughly documented through numerous studies and is nothing new. It is the reason beta blockers are contraindicated in treatment of hypertensive people with these types of conditions. Your doctor is well aware of this fact. That is also the reason your pulmonologist told you to stop your beta blocker rightaway with the worsening of your breathing problems.
Toprol X-L is metabolized by the enzyme CYP2D6. Coadministration with certain enzyme-inhibiting drugs in poor metabolizers results in high blood concentration, which causes the beta blocker to lose its cardioselectivity. Also, some of us lack this enzyme and the drug is not metabolized properly, resulting in high concentrations. It reduces blood pressure by about 8.1/7.7mmHg.
When discontinuing this drug, it should be done over 1-2 week period with your doctor monitoring you. The dosage is reduced gradually. Some people have hidden coronary artery disease of which they are not aware. These people might run into problems if they stop the drug suddenly. People with angina might find their symtoms getting worse. When this happens, Toprol should be temporarily reinstated until the other issues have been dealt with. Good luck, Vanessa. I hope your doctor will be understanding about you wanting to discontinue this drug. There are so many other drugs for him to choose from. It should not be a big deal.

flowergirl

 
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