pharma sheet #15 - Mohammad A.okdeh

Pharmacology
Tuesday 19.10.2010
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Note about yesterday lecture: Talking about ephedrine, just for your knowledge, the dosage slide is put here because physicians didn’t use to prescribe ephedrine for children younger than 6 years and older than 12 years. But now this is possible. Now if you were obliged to administer this drug for children less than 6 years old then you have to ask the child’s physician or at least a specialist.

The last few lectures we talked about adrenergic receptors agonists, and their effect on the human body physiology. Today we will talk about adrenergic receptors antagonists and we’ll continue to see how they affect our bodies.
This topic is a serious one. Cause it has many interactions with our patients and many applications in dental practice. And what makes this more complicated is that many people take β blockers (β antagonists).
This antagonism exerts its effect by more than one mechanism, one of these mechanisms is by inhibiting the α receptors, and this mechanism by itself has further complications, for example α1 receptors respond by giving adrenergic effect (constriction in the vessels) while α2 receptors respond by opposing this adrenergic effect(feedback inhibition toward noradrenalin release), and here we talked about a drug called clonidine which stimulates α2 (α2 agonist)or it can be considered literally as an adrenergic antagonist.
So when giving a drug that is not selective toward α1 or α2 this will produce mixed action, and thus selectivity of α receptors antagonist is very important because of the opposite responses of the two α receptors.
β receptors antagonists are also very important, they are used every day. Students who have seminars, people who have to stand in front of crowds or maybe official representatives of big corporations use these drugs to reduce sympathetic activity and thus the effects of GLOSSOPHOBIA (fear of speaking in front of people).
NOW THE DR. IS TALKING ABOUT THE SLIDE THAT CONTAINS THE DRUGS AND THEIR AFFINITY TOWARD EACH RECEPTOR
- Why do we use the adrenergic antagonists?! Actually we use it to reverse the chronic sympathetic symptoms, for example when we want to reduce anger, or treat excessive hypertension by reducing peripheral resistance (especially during hypertension episodes which requires a very potent agent that act on α1 receptors), or maybe to oppose tachycardia.
Excessive sympathetic activity is a characteristic of a number of pathological statuses like :
- Hypertension
- Angina pectoris
- Cardiac arrhythmia
For example in angina pectoris, which is a disorder where oxygen supplies for the heart do not meet the demands, heart rate increases in order to compensate for this oxygen shortage. But this will increase the load on the heart, and this will lead eventually to a cycle of positive feedback. So to prevent this fetal condition, we administer β blockers to preserve heart rate normal range.
Sympatholytics: are those drugs that lyses sympathetic neurotransmitters, and so they act as antagonists. These substances bind to both α and β receptors and here we again highlight the selectivity issue. As we want to obtain the therapeutic effect, then the drug should be selective toward α1 and β1 receptors. And by this we avoid the side effects that will result from the binding to α2 and β2 receptors such as bronchoconstriction and the activation of the sympathetic pathway caused by the binding to α2 receptors. So the best antagonists are drugs with high selectivity toward α1 and β1 receptors.
Alpha adrenoreceptors blocking agents:
- Non-selective type:
We have two types, reversible and irreversible binding. The irreversible binding has a unique advantage, which is the duration of the effect. These irreversible agents are long-acting. Their effect is sustained because as they bind irreversibly to the receptors the body tend to overcome this irreversible binding by synthesizing new receptors, and this process needs about 24 hours to begin and thus the effect persist for a longer time.
But when do I need the effect to be sustained?! In some pathological cases where the adrenal medulla is invaded by tumor cells, the medullary production of catecholamines (adrenaline and nor adrenaline) is increased excessively, this disorder is a chronic one that needs surgical intervention. So to oppose this over production of catecholamines we give the patient a long-acting alpha antagonist agent.
- Phenoxybenzamine (B),an irreversible alpha antagonist, binds irreversibly to α1 and α2 receptors. It’s used to reverse vasconstrictional shock And also in acute hypertension (although its use is largely reduced nowadays). This drug as any other drug has some adverse effects like; hypotension (due to lack of sympathetic vasoconstriction) and tachycardia; tachycardia occurs due to hypotension (reflex tachycardia) and mainly due to the binding to α2 receptors that increases the sympathetic activity. So this drug (if it is to be used) should be administered in accompany with β blockers to prevent arrhythmia.
The only application it has in dentistry that patients who use this drug are susceptible to have xerostomia.
Here somebody asked: In the case of ultra-rapid metabolizers, where we increase the dose in order to overcome the rapid metabolization and to guarantee an effective dose level, can we administer an irreversible agent instead? And by this we decrease the toxicity that may result from the high doses? The dr. said as a pharmacist he would increase the dose without being afraid of the toxicity because as these patients’ metabolism is high they will eliminate the drug faster than normal people and by this there will be no toxicity.
Another question: If the patient after was given Phenoxybenzamine suffered from hypotension, what is the medical procedure should be done to reverse this adverse effect? The dr. said the better procedure is to give him dopamine because it has an effect on receptors other than α1 receptors (D receptors). Or you can give something that will affect the entire sympathetic system of the body. (Anything that will antagonize phenoxybenzamine physiologically can be given).
- Phentolamine (A) is a very important drug in dentistry, it binds to α1 and α2 receptors reversibly.
Phentolamine mesylate (also known as OraVerse) is used as a reversal agent (i.e. any drug that have an effect opposite to the originally administered drug, and can reverse its effect if it was given after the first drug) in the treatment of reversal of anesthesia, by injecting it after the completion of the medical procedures in patient’s mouth in the same technique we followed to inject the anesthesia and actually in the same location. Moreover we inject it in a quantity equal to the quantity of adrenaline injected (Ratio = 1:1). The mechanism of action can be summarized by that this drug competes with adrenalin (which was used to localize the injected anesthesia and to increase the duration of action) on α1 receptors and by this terminating the effect of adrenalin and therefore numbness.
In the handout we have a statistical study that illustrates the effect of Phentolamine mesylate on the time needed to recover from anesthesia, refer to it to know more.
- Side effects:
• Trismus which is the inability to normally open the mouth due to many reasons that affect muscles of mastication.
• Parasthesia which is the sensation of tingling, pricking, or numbness of a person’s skin with no apparent long-term physical effect. It is more generally known as the feeling of "pins and needles" in the site of needle insertion.
- NEXT LECTURE WE”LL COMPLETE ABOUT THE ALPHA SELECTIVE ANTAGONISTS.




God Bless You
Mohammed A. Okdeh
19/10/2010

tz no 15 :D