pharma sheet #16-Sura Ala3mar

بسم الله الرحمن الرحيم

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http://www.mediafire.com/?1n5rb52k1hvh2s8
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By the Name of God
Pharma Lec. 16 24.10.2010
Adrenergic Antagonists/part 2


Last lecture we start talking about adrenergic antagonist, including non-selective α adrenergic blockers which are of two types... Irreversible binding to α1 and α2 receptors which include Phenoxybenzamine (B) That is rare to be used in dentistry except in case of adrenal tumor which will lead to spread adrenalin and noradrenalin in the body and as a result cause xerostomia , in this case we should make counter attack operation (which decrease sympathetic in the body)...

The reversible binding include Phenetolamine (A) which is widely used in dentistry as a reversal agent against anesthesia (if the anesthesia present in the mouth for along time so we have to reverse it ),, also if you give cartridge of anesthesia so you must give cartridge of phenetolamine with it..


In our lecture today we will talk about selective α1 blockers, β adrenergic blockers including selective β1 blockers and non-selective β blockers...

selective α1 blockers


They are called prazosin Family which include (doxazosin, prazosin, terazosin). The most famous agent is terazosin, the 1st and the oldest is prazosin and the one that is used in our countries is doxazosin (cardura).

As we know that the non-selective α blockers are α2 antagonists, that they block α2 receptors (which are for feedback inhibition) which will lead to decrease the feedback inhibition and increase adrenalin secretion lead to increase sympathetic...

Because of that we make new drugs which are selective α1 blockers that are widely used in two cases:
 As anti-hypertensive in patients with chronic hypertension (50-60 years old) who cannot respond to normal type of anti-hypertensive, so blocking α1 will lead to vasodilatation which will lead to tachycardia as a response of reflex.

 And in cases of prostate benign enlargement (hyperplasia) which occurs in old men (50-60 years old) within percentage of 60%. Those patients take prazosin mainly and doxazosin because on prostate gland we have α1 receptors (responsible for nutrition and enlargement) and if we make blockage to them so reduction in enlargement occur.



The side effects of these drugs include…

- Too much vasodilatation which will lead to something known as orthostatic hypotension which is a form of hypotension in which a person's blood pressure suddenly falls when the person stands up because of the pooling of blood in lower limb veins as a result of long time sitting. So in those patients who take prazosin family, dilatation more than in normal people and the pooling capacity of the legs more, result in less circulation. It’s recommended to set the patient for a while after getting out of dental chair to avoid fainting. You must know that heart failure patients shouldn’t lie on their back because this increases the work on heart.


- Xerostomia is other side effect. Now why these drugs make xerostomia?
As we know salivation and sweating are under sympathetic activity but the one who responsible for them is ach... Meaning that all ganglion, pre ganglion, post ganglions and their fibers are sympathetic but release ach at their ends. Now any drug against sympathetic or against ach (although they are against each other but the innervations is different so different effect) make xerostomia. So these drugs block α1 receptors so anti-sympathetic result in xerostomia.

- Nasal Congestion... This may result from all α blockers including (Phenoxybenzamine, Phenetolamine, doxazosin, prazosin, terazosin). These drugs antagonize Phenylephrine and ephedrine which are de-congesting.

- Lack of energy... All drugs that make vasodilatation make lack of energy.
- Drowsiness... Occur as a result of decrease blood supply to the brain because we have dilution toward vessels and this decrease the performance of the circulation.


Now we finished talking about α blockers let us go to β blockers..
b-adrenoreceptor blockade


These drugs are the drugs of choice for hypertension... In the 1960's β-blockers were developed, and the earliest prototype β-blocker was Propanolol, a non-specific β receptors antagonist, which is still widely used.While β -blockers are still widely used for the treatment of hypertension, exactly how they lower blood pressure has never been clarified.

β -blockers have a number of clinical applications including treatment of…
1. Migraines (use these blockers mainly propanolol as profelactive agents; meaning that u take for example One tablet per day and the pain will decrease gradually).
2. Hypertension 3. angina pectoris 4.cardiac arrhythmia(rapid pulsation of the heart)
5. Glaucoma (these drugs decrease the production of aqueous humor in the eye)

β-blockers are classified into three types selective, non-selective and intrinsic activity.

Non-selective β blockers

They are nadolol, pindolol, propranolol, tomilol.

These drugs block both β 1 receptors in cardiac tissue and β 2 in smooth muscle, liver and other tissues.

Now the blockage of β1 result in two types of activity; negative chronotrope (decrease in the
Heart rate) and negative inotrope (decrease pulse and contractility strength of the heart). This is exactly antagonizing Dobutamine which is β1 agonist.

The blockage of β2 will lead to side effects; broncoconstriction (asthma) which is the most important one and limit glycogenolysis (is the conversion of glycogen polymers to glucose monomers). These are the side effects of non-selective β blockers.
Remember that blockage of β2 has no clinical applications; it’s a side effect (adverse effect) because it's blocking as we said cause broncoconstriction so nothing known as β2 antagonism.

Patients medicated with nonselective beta-blockers have a significant risk for acute hypertensive episodes if they receive vasopressors contained in local anesthetics... in this case a drug – drug interaction between β blocking and adrenalin occur and this is result in hypertension why?
Because blocking of β2 cause vasoconstriction and also adrenalin cause vasoconstriction so result in excessive vasoconstriction which result in increase blood pressure. So you have to ask your patient whether he take β blockers or not.

We are going to talk in details about propranolol which is the most common drug taken.


Propranolol (B)

Unselective β blocker. It decreases the heart rate, cardiac output, decreases total coronary blood flow and oxygen consumption. It also causes bronchoconstriction by blocking β2 receptors in the lung, and Disturbances in the glucose metabolism.
The antihypertensive effect is still not clear. However, it inhibits the renal secretion of the renin which may play a role.


 Its therapeutic uses are wide and include…

1. Treatment of hypertension, often in combination with a diuretic.
2. Prophylaxis of angina pectoris and ventricular and superventricular arrhythmia, long-term prophylaxis of myocardial infarction (with a high risk of infarction and sudden death).
3. It is also used as a prophylactic of migraine.
4. in treatment of Hyperthyroidism, effective in blunting the widespread sympathetic stimulation that occurs in acute hyperthyroidism.
5. Propanolol and other b blocker may be lifesaving in protecting against serious cardiac arrhythmias.

 Propanolol and other β blockers (Timolol) are effective in diminishing intraocular pressure in glaucoma, this occur through inhibiting the secretion of the aqueous humor from the caliary body. Many patients with glaucoma maintains with these β blocker. Nonetheless in an acute attack of glaucoma, Pilocarpin is still the drug of choice.


 Side effects of propanolol... include heart failure, especially in patients with compromised myocardial function and Rapid withdrawal can lead to supersensitivity of β receptors, which can provoke anginal attack, arrhythmia, or myocardial infraction in addition to Rash, fever and prolonged use may cause fatigue, depression, sexual dysfunction

 Contraindications in using propanolol:
a. Propanolol must never give to any individual with chronic obstruction pulmonary disease because it causes an immediate contraction of the bronchiolar smooth muscles, which may result in a serious and potential lethal side effect.
b. Propanolol affects the carbohydrate metabolism, and may increase the action of insulin, so diabetics treated with insulin should use it with caution.


Note that the doctor told us to read propanolol from slides and ask him anything we don’t understand so I prefer to write it here to avoid confusing while studying.

Now we finished talking about non-selective β blockers, let us go to …

Selective β1 blockers


Also known as cardio selective β blockers. They are Acebutolol, atenolol, esmolol, metoprolol. Researches found that patients who take these drugs, on long term, vasodilatation occur because β1 blockers lead to inhibit renin secretion so inhibition of angiotensin II which is the most potent vasopressor.

Two mechanisms control blood pressure... Short term control known as reflex-tachycardia (reflex vasoconstriction)… and long term control known as renin- angiotensin system.
But remember that we said blocking α1 will lead to vasodilatation which will lead to tachycardia as a response of reflex.

Now these agents give to asthma patients as well as to diabetic patients but diabetic patients should not take non-selective β blockers in general, because they block β2, interactions occur as a result of excessive insulin secretion in high dosage.





Now look at these graphs...
These graphs compare the effects of 1-antagonist
and 1-antagonists on :-

1. Peripheral vascular resistance.
If we give patient 1-antagonist (prazosin Family)
So the peripheral vascular resistance decreases more.
But 1-antagonists have no effects at all on peripheral
Vascular resistance.



2. Cardiac output.
1-antagonist has no effect on cardiac output because
It is selective only to α1 receptors. But 1-antagonists
Affect the cardiac output by decreasing heart rate
And cardiac output.




3. Mean arterial blood pressure.
Both 1-antagonist and 1-antagonists decrease
the mean arterial blood pressure because α1 affects
the vessels and β1 affects the heart.








Guidelines to consider when using vasopressors in patients medicated with  blockers…

Patients who take atenolo must:-

 1st Avoid the use of vasopressors, if reasonable.
 2nd If a vasopressor is to be used, record blood pressure and heart rate, then proceed as follows:

(a)after the injection of each cartridge, pause 5 minutes and reassess vital signs (HR,BP) before administering any additional local anesthetic; or


(b) Infiltrate the entire region to be treated by using a cartridge to provide constriction of local vessels, and then re-inject the region with a local anesthetic free of vasopressor.

In local infiltration anesthesia small nerve endings in the area of the dental treatment are flooded with local anesthetic solution, preventing them from becoming stimulated and creating an impulse. In another way its intra-ligamentary anesthesia using during restorative operations or extractions.



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The End
Best wishes …. Sura Al-A3mar



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