pharma sheet #19 - Enas Mahmoud

Pharmacology lecture

Note that I try to write what the Dr. said as much as possible and not what I have understood.. so you we will find some information repeated in the sheet because Dr. repeat them.. and I hope that you will enjoy with NSAID..

Now we will complete the story of NSAID..
Aspirin
-One of the best drugs ever been used .
-one of the most drugs used in life and it's very old.

When we talk about aspirin we talk about 3 ideas :
1-antiinflamatory.
2-analgesic.
3-antipyretic.
But How ?...... aspirin induces the inhibition toward COX1 and COX2 … so it inhibit PG's (prostaglandin's) synthesis.
Note that we don't differentiate between PG's subcategories but we give attention for thromboxane A2 . so while aspirin inhibits PG synthesis,it is also inhibits thromboxane A2 synthesis and remember that aspirin is the only NSAID whichcould induce this function. WHY?.....why because it inhibit ( binds to ) COX irreversibly.
So it is the only NSAID used as a prophylactic agent (drug ) against MI (myocardial infarction) and heart attack.
(Dr mentioned number of NSAID and he said that we will talk about all of them later on so I will not write them .)

We also talked about very nice idea..DOSING ISSUE.. we will talk about profen as an example ( but after that we will continue talking about aspirin). Regard profen tablets we will find tablets with 400 mg , 600 mg . it is very important that when you prescribe a drug such as profen you should determine number of tablets and the amount of the drug found in the one tablet if it is (for example) 400 ,600 …etc.
Now regard profen we have a nice relation between its analgesic effect and the the dose. if the patient takes certain dose of profen because of pain BUT after that if the patient still feel the pain then we will increase the dose for him. This means that analgesic effect depend on the dose and it is a direct relation.
All NSAID have a nice relation between their effect and their dose.
Regard Aspirin..if we give the patient:
-(1) tablet three times a day.. the effect is antipyretic just.
-(2) tablets three times a day.. the effect is analgesic.
-(3) tablets three times a day..the effect is anti inflammatory.
Note that the tablet of aspirin in the previous cases contain 350 mg.
BUT baby aspirin ( contain 81 mg ) inhibit thromboxane A2 and so inhibit platelet's synthesis and aggregation.
Dosing issue for profen is very important for you as a dentist more than aspirin.

Now….Back to aspirin…
We are talking about aspirin very much because it is the protype and we compare the others toward it. for example we say that profen is better than aspirin in 1-….,2-……, etc.
Aspirin is also important because patients with Rheumatic Arthritis also take it , you should understand how to deal with these patients.
The main idea regard aspirin in dentistry that you are dealing with patients (who take aspirin) have a tendency toward bleeding. WHY? Because aspirin inhibit platelet aggregation.
Remember that most of these patients take high dose of aspirin and this high dose will inhibit platelet aggregation surely.
Now.. what is the solution?
If the patient takes aspirin because of rheumatic arthritis then he should stop taking of aspirin 4-6 days and some books say 14 days ( although some studies advice not to do this).
The question was.. why should the patient stop aspirin taking for 14 days ( the safest line) before any surgery in general including that for dental procedures?
Because the half life for platelet is 14 days, so we give the body a chance to synthesis new platelets..why new platelets? Because in the old platelets aspirin binds to COX irreversibly and so the only solution is to have new platelets where aspirin is not bind to COX..
The patient could stop aspirin for a week and it could be sufficient But the safest line is 14 days which allow complete elimination for aspirin effect from the body.
( Now Dr. starts reading from the slides then he says that there is some things called ABT and Prothrombin time which used to measure the bleeding time..regard these things we will take about it in the topic of anticoagulants and antiplatelets)
The main idea that we have prolonged time for bleeding and we don’t want to have bleeding during surgery which is very pad.
Low dose of aspirin is safe but in high dose you should take care.
Low dose does not induce a wide range of bleeding risk following minore dental surgery But in extensive surgery it may require some considerations.
This may be of even greater concern for patients medicated with Clopidogrel..Why clopidogrel? What is its role?.......the elderly take aspirin and clopidogrel ..clopidogrel act as anticoagulant , given to patients who have high occurance of MI and other heart problems and many patients take it.. its trade name is Plavix..
Remember that Baby Aspirin is also anticoagulant…( prophylactic). So deal take care with patients take the two drugs.
Remember to take history from your patient.. you should understand the situation of the patient..for example : patient with hemophelia .. do not touch him..
So in general..for low dose of aspirin there is no much considerations if the patient is not taking other doses of some drugs like clopidogrel.. with high dose you should prepare yourself.. you should have certain equipments and certain gauze that you will use..
Question by a student : if an elderly has a wound in general which causes bleeding , shall him stop taking anticoagulant like clopidogrel ?
Answer : No. there is high consideration even in dentistry, there are many ways to solve this problem which need caution.. we are talking about benefit and risk.. benefit ( stop bleeding ) and risk ( thrombosis ) ..
Remember that we are going to talk about coagulants later on.

Back to adverse effect for aspirin
The most common is the GI effects including epigastric distress and vomiting, so aspirin should be taken with food and extra fluids to diminish the GI disturbances…. Why ?.... because of its acidity, But the main cause is that aspirin work within half an hour and if there is no food in this period that’s mean no protection.
There is an idea related to dentistry…all patient with ulcer problems or have a tendency toward ulceration should not take any one of NSAID except one type which we will talk about it later on..Why? because nonselective ones inhibit the protection toward stomach.
Now Dr read the second paragraph slide 16… if the normal patient (who does not have ulcer ) take anticoagulant for example clopidogrel or warfarin , then he should not take NSAID in general ?...Why? … First of all, taking anticoagulant in addition to aspirin will increase bleeding tendency.. The Second point is that taking anticoagulant and other NSAID (including aspirin) ( which cause peptic ulcer ) , then all these conditions will increase the tendency toward bleeding from stomach more than normal patients…
GI disturbances in normal patient when he takes aspirin 5-8% , regard profen 4-6% .
Risk of GI bleeding increases from 2-3 folds in patient medicated with clopidogrel who are prescribed an NSAID concurrently ( at the same time) .
Warfarin as anticoagulant is stronger than antiplatelets.

Big proplem in children…aspirin should not be given to children..Why ?
– Risk of Reye syndrome … if the child has any type of infection which could be caused by bacteria or virus ( ex: chikenbox ) and he take aspirin then he will have high risk for Reye syndrome..
Reye syndrome in its beginning represented by fatty liver then building up of toxic material toward encephalopathy.. this disease could cause death so aspirin is contraindicated in children.. although percentage of its occurrence is not too much high (2-4%) but it is very dangerous .
-Hypersensitivity toward aspirin in some patients .. But hypersensitivity does not lead to contraindication.. we have to do allergic test to determine hypersensitivity then if there is hypersensitivity , the drug should not be given to the patient..
But regard aspirin it is contraindicated for children even if they do not have hypersensitivity toward it because of the risk of Reye syndrome .
Keep in your mind that aspirin is an old drug but we still use it .

Kawasaki syndrome .. " autoimmune disease that manifests as a systemic necrotizing medium-sized vessel vasculitis and is largely seen in children under 5 years of age ." Wikipedia…the children have red skin.. children who suffer from this disease given aspirin which allowed in British but Dr is not sure regard USA if they allow or not .
In this case we remember ( benefit and risk ) risk of hypersensitivity and Reye syndrome , and the benefit of the only drug that used to treat Kawasaki… remember cancer in this issue .. benefit of cancer treatment and risk of the damage occurs to the normal tissues .

If the patient is taking baby aspirin and we give him profen at the same time then we will have pharmacological interaction..
Remember that they are acting at the same site COX1 , COX2…aspirin bind irreversibly , profen bind reversibly..
Profen will interfere the binding of aspirin with COX1, COX2.. this interference is not too much but it will affect the antiplatelet activity of aspirin.. and remember that most of elderly have many heart diseases and any small problem could lead to death.. those patients take aspirin daily for many years and it make a nice curve in their bodies and so we don’t want to make interruption to this curve..
In this case should you stop profen prescription to patients who take baby aspirin ??... No, we will give them peofen managed way…How ? ..
The patient should take aspirin firstly because it bind irreversibly and if we take profen after aspirin then profen will not interfere the action of aspirin because aspirin is already binding.. so no reaction will occur.. but if we give profen firstly then interaction will occur.
Aspirin given firstly then after 0.5-1.0 hour you could give profen at any time in the day..(0.5-1.0) to let aspirin to begin its function..
Dr read slide # 17..

Regard the teratogenic effect.. first of all some pregnant ladies who have a tendency toward abortion ( due to high phosphiolipids) are given aspirin.. note that there is no theoretical evidences (under the way of action) but according to experimrents.
If pregnant ladies given aspirin in the first 3 months then it will decrease abortion incidence.. aspirin is not teratogenic so pregnant ladies could use it..
But they should not use it ( specially in large doses and in chronic way) during the last trimester and this is true for all NSAID..
Although they have risk in the first 6 months but this risk is not too much high..
So aspirin is not contraindicated in pregnancy in the first 6 months but it is contraindicated in the last trimester.. before 3 years aspirin was contraindicated totally for pregnant ladies..
The last notes regard aspirin..
Dentists does not prescribe aspirin in general but they may prescribe it.. for dental pain you prescribe 2 tablets every 4-6 hours .. 2 tablets=650 mg.
Activity is not too high.. it is equal to paracetamol activity ( regard analgesic effect ) .
Nice property for aspirin is heat dissipation and it is stronger than paracetamol in this point( antipyretic activity ).
For antiinflammatory activity 3-4 tablets each 6 hours which is equal to 24 tablets/day ( that was what the Dr said but mathematically it is 12-16 tablets /day ).
NSAID could cause renal toxicity (nephrotoxicity) so we need monitoring for renal activity .

********************

Now .. New drug ..Paracetamol.. Acetaminophen .. drug A
Very nice , no side effects , recommended for children specially younger than 1 year , recommended for pregnant ladies for any type of pain..
For you as a dentists , the safest drug for pregnant and children ( as analgesic and antipyretic ) is acetaminophen.
The mechanism is through inhibition of PG synthesis..
Has weak antiflammatory effect.. Why ? because it has less effect on COX enzyme in the peripheral tissues ( work on CNS ) .
Acetaminophen is not NSAID..but many books when talk about NSAID, they also talk about it .
Does not affect the platelet function nor increase the blood clotting time.. no relation with clopidogrel nor warfarin ..
No effect on stomach .
Small problems talk about it later on..
Dr read slide #19 and #20
We have adol ** for children which is composed of acetaminophen .
** تحاميل
Acetaminophen is clear from side effects at the therapeutic dose , But if we have over dose then liver toxicity will occur .( over dose is not common ).
Trade names for Acetaminophen… Panadol , Banda , Revanin , Tylenol (which does not exist in Jordan) and Midrone… lemsip contain paracetamol in addition to other drugs such as phenylphrine as decongestant..
Dr. read slide #21
Remember to keep pregnant ladies away from drugs as much as possible.. avoid chronic and large doses of acetaminophen .. do not give here more than 12 tablets / day ….Why ? ..it could affect her liver and fetus' liver..
If someone ask you if taking one tablet of acetaminophen is good , the answer would be No.. Why ? ..because one tablet contain 500 mg and this amount does not give analgesic activity.. so the patient should take 1000 mg ( 2 tablets of the one that contain 500 mg )…note that some Bandas' tablets contain 1000 mg so one tablet is enough , but generally most paracetamol drugs contain 500 mg so the patient will use 2 tablets usually.

A very important point .. we have something called Banda extra ,Midrone extra , gold Panadol .. All these drugs contain additive for paracetamol.. Why ?.. efficacy for paracetamol is less than profen .. Emax for paracetamol is less than Emax for profen…
See diagram A in the last page ( note that all the diagrams would be in the last page)
If we give the patient 2000 mg of paracetamol every 4 hours ( just for example and this dose is not safe ) then the effect of 2000 mg would be as that of 1000 mg nearly ..
See diagram B..
But profen (for example) …we begin with 200-400 mg every 6-8 hours .. if there is no relief for the pain then we will increase the dose to 600 mg.. then if there is also no relief , the dose will increase to 800 mg.. During these steps the curve is going up.. See diagram C .
But regard paracetamole if you take 2 tablet ( = 1000 mg ) then additional two tablets ( =1000+1000 = 2000 ) there is no much effect because the dose 1000 mg is near the ceiling..
What is the solution ? … it is to add a new drug toward paracetamol then the efficacy of paracetamol would increase ( additive activity ).. for example , panadol extra contain codeine ( it is an opiate ) ..
See diagram D.
Remember that paracetamol is a weak COX inhibitor..
We could put another drug rather than codeine .
Could we give panadol extra , midrone extra ….etc for pregnant ladies ? general speaking they are safe but we try to keep pregnant ladies away from them… codeine could cause certain problems and we do not want this .. So no recommendation for codeine use by pregnant ladies..


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Good luck
Done by : Enas Mohammed
Lecture # 19
31/10/2010