pharma sheet #3

بسم الله الرحمن الرحيم

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on that link :

http://www.mediafire.com/?ouuz4t9x9fjr2q3

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In this lecture we will talk about:

ü Summary of pharmacokinatics
ü Drug absorpition
ü Bioavailability
ü Route of administration
ü Distribution

Note: all drugs spelling in this sheet are corrected from the doctor

Summary of pharmacokinatics:

When you take drug it will absorbed at the site of administration (ex:stomach) and then it will distributed to the site of action (what we call pharmacodynamics) after that metabolization (break down) of the drug will take place in the liver finally the drug will be eliminated





Drug absorption:

the absorption depend on :

1. bld flow to the absorption site:

Ex :a. we take some drugs under the tongue because there is a lot of bld flow under the tongue
B. a lot of bld go to the intestine more than which go to the stomach so the absorption in the intestine is more
2. total surface area available for absorption :
Ex: intestine has bigger surface area (due to presence of microvilli ) so the absorption in the stomach is much more than stomach
3. contact time at the absorption surface
It is the most important factor and has more applications in pharmacology (the tow previous factors have more application in physiology )
Ex: patient who has diarrhea the motility of the intestine so the drug will move quickly through GI that means contact time short so the absorption of drug will be low or it won't be absorbed at all , so that you shouldn't prescribe drug with narrow therapeutic index to the patient has diarrhea cause if we increase the dose to increase the probability of absorption the toxicity will also increase


Bioavailability:
Amount of drug absorbed after you take the drug
Ex: when we say the bioavailability of drug is 20% that means only 20% of drug is absorbed and reach the circulation
_bioavailability for injection 100% because all the drug reach the circulation but when you take the drug orally bioavailability less than 100% because there is many factors influence in the bioavailability when we take it orally

_factors influence bioavailability :

1. first pass hepatic metabolism
or biotransformation or breaking down …. Same meaning_ of the drug occur (loss of drug by this passage called first pass metabolism)
ex: if 20% of drug broken in the liver so the bioavailability for this drug 80%
notes:
*if the bioavailability of drug less than 50% that means the drug isn't effective ,even so in some special case we prescribed drugs that have bioavailability less than 50% orally but this is exceptions
*whenever the bioavailability of drugs come less and less by the oral administration we need to use the injections

2.solubility of drug :
Hydrophobic drugs can cross the plasma membrane easily so it absorbed more than the hydrophilic drugs that is unable to cross the plasma membrane

3.chemical stability of the drug:
Some drugs are not stable in the PH of the gastric content
Ex: insulin one of the drugs that is destroyed in the GI by the degradative enzymes so when we take insulin orally the bioavailability of it is 0% so that insulin take by intravenous injections

Q:since the bioavailability of the injections is 100% so why we don't give all drugs by this method?
A: because there is sth called compliance of the patient some peoples have phobia from injections so most of patients favor take the drugs orally
ex : in the case of anesthetization if the patient is compliant and relax we give him dose one time but if he afraid and incompliant we have to give him a new one or more (so whenever the patient is compliant the amount of the drug that use is need)


rout of administration:
there are many routs of administration and you as a dentist will use some of them such as :1.oral rout when you prescribe antibiotics 2.inhilation in anesthetization (ex: No) 3.intravenous or intramuscular parental routs

rout of administration divided into 3 category:
1.Alimentary routs (it has openings in the body) such as:
a. Oral rout , by the mouth
b. rectal rout, by anus
c. sublingual, by mouth



A. oral rout:
Advantages for this rout:
1.very efficient and convenient to the patient
2.most safe rout since the delivery of the drug into the circulation is slow after the oral administration (ex: if someone take overdose of the drug orally or child drink all the bottle of drug then drug have to go to the stomach and absorbed then distributed so it take time before toxicity occur so we can make lavage for stomach because there is enough time before toxicity take place).


Disadvantages for this rout:
1. it cause irritation of mucosal surface
Ex: tetracycline group of drug (ex: aspirin) has irritation effect on mucosal surface of the stomach
2.most variable, also there are variations in the sublingual and rectal routs but most variation seen in the oral rout , variation happen because of the drug absorption depend on many things ,such as :
A. acidity of the stomach, for example :
-when the stomach more acidic the absorption of aspirin increase , if the patient drink orange juice or drink
PH of the stomach decrease so if he take aspirin absorption of aspirin will be more
-amphetamine , this drug become toxic if the stomach more alkaline and it affect CNS , so if someone take antacid and then take this drug toxicity occur (be care this drug forbidden for human and if you take it you still awake all night ,this drug given to horses to make it stronger and run faster)
-digoxen, this drug affected by PH of the stomach and it has very narrow therapeutic index

B. psychology or character of the patient :
It happen more in women , some of them develop vomiting reflex for any psychological reason as you know vomiting has relation with motility of the stomach :
In the case of the stress :the motility decrease due to depletion of acetylcholine (decrease the sympathetic activity)
In the case of relax :motility of the stomach increase due to sympathetic activity

c. food ;what type of food the stomach contain affect the absorption of drugs , for example:
*L-dopa (levadopa): this drug compete the amino acids at the site of absorption ;so if the patient eat food rich in a.a and proteins and take this drug the absorption of this drug will be less
*some food affect the PH of the stomach as we explain before




d. first pass metabolism:
also there are variations in the first pass metabolism because enzymes in the liver different btw people and react differently in different people
Q: why enzymes different in people?
A:because there are 2 types of people :
1.white –red people (Anglo-Saxon)
2.black people
The intermarriage btw these 2 types give a mixture of people and there are types of gene begin to deplete as the new mixture intermarriage and so on ….(dilution of gens occur) ,so that people different in their gens and enzymes


B. sublingual rout
c. rectal rout
_these routs (sublingual ,rectal) to overcome the first pass metabolism , stomach acidity and irritation that affect the oral rout, so by these 2 routs the drugs won't go to the stomach or portal vein
_drugs should be lipophilic because it has to penetrate toward the membranes of the cells
_they are very rapid routs :
Ex: *trinitroglycerine for the status angina ,it make dilation for the vessels
*isoprenaline infrequently use for the asthma rather than ventoline salbutamol


2. parenteral rout (injections) :
it's many types such as:
1. intravenous
2.intramuscular
3.submucous
4.intrathecal ,it given in the spinal cord such as in case of delivery and we called it subdural in the CSF this types of injections is very dangerous and serious and need an expert to give it not anyone
5.intra-articular ,it given to the patient who has rheumatism
Note: intravenous, intramuscular and submucous are the most important



When to use this route ?
1.drug is poorly absorbed through mucous membrane
2. to avoid first pass inactivation in the liver ,so we avoid variation btw patients
3.to avoid uncertainty about amount absorbed
Ex: if we need to give the patient 1gm of certain drug we can do that by injections easily because the bioavailability is 100% and we avoid the variations btw patients ,but if we given him this drug orally there are variation in the absorption btw patients for many reasons as we said before so maybe 80% of the 1gm absorbed and 20% of it metabolized or maybe 40%absorbed and 60% metabolized we don’t know because there are variations but in the case of injection we sure that all the 1gm of the drug absorbed

d. to give a rapid response
so it useful in the case of the emergency

e. the drug cause vomiting
ex: anticancer drugs(except someone) we can't give them orally because they cause vomiting


disadvantages for this rout :
1.very fast and raid absorption
Ex : if doctor by mistake injected the patient another drug rather than what he want to use this will cause rapid toxicity for the patient and the only way to avoid this toxicity by giving him antidote but if there isn't antidote doctor can't do anything for the patient

2.chance of allergy is more in the case of injections especially at the in the site of the injection
Ex: in some case of injections allergy develop sth called phelliphites in the site of injection

3.it need sterile formulation and aseptic techniques ,because the infections can be easily transferred and the contamination occur so injection must be covered
Ex: in some case doctor may inject himself by mistake and its common so to avoid the contaminations doctors are vaccinated by hepatitis c


3.miscellanous rout:
Such as :
1.topical administration , useful in dermatology and sometimes in anesthetization
2.inhalations, we will use it in the anesthetization (ex: by using No)


Distribution :
We have in the body 3 water (liquid) compartments once the drug enters the body it will distribute into one of them , these compartment are:
1. plasma
2.extracellular fluid
3.intracellular fluid

Note: also there are lipid compartments in the tissues

*if the drug is very big and not lipophilic it mostly will distribute in the plasma, because it's too big to enter the junctions btw the cells
Ex: heparin _ used as anticoagulant for bld _ its too big drug so it only distribute in the plasma

*if the drug small and hydrophilic it will distribute in the junctions btw the cells in the extracellular fluid

*if the drug is small and lipophilic it will distribute in the all the body (intracellular fluid) and store in fatty tissues in the body and there will be succinated release for it

Boold brain barrier :
Capillary membrane btw the plasma and brain cells is much less permeable than is the membrane btw the plasma and another tissue ,therefore the transfer of drugs into the brain regulated by bld brain barrier
1. it's only permeable to the lipophilic drugs ,but in the case of meningitis opening btw the junctions become bigger so the drugs that’s not lipophilic can enter to CSF (for example when we give the patient with meningitis penicillin it will enter to the CSF through the bld brain barrier but in the normal person it won't enter)
2.impermeable to ionic hydrophilic drugs
3.amino acids and glucose have specific uptake system


Drugs binding to the plasma albumen:
Albumin is very important carrier for many drugs
_Q:when there are 2 drugs and both of them bind with albumen which of them will bind to the albumin?
_A: the drug that has higher affinity

*interaction btw drugs during the distribution:
When there are 2 drugs that have affinity to bind with certain plasma protein or albumen and they are prescribed to the patient at the same time one of the 2 drugs (which has higher affinity) will displace the other ,and if the drug that is displaced (which has lower affinity) has narrow therapeutic index the toxicity occur because the concentration of the displaced drug increase in the bld and because it has narrow therapeutic index so when the concentration increase toxicity also will increase


Ex:
Warfarin it’s a drug used as anticoagulant it can be displaced by phenylbutazone (anti-inflamatory)if they given at the same time and this cause bleeding because the concentration of warfarin which is anticoagulant increase in the bld

Note:
Doctor can prescribe 2 drugs that have affinity to bind with albumen but he should :
1.give enough time btw them
2.decrease the dose


Note:
For the patient who have more than one disease and used more than one type of drug doctor should take care for the interaction btw drugs
Ex: clavex is a drug has unknown interaction with another drug called nexuim

I hope everything is clear and sorry for any mistake (corrections are welcomed )


Done by : Mays smady
Lec#4 , Tuesday 28/9/2010