Download Practice slide 8 tafreeg 2

Practice slide 8 tafreeg 2
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Last time we said that drug absorption interactions can happen due to many
reasons:
Changes in gastrointestinal PH
Adsorption, chelation of medications
Changes in gastrointestinal mortality
Altered drug transport (p-glycoprotein)
P-glycoprotein: are distributed in the intestines in the mucosal cells, it's an ATP
dependent efflux pump which pumps the drug from mucosal cell to the intestinal
lumen (prevents the absorption of the drug).
* So if we gave something that inhibits the action of this P-glycoprotein, what happens to
the drug concentration?
- it will increase the drug absorption which sometimes could cause safety problems (toxicity)
If we take P-glycoprotein substrate with P-glycoprotein inducer, in this case the effect of the
drug from mucosal cells to intestinal lumen will increase therefore decreasing the drug
absorption, which could cause efficacy problems  we will have to give higher doses of the
drug.
Drugs that are called P-glycoprotein inducers and at the same time can be called Pglycoprotein inhibitors  Amiodarone
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EXAMPLES of drugs as P-glycoprotein inducers  (Amiodarone, digoxin, diltiazem,
statins, immunosuppressant's (cyclosporine and tacrolimus)
- EXAMPLES of drugs as P-glycoprotein inhibitors  ketoconazole, rifampil,
immunosuppressant (cyclosporine)
*ketoconazole:
1- mostly used topically .. rarely taken orally because of high D-D interaction
2- inhibitor for P-glycoprotein and CYP450.
If we gave ketoconazole with digoxin, we have to decrease the digoxin dose because it's
taken with P-glycoprotein inhibitor  ketoconazole
If we gave amiodarone with digoxin, we have to decrease the digoxin dose because in this
case amiodarone works as a P-glycoprotein inhibitor. but if we gave amiodarone with
ketoconazole, here amiodarone will work as a P-glycoprotein activator.
If we gave carvedilol which is a P-glycoprotein inhibitor with diltiazem which is a Pglycoprotein substrate, we expect an elevation in diltiazem's concentrate
 Therefore, the toxicity has two reasons here:
1- Increase in the risk of hypotension (dynamic interaction)
2- Effect of P-glycoprotein (additive interaction)
Also cyclosporine (immunosuppressant) works as a P-glycoprotein substrate and inhibitor
(like amiodarone)
*EXAMPLES of P-glycoprotein inducer: Ritonavir (antibiotic, rarely used)
If we gave ritonavir with digoxin, what will happen?
The absorption of digoxin will decrease which will reduce its efficacy, therefore we may have
to increase digoxin dose.
P-glycoprotein also exist in brain and kidneys, is important in these tissue to decrease the
access of unwanted substrates to the blood.
Digoxin for examples is eliminated in the kidneys with the help of P-glycoprotein but if we
take digoxin with a P-glycoprotein inhibitor. this will increase absorption of digoxin,
therefore increase the toxicity.
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Drug distribution interaction
we will take in this topic about protein bindings:
when the drug enters the body it either stays free or it binds to plasma proteins such as
(albumin or α-glycoprotein)
basic drugs usually bind to α-glycoprotein
acidic drugs usually bind to albumin
a great portion of the drugs are bound to proteins in the blood, but a few of them are
found in free form.
*the degree of protein binding is variable, rarely from less than 10% to 99% or greater
The 1% left which is free always exist in equilibrium with the bound form, because there
is constantly a portion goes through (metabolism + excretion) and another portion
dissociate from proteins and become in the free form to achieve equilibrium.
Physiology active form  free form of the drug
Problems is when we have a drug which is highly bound to plasma protein, administered
with another drug which is also highly bound to plasma protein.
There will be interaction between them, but if the second drug wasn't highly bound to
plasma protein no interaction will occur between them.
*EXAMPLES of highly bound to plasma protein ( >90%) :
Warfarin, antiepileptic drug (phenytoin)
The drug having the higher tendency to bind to plasma protein will displace the other
bound drug and increase its toxicity.
When a person takes 2 drugs, one is >90% protein bound, and the other is <90% protein
bound  there are no worries of displacements or interactions. Even if they happened
there will be no significant clinical outcomes. WHY?
1- Because when the drug has wide therapeutic range it doesn't matter if a part of it
was displaced and became free in the blood (no matter how much it was displaced
there won't be a significant consequence and no toxicity will occur. (increase in
concertation but without any toxicity)
2- The portion that become free won't stay in the blood, part of it will be excreted,
another part will be metabolized or distributed to the site of action, therefore
equilibrium will be formed again to maintain the free form concentration in the
blood.
Drugs that are protein bounded have longer half-lives.
Sometimes we may have a delay between PD interaction (displacement) and PD
interaction (response)
Interactions of phenytoin and warfarin:
Phenytoin will displace the warfarin  increase conc of warfarin (PK interaction) and
this increase the PD interaction  but we won't see this interaction because the onset
of warfarin is delayed.
We measure the effect of warfarin through the life spam of clotting factors. We already
have activated clotting factors but warfarin won't work on those but it works on the
newly made clotting factors from the liver, therefore the already activated clotting
factors won't reflect the effect of warfarin. So we have to wait for them to die and be
eliminated from the body. After that we can see warfarin's effect on the new clotting
factors.
That's why it has a delayed onset of action 3-5 days (during this period the free form will
be excreted, metabolized or distributed, therefore we won't see PD response) , and its
full effect may take up to 2-3 weeks.
When we have a drug like warfarin (has a delayed onset at action) even if PK interaction
occurred there won't be a PD interaction.
Between phenytoin and warfarin we see the effect of metabolism ( phenytoin increases
the metabolism of warfarin by induction of CYP450  therefore we need to increase the
dose ) not disturbtion ( the interaction that happened because of disturbtion resulting
from the displacement on the protein ) so we have actual interaction between
phenytoin and warfarin due to metabolism and the drug therapy needs to be modified.
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Altered drug transports:
P-glycoprotein in the endothelial cells of brain capillaries is oriented to pump drug out of
the cell and into the blood.
Some drugs if entered the CNS will cause toxicity, but they don't enter because of the Pglycoprotein, that's why if we gave the drug with a P-glycoprotein inhibitor, it will enter
the CNS and cause toxicity.
*EXAMPLES: loperamicle (antidiarrheal  by decreasing peristalsis)
It works peripherally in the GIT and can't cross BBB (and that's what we want)
If it enters the brain it will cause CNS toxicity and may even cause respiratory
depression!
Here we aren't talking about P-glycoprotein in the GIT that's why there won't be any
effect on the efficacy, but safety is what we're concerned about.
 Drug metabolism interactions:
All what's in the slide is required, but the doctor will say them briefly
Elimination of drugs is mainly from the kidneys or the liver, but we have a very small portion
that breaks down in the blood.
Drugs that go straightly to the kidney such as hydrophilic drugs that go to the liver such as
nonpolar compounds
There are many drugs that don't go straightly to the kidney, but rather they go through the
liver and get metabolized and become more polar.
We have two types of metabolism:
1- Phase 1: oxidation / reduction / hydrolysis (to increase polarity of compound)
2- Phase 2: conjugation by (glucuronic acid / sulphate)
Most of the interactions that happen due to metabolism are the result of inhibition or
induction of CYP450 rather than the effect on the enzymes of glucoronate or sulfation.
Most of the interactions that happen are phase 1 interactions mediated by CYP450.
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Enzyme inhibition:
We need CYP450 either for
a) activation of prodrugs
b) elimination or inactivation of drugs
if we have a prodrug that is given with a CYP450 inhibitor  this will prevent the activation
of the drug  will affect the efficacy
*EXMAPLES:
prodrug – (clopidogrel)
CYP450 inhibitor – (protein pump inhibitor (PPI))
If given together, we'll be concerned about thrombolysis (a form of clotting)
But if we take an active form drug with CYP450 inhibitor, here we'll have a safety problem
CYP450 inhibitor + prodrug  efficacy issue
CYP450 inhibitor + drug (active form )  safety issue ( increase conc of the drug )
The enzyme inhibitor can bind on the binding site of the enzyme (competitive inhibition) or
can bind on a site other than the active site (non-competitive inhibition)
The effect of the inhibition of the enzyme is fast. But in case of the induction of the enzyme
 the enzyme inducer works on the gene level (inc. expression of the enzyme by gene
expression  inc. response) needs time.
That's why the effect of (enzyme inhibitors) are faster than (enzyme inducer)
If we take a drug that works by gene expression as an (enzyme inducer) it needs 2-4 weeks
to show an effect.
If it was enzyme inhibitor  faster interaction
If it was enzyme inducer  slow interaction 2-4 weeks
 Effect of the enzyme induction and enzyme inhibition on the AUC of the drugs:
- The most representative thing for drug's concentration in the blood is AUC
Dec. conc  Dec. AUC
Inc. conc  inc. AUC
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How we represent enzyme inhibition or induction?
also here the effect of the enzyme inhibition on the AUC is more.
Enzyme induction inc. CL  Dec. AUC
Enzyme inhibitor Dec. CL  inc. AUC
When the decrease
In CL = 50% if  enzyme inhibition AUC =100
Enzyme induction AUC = 33
*from slide 70
Slides 73, 74 ,75 aren't included
Done by:
Sahar Alazzam
Christine Haddadin
Danya Aljabrah
Slide 8 tafreeg 3
Today we'll be talking about interactions due to change in excretion
Excretion  could be by the liver or kidney
We have several things that can change the drugs excretion as a result of interacting with
other drugs:
abcd-
Change in urinary PH
Changes in active kidney tubule excretion
Changes in kidney blood flow
Biliary excretion and the entero-hepatic shunt
Now in more details:
1- Changes in urinary PH
This occurs if we have a drug that affects the urine PH and the other drugs is affected by the
change of urine PH and this other drugs should be:
a) Excreted uncharged in the urine: the number of drugs excreted uncharged in the
urine is small and most drugs undergo metabolism and reach the urine as inactive
metabolites.
That's why we don't see this type of interaction very often.
b) Ionized
*EXAMPLES: salicylate and antacids  antacids inc. PH of the urine so the excretion
of salicylate will inc. because it becomes ionized.
Therefore if we gave antacid with salicylate it's conc. In the body dec. because it will
be excreted more readily.
But if we gave salicylate with a drug that Dec. PH  the excretion of salicylate will
Dec.  inc. it's plasma conc.  inc. in its toxicity
2- Changes in active kidney tubule excretion:
There are some drugs that are excreted in the urine by transporters (not by passive
diffusion)
In some cases 2 drugs are excreted from the same transporter, therefore the drug that
overcomes the other and gets transported is excreted, and the other drug gets trapped
in the body and it's plasma conc. Inc.
-also this type of interactions isn't very important, because the number of drugs using
this interaction is small.
*EXAMPLES: probenecid (was been used for gout (hyperuricemia) in the past) With
penicillin
They both get transported by an active transporter in the kidney tubular and competition
develops between penicillin and probenecid on the same transporter. Probenecid
overcomes penicillin and gets excreted, while penicillin conc. Inc. in the blood causing
potential toxicity (safety issue)
3- Changes in kidney blood flow:
Many drugs affect kidney blood flow, potentially dec. it like NSAIDs (indometacir, diclofenac,
naproxen. etc.) through affecting prostaglandins.
NSAIDs dec. prostaglandins therefore decreasing kidney blood flow.
For the drug to be affected by kidney blood flow it has to have a narrow therapeutic index.
-an example of the drugs affected by using NSAIDs due to decreased kidney perfusion is
(Lithium), because it mainly depends on the kidney perfusion for its excretion, plus it has a
narrow therapeutic index. Therefore when the kidney perfusion is decreased, the conc. Of
lithium in the blood inc. toxicity
That's why patients taking lithium are prohibited from taking NSAIDs
The number of drugs affected by this type of interaction is small, and they're:
a- Have a narrow therapeutic index
b- Their excretion is highly dependent on kidney perfusion
4- Biliary excretion and the entero-hepatic shunt
Drugs which are affected by this interaction enter the entero-hepatic circulation which
means the drug enters the liver, gets conjugated and removal with the bile back to the GIT,
then it's supposed to exit with the feces.
But what happens: the gut flora breaks down the conjugation bond, and it behaves like a
normal drug which didn't get metabolized, so it gets absorbed and enters the liver again.
This will inc. the drugs conc. In the blood, duration of the action and its half-life, therefore
the effect of the drug will inc. with the entero-hepatic circulation.
*how can we end this circulation?
By reading the gut flora's activity by giving an antibacterial agent, therefore the drugs
plasma conc. Will dec. so its half-life, and we'll have an efficacy issue because the effect of
the drug will reduce.
*EXAMPLES: oral contraception's (go through entero-hepatic circulation) when give with
antibiotics  they won't go through the entero-hepatic circulation and will be excreted in
the feces without going back to the liver this will reduce the oral contraceptives efficacy and
result is pregnancy.
We're done with the four different types of interactions.
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When we want to decide the importance of the interactions, which one has a priory
over the other and how to decide the clinical significant of different drug
interactions:
1- Severity of the interaction: severe is more important than moderate and
more than minor.
- major  life threating, permanent change
Ex: statin with glimepiride  rhabdomyolysis / warfarin with aspirin risk of
bleeding
-
moderate  deterioration of patient's status
Ex: interaction causing hypokalemia
-
minor  bothersome or little effect (considered minor when it has little
consequences)
Ex: using 2 antihypertensive agents
2- Reliability rating: likeability of the interaction to happen
- excellent  proven to occur in well controlled studies
- good  suggestive data, well controlled studies are lacking. they do exist
but their content as studies are less than excellent
- fair  available documentation suggestive, good documentation for similar
drug. there is documentation about interaction related to the drug's family
not the drug itself
- poor  limited data but theoretically possible. like in case of drugs which
have the same mechanism of action
- unlikely  poor documentation, lacks pharmacologic basis. no logic behind
it.
*the interaction is considered important and is called suspected interaction if its
reliability rating is (excellent or good), and considered less important and is called
possible interaction if its (fair, poor, or unlikely )
*** so depending on the documentation they can be classified to:
a- Suspected interactions
b- Possible interactions
*** and generally we can prioritize these interactions into 5 categories:
1.
2.
3.
4.
5.
Major / suspected
Moderate / suspected
Minor / suspected
Major or moderate / possible
Minor / possible
Highest priority (most
important)
Lowest priority
-pay attention that (suspected > possible) always
-we've taken into consideration the severity of the interaction and reliability rating.
3- onset of interaction: to determine the speed of the interaction rapid (within 24 hrs or
delayed (days to weeks)
*EXAMPLES: verapamil makes enzyme induction
This interaction has delayed onset because it happens on the gene transcription and
translation level, therefore the interaction offered can be delayed, while in case of an
enzyme inhibition interaction we need a fast intervention
-
Intervention: drug dosing adjustment, monitoring, therapy modifications ( switch or
withdraw specific drugs )
4-risk rating: is determine by C, D, X ..etc.
C  Benefit > risk -- that's why we do the monitoring
D  Benefit > or < risk -- we have to do therapy modification by adding, withdrawing,
switching drugs or changing the dose or intensify the monitoring
X  risk > benefit -- avoid combination ((contraindicated))
Done by:
Sahar alAzzam
Christine Haddadin
Danya Aljabrah