drug interactions

Question 1

what are pharmacodynamic interactions?

Answer 1

drugs competing at the pharmacological target or that have similar or opposing pharmacodynamic therapeutic effects. this is mediated by many mechanisms and must be studied on a case by case basis

Question 2

what are pharmacokinetic interaction?

Answer 2

changes in pharmacokinetic parameters and cause ADME modifications. the victim is the one being effected, the perpetrator is the one affecting the pharmacokinetics of the victim.

Question 3

drug interactions are a common and important problem in pharmacological therapy - why?

Answer 3

drug interactions can cause variability in outcomes of therapy, may decrease treatment efficacy or may cause fatal adverse effects - this could lead to increased hospital admissions and therefore increased healthcare costs.

Question 4

in absorption interactions the solubility, dissolution or absorption of a drug may be affected by extrinsic factors, what are common causes for drug interactions concerning absorption?

Answer 4

• variation of gi pH - important for drugs with ph dependent solubility/dissolution
• drug binding to dietary components
• altered intensinal active transport affecting uptake or efflux
• modified gastric emptying and motility
• nmodified intetstinal wall first pass effect - enzyme interactions

Question 5

how can protein binding displacement interactions affect drug distribution?

Answer 5

this is higher risk for highly bound drugs with a narrow therapeutic window - it must be considered in therapeutic monitoring when predicting tht free concentration responsible for efficacy/toxicity from the total concentration measured in a teast.

Question 6

how can drug interactions cause variation in distribution of drugs?

Answer 6

through modulation - either inhibition or induction - of active transporters - either uptake or efflux - that alters the distribution to a tissue relevant for toxicity or efficacy.

Question 7

how can drug interactions occur that effect the elimination of a drug?

Answer 7

the excretion or metabolism of a drug may be effected by another chemical, this can be at a transporter level or at an enzymatic level. a lot of drugs are metabolised by CYP3A yet many also inhibit CYP3A

Question 8

how does st johns wort have drug interactions?

Answer 8

st johns wort is often used for depression, chronic uptake induces CYP3A having a greater effect in the small intestine than the liver. there is also increased expression of intestinal p-gp. this has caused low levels of indinavir and cyclosporine resulting in rejection.

Question 9

how does grapefruit juice have drug interactions?

Answer 9

grapefruit juice inhibits intestinal CYP3A, p-gp and OATP. it has variable effects.

Question 10

how does cranberry juice have drug interactions?

Answer 10

cranberry juice is a suspected perpetrator in cases of excessive warfarin and anticogulation

Question 11

how does a drug get metabolised? (outline the process)

Answer 11

the drug enters the liver through hepatic sinusoids, the drug can either be blood bound, protein bound or free yet only the free molecules can enter the hepatocytes. in the hepatocyte the drug may either be absorbed into the bile duct for biliary elimination or it may be metabolised, the metabolite may then enter the bile duct for biliary excretion or it may enter the hepatic sinusoid entering the circulation.

Question 12

given the volume of distribution and the clearance of a drug in healthy patients we can determine whether the drug has a high or low extraction ratio and we can predict whether the pharmacokinetics of the drug will be modified in what variations?

Answer 12

we can predict whether the pharmacokinetics of the drug would be modified in drug interactions, in hepatic disease where there is decreased hepatocellular activity or in disease that modifies the hepatic blood flow. if we know the modifications to the pharmacokinetics we can therefore adjust the dose accordingly.

Question 13

whats the hepatic clearance?

Answer 13

hepatic clearance measures the loss of drug accross the liver by metabolism and biliary excretion. the hepatic clearance is the volume of blood entering the liver from which all the drug is removed per unit of time.

Question 14

whats the hepatic extraction ratio?

Answer 14

the hepatic extraction ratio is the fraction of a drug passing by the liver which is eliminated, it can be calculated by doing hepatic clearance divided by hepatic blood flow.

Question 15

what does it mean if the hepatic extraction ratio is 0?

Answer 15

no drug is eliminated as cin = cout

Question 16

what does it mean if the extraction ratio is 1?

Answer 16

all of the drug is eliminated

Question 17

what would it mean if the Eh was 0.8 as it is for propranolol?

Answer 17

0.8 would mean 80% of the drug is cleared

Question 18

what is the hepatic clearance f a drug determined by?

Answer 18

the rate of drug presentation to the liver (hepatic blood flow) and the efficiency of drug removal by the liver (extraction ratio)

Question 19

drugs with a high extraction ratio mean most of the drug being delivers by the blood is removed by the liver, what causes this?

Answer 19

if the drug is very quick at leaving blood cells, dissociating from plasma proteins, diffusing hepatic membranes, being metabolised and entering bile then it will have a high extraction ratio. Eh is greater than 0.7 and the clearance of the drugs will approach hepatic blood flow.

Question 20

why might some drugs have a low extraction ratio?

Answer 20

some drugs may be very slow at dissociating from rbcs, slwo dissociation from plasma proteins, slow diffusion etc hence the extraction ratio will be less than 0.3 and the clearance of the drug will be very low

Question 21

hepatic extraction ratio only tells us how efficient the liver is, whats a downside to this?

Answer 21

the drug may be metabolised or excreted elsewhere in the liver.

Question 22

how are drugs with a high extraction ratio perfusion rate kimited?

Answer 22

the hepatic clearance of the drug depends on the rate of presentation to the liverhence the hepatic clearance is very sensitive to chages in blood flow but relatively insensitive to changes in plasma binding and cell metabolising activity.

Question 23

why do drugs with a high extraction ratio have a low oral bioavailability?

Answer 23

the drugs are extensively metabolised by the first pass effect hence not very much drug will reach the systemic circulation after oral delivery.

Question 24

what causes drugs to have a low extraction ratio?

Answer 24

there must be a rate limiting process causing a low hepatic clearance like dissociation from blood cells etc. usually the drug is a poor substrat for the enzymes. hepatic clearance is sensitive to changes in plasma binding and cell metabolising activity whilst insensitive to changes in blood flow.

Question 25

why do we predict drugs with a low extraction ratio to have a high oral bioavailability?

Answer 25

a drug with a low extraction ratio would not be greatly effected by the hepatic first pass effect - although it could have a low bioavailability for other reasons like poor absorption or intestinal metabolism.

Question 26

what 3 factors determine the hepatic clearance of a drug?

Answer 26

the hepatic blood flow setermines the presentation of the drug to the liver
the free fraction as only the unbound drug molecules can enter hepatocytes where metabolism takes place
intrinsic clearance - this is the ability of the liver to eliminate d=the drug in the absence of restrictions imposed by protein binding and drug delivery to the liver by blood flow - it is the hypothetical value of hepatic clearance if hepatic blood flow was unlimited and all the drug was unbound.

Question 27

what does intrinsic clearance measure?

Answer 27

intrinsic clearance represents how efficient liver enzymes are in metabolising a given drug

Question 28

what does intrinsic clearance depend on?

Answer 28

intrinsic clearance depends on the amount of enzyme present and the affinity of a drug for the enzyme. the liver cannot metabolise a drug faster than it is presented so hepatic clearance is always less than the intrinsic clearance.

Question 29

how is the intrinsic clearance affected by drug interactions?

Answer 29

inducers will increase the intrinsic clearance of the drug whilst inhibitors will reduce intrinsic clearance.

Question 30

whats the well stirred model for hepatic elimination?

Answer 30

this model suggests instantaneous and complete mixing occurs in the liver, its useful to predict trends in clearance and other pharmacokinetic parameters.

Question 31

when ther is a high extraction ratio Qh can be eliminated from the equation, what does this mean?

Answer 31

the hepatic clearance will equal the hepatic blood flow hence the drug will not be effected by drug interactions unles they affect the blood flow to the liver.

Question 32

when there is a low extraction ratio (abound x Clint) can be removed from the equation, ehat does this mean?

Answer 32

the clearance is equal to the amount in blood x intrinsic clearance so the drugs will be effected by drug interactions

Question 33

this model predicts the maximum oral bioavailability of a drug is 1 minus the fraction metabolised by the first pass affect, what else could lead to a low F?

Answer 33

intestinal wall first pass effect, GI degradation, poor formulation, poor solubility and poor permeability.

Question 34

what does protein binding of drugs in the blood effect?

Answer 34

the hepatic clearance, first pass effect, renal clearance and the volume of distribution

Question 35

what does the half life of a drug depend on?

Answer 35

the half life of a drug depends on clearance and volume of distribution both of which may be modified by protein binding. as shorter half life may be due to increased clearance or reduced volume of distribution.

Question 36

when does a drug undergo restrictive clearance?

Answer 36

if the drugs extraction ratio is less than or equal to its unbound fraction in blood it will undergo restrictive clearance. this means hepatic extraction will be limited by protein bounding and will change with a, the unbound fraction in blood.

Question 37

when does a drug undergo non-restrictive clearance?

Answer 37

when the drugs extraction ratio is greater than the unbound fraction in blood it will undergo non-restrictive clearance. this means binding to the proteins does not protect from elimination hence hepatic exctraction is not modified by a.

Question 38

when will the induction of the metabolism of a drug with a high ectraction ratio have therapeutic implications?

Answer 38

when the drug is given orally but not when given intravenously.

Question 39

how will changes in blood flow affect drugs?

Answer 39

changes in blood flow only affect drugs with a high extraction ratio as these are perfusion rate limited.
if blood flow increases enzymes will have less time to metabolise drugs passing through hence F will increase.

Question 40

why do many drugs contain hydroxy groups?

Answer 40

in order to make hydrogen bonds to receptors in the body.

Question 41

what makes microcrystalline cellulose a good excipient?

Answer 41

it has low bulk density and high compressability to give a strong compact which freely disintegrates hence it is good for use as a diluent disintegrant or lubricant.

Question 42

what is methylcellulose used for?

Answer 42

as methylcellulose swells in cold water to form a viscous solution it can be used as a bulk laxative or a thickener for liquid preparations.

Question 43

what is carboxymethylcellulose used for?

Answer 43

carboxymethylcellulose is dispersible in water to give a colloidal solution and its ionic due to the carboxylic acid group. it can be used as a suspending agent in liquid preparation, a tablet binder, or a hydrophilic colloid laxative.

Question 44

what is cellulose acetate pthalate used for?

Answer 44

cellulose acetate pthalate is a cellulose ester that is resistant to acid but swells in base hence its used as an enteric coating for tablets as it will only dissolve in the basic environment of the small intestine.

Question 45

what is cellulose nitrate used for?

Answer 45

cellulose nitrate is used as a flexible component of flexible colloidon for holding surgical dressings in place.

Question 46

what is oxidiesd cellulose used for?

Answer 46

oxidised cellulose is used for a haemostatic gauze, it creates an artificial blood clot by a reaction with haemoglobin, it is then absorbed into the body as its completely biodegradeable into glucuronic acid and glucose.

Question 47

what is starch used for?

Answer 47

starch is a polysacharide of amylose and amylopectin, it forms a viscous colloidal suspensin and can be used as a filler glidant and disintegrant in tablets.

Question 48

what is sodium alginate used for?

Answer 48

sodium alginate is used in antacid preparations, alginate conjugated with aluminium forms a raft in the stomach blocking acid from escaping up through the cardiac sphincter.