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DRUG INTERACTIONS



azalia arif fkui

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Drug interactions occurs when :

The effects of one drug altered by the effetcs of
another drug

Drug that precipitate precipitant

Drug whose action affected object drug

Can result an increase or a decrease the effect
of the object drug

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example :
amiodarone inhibits a cytochrome P
450
(CYP2C9) metabolisme of S(-) warfarin
and anticoagulant effect

carbamazepine anticoagulant effect of S(-)
warfarin by increasing its hepatic metabolism
cytochrome P
450

occasionally in an interaction the effects of both
drug are altered i.e the complex interaction of
phenytoin with phenobarbital
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Although drug interaction usually result in an
adverse drug reaction; in some cases an
interaction is beneficial i.e :

The pharmacodynamic synergy between
diuretics and angiotensin-converting enzyme
(ACE) inhibitor in the treatment of hypertension
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Incidence of significant drug interactions :

the more drugs a patient is taking the
greater the chance of an interaction

several factors that make patients
vulnerable to interactions :
- advance age
- multiple medications
- acute severe illness
- poor renal and hepatic functions
- more than one prescribing doctor
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Drugs that are likely to precipitate drug
interactions

drugs that are highly protein bound likely
to displace object drugs from protein-binding
sites

drugs that alter (stimulate or inhibit) the
metabolism of other drug (see table)

drugs that affect renal function and alter the
renal clearance of object drugs i.e diuretics,
probenecid
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drugs that are likely to be the object of drug
interactions :

those that have a steep dose-response curve
i.e drugs for which a small change in dose
results in a relatively large large change in
therapeutic effect causing reduced efficacy
of the object drug

drug that have a low toxic/therapeutic ratio
i.e ??
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Pharmaceutical interactions

are physicochemical interactions :
a drug with IV infusion
two drugs in the same solution loss of
activity the drug involved

are too numerous to remember in detail

can be simply to be avoided by adhering the
following principles :
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1. Give IV drugs by bolus injection or via an IV burrette

2. Do not add drugs to infusion solution other to
dextrose or saline, some drugs are unstable and
some are light sensitive (see table)

3. Avoid mixing drugs in the same infusion solution,
unless is known to be safe

4. Look for specific warning in manufactures literature

5. Mix the drug thoroughly in the infusion solution and
check regularly for visible changes (turbidity,
precipitation or color change)
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6. Prepare solution only when needed

7. Label all infussion bottles clearly with the
name and dose of drug added, the time of
starting and ending the infusion

8. Use two separate infusion sitesif two drugs
must be infused simultaneously, unless you
are sure there is no interaction

9. Consult the local hospital pharmacist if in
doubt
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Pharmacokinetic interactions
occur when the absorption, distribution,
metabolism and elimination of the object
drug is altered by the precipitant drug

Absorption interactions
the absorption of a drug can be reduced by
another drug in several ways :


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The git absorption of drugs may be affected
by concurrent use of other agents that :

have a large surface area of absorption
bind or chelate
alter gastric pH
alter git motility
affect transport protein such as P-glycoprot.

reduction of absorption will be clinically
important if it results in subtherapeutic serum
levels
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reduced git motility caused by morphine-
like drugs and drugs with anticholinergic
effects, such as tricyclic antidepresant

chelation of Ca, Al, Mg and iron salt by
tetracyclines

binding of warfarin and digitoxin by
cholestyramin
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The mechanism by which drug interactions
alter drug distribution include :

competition of plasma binding protein

displacement from tissue binding site

alteration in local tissue barriers i.e
P- glycoprotein inhibition in the BBB
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The metabolism of drugs can be stimulated or
inhibited by concurrent therapy

Induction (stimulation) of cytochrom P450
isoenzyme can be caused by drug such as :
barbiturate, carbamazepine, phenytoin,
rifampin and others (Katz. p1082)

Enzyme induction can also increase the
activity of phase II metabolism such as
glucuronidation
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Enzyme induction usually occurs 7 10
days and requires equal/longer time to
disappear after the inducer stopped

Rifampin, may produce enzyme induction
after only a few doses

If the half-life of the affected drug is long, it
may take a week or more to reach the new
steady state concentration


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Drugs that may inhibit cytochrome P450
metabolism of other include :

amiodarone, androgens, atazanavir,
chloramphenicol, cimetidine, ciprofloxacin and
others (Katz. p1082)
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The renal excretion of active drug can also be
affected :

weak acid or weak bases may be influence
by other drugs that affect urinary pH due
to ionization of the drug


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Pharmacodynamic interactions

precipitant drug alters the effect of the object
drug at its site of action direct or indirect

Direct pharmacodynamic interactions

occur when two drugs either act on the
same site (antagonism or synergism)
or act on two different sites with a similar
end result
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Antagonism at the same site

many example, some of which are
therapeutically beneficial

i.e the reversal of the effectsof opiates
with naloxone and
the reversal action of warfarin by
vitamin K

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Synergism at the same site

1. The effects of warfarin can be incresed or
decreased in direct synergistic interaction :
The pricise mech. of this interaction is not
clear could be :

a. changes in the affinity of warfarin for
vitamin K epoxide reductase (clofibrate,
D-thyroxine, & anabolic steroids)
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b. alteration in the synthesis rate of clotting
factors ( anabolic steroids)

c. changes in the activity of clotting factors
(tetracyclines)

d. reduced availability of vitamin K secondary to
reduced plasma lipid conc. (d-thyroxine and
anabolic steroids)
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2. The effects of depolarizing muscle relaxant
potentiated by some antibiotics ( colistin,
aminoglycosides and polymixin B) and by
quinine and quinidine due to the curare-
like effects on the motor end plate of skeletal
muscle

3. Verapamil and - adrenoceptor antagonist
higher frequency of cardiac arrythmia
This combination is also associated with an
increased risk of heart failure both have
negative inotropic effects on cardiac muscle
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4. drugs that prolong QT interval
can cause ventricular arrhythmia, particularly
the form of polymorphous ventricular
tachycardia called torsade de pointes i.e
halofantrin and antiarrhythmia



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Synergysm of similar effects at different sites

two CNS depressant will potentiate the effects
of each other, whether or not the two drugs act
on the same receptors : alcohol with CNS
depressant

beneficial : combination of cytotoxic drugs in
the treatment of malignancies

combination of antibiotic in the
treatment of infection
(tuberculosis)
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Indirect pharmacodynamic interactions

Coagulation : warfarin and other anticoagulant
can be involved in indirect
interactions in 3 ways

1. Platelet aggregation these drugs reduced
the ability of platelet to aggregate ; salicylate,
dipyridamol, sunfinpyrazone, mefenemic acid,
phenylbutazone and other.

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2. gastrointestinal ulceration
if a drug causes git ulceration it provides
bleeding in patient taking anticoagulant ( e.g
aspirin, phenylbutazone, indomethacin and
other AINS drug)

3. fibrinolysis enhance the effect or warfarin


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Fluid and electrolyte balance
changes in electrolyte balance alter the
effect of some drug

- the effects of cardiac glycosides are
enhanced by potassium depletion digitalis
toxicity
- hypokalemia risk of arrhythmia in patient
taking antiarrhythmia that prolong QT
interval e.g quinidine, procaineamid,
encainid and flecainide)

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- thiazide effect hypoglycemic sulfonylurea