11

DRUG INTERACTIONSDRUG INTERACTIONS

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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 P450 (CYP2C9) ↓ metabolisme of S(-) warfarin and ↑ anticoagulant effect

• carbamazepine ↓ anticoagulant effect of S(-) warfarin by increasing its hepatic metabolism cytochrome P450

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 curvei.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 ratioi.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 manufacture’s 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 interactionsoccur when the absorption, distribution,

metabolism and elimination of the object drug is altered by the precipitant drug

Absorption interactionsthe 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 similarend 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 β- adrenoceptor antagonist higher frequency of cardiac arrythmiaThis combination is also associated with an increased risk of heart failure both havenegative inotropic effects on cardiac muscle

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4. drugs that prolong QT intervalcan 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 balancechanges 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