Download Drugs Interactions May 2010

DRUG –DRUG INTERACTIONS
Dr.Abdul latif Mahesar
King Saud University
May 2010
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DRUG – DRUG INTERACTION
• When one drug is administered, a response occurs, if a
second drug is given and response to other drug is
altered , a drug interactions is said to have occurred
• This effect may be
• Desired or beneficial (efficacy ↑es with out ↑in
toxicity)
e.g. Multi drug treatment of T.B
Amoxicillin + clavulanic acid
L-Dopa + Carbidopa
Naloxone to treat Morphine overdose
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• Undesired or harmful (toxicity is ↑ed with ↓in
efficacy)
•
Aspirin and Warfarin
•
Propranolol + Salbutamol
•
Paracetamol + Alcohol
•
Gentamycin + loop diruetics
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Clinically important drug interactions •
• 1. Drugs that have steep dose response curve and small
therapeutic index, small change in concentration at site will
lead to substantial increase in effect.
e.g. Digoxin , Lithium
2. Drugs that are known enzyme inducers/inhibitors
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3. Drugs that exibit saturable metabolism
e.g. Phenytoin , Theophylline
4. Drugs used for prolong period and precise plasma
concentration are required
e.g. oral contraceptive , antiepileptic drugs , lithium
5.
Different drugs used to treat same disease
e.g. Theophylline, Salbutamol
6. In patients with impaired kidney and liver functions
7. In elderly who receive several drugs at the same time
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PHARMACODYNAMIC INTERACTIONS
• Both drugs act at same target site exerting synergism
or antagonism
• Drugs may act at same or different receptors or
process.
• The effect may be Synergistic or Antagonism
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SYNERGISTIC PHARMACODYNAMIC DRUG INTERACTIONS
DRUG
TUBOCURARINE
ORAL
HYPOGLYCAEMICS
DIGITALIS
ANTIHYPERTENSIVES
INTERACTS WITH
AMINOGLYCOSIDES
QUINIDINE
PROCAINE
SALICYLATES
PROPRANOLOL
PROPRANOLOL
GUANETHIDINE
VERAPAMIL
RESULTS IN
DIURETICS
ENHANCED
HYPOTENSION
PROLONGED
PARALYSIS
EXCESSIVE
HYPOGLYCAEMIA
BRADYCARDIA
DRUG INTERACTIONS MAY BE ANTAGONISTIC
PRIMARY DRUG
INTERACTS WITH
RESULTING IN
SALBUTAMOL
-PROPRANOLOL
ANTIHYPERTENSIVES
-NSAIDS
ANTIAGONISM OF
BRONCHODILATION
ANTAGONISM OF
HYPOTENSIVE
EFFECT (Na+ RETENTION)
NO SIGNIFICANT
EFFECTS ON Na
ANTAGONISM OF
ANTIMICROBIAL
EFFECTS
WARFARIN EFFECT
ANTAGONIZED BY
INCREASED
CLOTTING FACTOR
SYNTHESIS
ANTAGONISM
SULPHONAMIDES
- SELECTIVE COX 2
INHIBITORS
-L. ANAETHETICS
-(PABA)
WARFARIN
OESTROGENS
OPIOIDS
NALOXONE
PHARMACOKINETIC INTERACTIONS
•
Drug act remotely from target site to alter plasma
concentration
e.g. enzyme induction /inhibition
interaction may be synergistic or antagonistic.
Drug interaction can occur at
1.
2.
3.
4.
5.
6.
out side the body
At site of absorption
During drug distribution
During drug metabolism
During drug excretion.
On receptor or body system.
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Interaction out side the body
• Drugs are added to reservoir or syringes to make
drugs soluble they are prepared in salt forms, mixing
these drugs may lead to precipitation
(incompatibility)
• Dilution in reservoir may also lead to loss of stability.
• Protamine in zinc insulin may bind with soluble
insulin and delay its effects.
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AT THE SITE OF ABSORPTION
• Direct chemical interaction
e.g. Antacids + Tetracycline's ,Iron form insoluble
complexes ,this can be prevented if drugs are
administered at 2hrs apart.
• Gut motility: drugs which reduce gastric emptying
delay absorption of other drugs
e.g anti cholinergics , antidepressants
. •
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PHARMACOKINETIC INTERACITONS
AT THE ABSORPTION LEVEL:
EXAMPLES:
DRUGS
A) TETRACYCLINE +
A)
MECHANISM
CHELATION
EFFECT
MUTUALLY
Ca2+, Fe2+, AL3+, Mg2+
REDUCED
SALTS
ABSORPTION
B) ANTICOAGULANTS
OR THYROXINE
BINDING TO
REDUCED
OR DIGOXIN
RESIN
ABSORPTION
OR THIAZIDES
+
CHOLESTYRAMINE
• Purgatives reduce time spent in small intestine
and reduce absorption.
• Alteration in gut flora: antimicrobials
potentiates ant coagulants by reducing bacterial
synthesis of vit.K
• Affect the transport as P-glycoprotein
• Other than gut : Local anesthetics (xylocaine)
and adrenaline.
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DURING DISTRIBUTION
• Displacement from plasma proteins binding
e.g. Sodium valproate displaces Phenytoin
Sulphonamides displaces bilirubin ( in
neonates)
• Displacement from tissue binding sites
e.g. Quinidine displaces Digoxin
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Interaction during metabolism
• Enzme induction:
•
liver micsrosomal enzymes are induced by a wide variety of
drugs and these affect the metabolism of other drugs reducing
their concentration and hence effect.
• e.g oral contraceptive metabolism is enhanced if Phenytoin is
co-administered ,leading to unplanned pregnancy
•
eg loss of anticougulant effect of Warfarin leading to danger of
thrombosis if barbiturates are administered.
•
chronic use of alcohal shows tolerance to general anesthetics.
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EXAMPLES INCLUDE:
PRIMARY DRUG
INDUCING DRUG
EFFECT OF INTERACTION
ORAL
BARBITURATES
DECREASED
ANTICOAGULANTS
RIFAMPICIN
ANTI-COAGULATION
PHENYTOIN
DECREASED
CHLORPROMAZINE
HYPOGLYCAEMIA
PHENOBARBITONE
FAILURE OF
e.g. WARFARIN
TOLBUTAMIDE
ORAL CONTRACEPTIVES
PREDNISONE
CONTRCEPTION
BARBITURATES
DEXAMETHASONE
DOXYCYCLINE
REDUCED STEROID
LEVELS
BARBITURATES
REDUCED DOXYCYCLINE
LEVELS
QUINIDINE
PHENYTOIN
REDUCED
BARBITURATES
QUINIDINE LEVELS
Enzyme inhibition
• Certain drugs inhibit the liver microsomal
enzymes ,hence increase the activity of drugs
which are to be metabolized by these enzymes.
• Eg. Cimetidine potenciates the effects of
propranolol ,theophylline, warfarin and others
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INTERACTIONS OF LIVER ENZYME INHIBITORS
PRIMARY DRUG
INHIBITING DRUG
INTERACTION
PHENYTOIN
ISONIZID
PHENYTOIN
AZAPROPAZONE
INTOXICATION
CHLORAMPHENICOL
ORAL
ALLOPURINOL
ANTICOAGULANTS
NORTRIPTYLINE
e.g. WARFARIN
QUINIDINE
TOLBUTAMIDE
PHENYLBUTAZONE
CHLORPROPAMIDE
CHLORAMPHENICOL
HAEMORRHAGE
HYPOGLYCAEMIA
DISCOUMAROL
6-MERCAPTOPURINE
ALLOPURINOL
AZATHIOPRINE
ANY DRUG
BONE MARROW
SUPPRESSION
CIMETIDINE
RAISED PLASMA
KETOCONAZOLE
LEVEL OF DRUG
FLUOXETINE
Enzyme inducers.
Phenobarbital •
• Rifampin
• Grisofulvin
• Phenytoin
• Ethanol
• Carbamazepine
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Enzyme inhibitors
•
•
•
•
Phenylbutazone
Metronidazole
Cimetidine
Omperazole
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DRUG EXCRETION:
MAY BE CHANGED BY DRUGS WHICH ALTER
URINARY pH
► WEAK ACIDS LIKE (PENICILLINS,
PHENOBARB, ACETAZOLAMIDE,
NITROFURANTOIN).
BEST ELIMINATED IN ALKALINE URINE
► BASES LIKE (CHLOROQUINE, IMIPARMINE,
QUININE)
OR
BEST ELIMENATED IN ACIDIC URINE B)
DRUGS MAY COMPETE FOR RENAL TUBULAR
SECRETION
PRIMARY DRUG
COMPETING DRUG
EFFECT OF INTERACTION
PENICILLIN
PROBENECID
INCREASED
PENCILLIN LEVELS
METHOTREXATE
LITHIUM
SALICYLATES
BONE MARROW
SULPHONAMIDES
DEPRESSION
THIAZIDES
LITHIUM TOXICITY
HYPERNATRAEMIA
DIGOXIN
SPIRONOLACTONE
INCREASED PLASMA
DIGOXIN LEVELS
SALICYLATES
INDOMETHACIN
PROBENECID
INDOMETHACIN OR
SALICYLATES TOXICITY.
Haemodynamic flow
• variation in heaptic blood flow may influence
the rate of inactivation of drugs as in reduced
cardiac out put.
• Drugs which reduce cardiac out put like
Propranolol may reduce the metabolism of
other drugs.
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B- Drug may alter drug distribution: Mechanisms:
- Competition for plasma protein binding
- Displacement from tissue binding sites
- Alterations in local tissue barriers (P-glyco proteins
inhibition in BBB).
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- Displacement from tissue binding sites would tend
to transiently increase blood concentration of
!displaced drug.
This effect is transient because of compensatory
increase in drug disposition.
• When one displacing drug additionally reduces
elimination of the 1st drug , so that free
concentration is increased not only acutely but also
chronically at new steady state, severe toxicity may
occur.
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Salicylates displace methotrexate from albumin
and also reduce its secretion into nephron by
competition with anion secretory carrier.
Quinidine, verapamil, & amiodarone
displace digoxin from tissue binding sites &
reduce its renal excretion leading to digoxin
toxicity
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• Drugs metabolism:
Drugs can either inhibit/ induce drug-metabolizing enzymes.
Enzyme inducers (stimulation of cytochrome P450 in liver):
requires some days
- Barbiturates
- Ethanol
- Carbamazepine??
- Phenytoin
- Rifampicin??
- Efavirenz??
- They also increase glucuronidation (phase II) metabolism
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Enzyme inhibitors: (inhibit cytochrome P450);
more quickly than enzyme induction
-
Amiodarone
Androgen??
Chloramphenicol
Cimetidine; decrease warfarin metabolism
Ciprofloxacin, clarithromycin, erythromycin
Cyclosporine, ??isoniazide,?? ketoconazole,
Delavirdine??
Disulfiram.‫؟؟‬
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