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1
DRUG – DRUG INTERACTIONS
By
Dr. Faraza Javaid
2
DRUG – DRUG INTERACTION
When one drug is administered, a response occurs, if
a second drug is given and response to the drug is
altered ,a drug interactions is said to have occurred
This 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
Undesired or harmful (toxicity is ↑ed with ↓in
efficacy)
• Aspirin and Warfarin
• Propranolol + Salbutamol
• Paracetamol + Alcohol
• Gentamycin + loop diuretics
3
4
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
5
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
6
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
SYNERGISTIC PHARMACODYNAMIC DRUG INTERACTIONS
DRUG INTERACTS WITH RESULTS IN
TUBOCURARINE
AMINOGLYCOSIDES
QUINIDINE
PROCAINE
PROLONGED
PARALYSIS
ORAL
HYPOGLYCAEMICS
SALICYLATES
PROPRANOLOL
EXCESSIVE
HYPOGLYCAEMIA
DIGITALIS
PROPRANOLOL
GUANETHIDINE
VERAPAMIL
BRADYCARDIA
ANTIHYPERTENSIVES DIURETICS ENHANCED
HYPOTENSION
DRUG INTERACTIONS MAY BE ANTAGONISTIC
PRIMARY DRUG INTERACTS WITH RESULTING IN
SALBUTAMOL -PROPRANOLOL ANTIAGONISM OF
BRONCHODILATION
ANTIHYPER-
TENSIVES
-NSAIDS
ANTAGONISM OF
HYPOTENSIVE
EFFECT (Na+
-
RETENTION)
- SELECTIVE COX 2
INHIBITORS
NO SIGNIFICANT
EFFECTS ON Na
SULPHONAMIDES
-L. ANAETHETICS
-(PABA)
ANTAGONISM OF
ANTIMICROBIAL
EFFECTS
WARFARIN OESTROGENS
WARFARIN EFFECT
ANTAGONIZED BY
INCREASED
CLOTTING FACTOR
SYNTHESIS
OPIOIDS NALOXONE ANTAGONISM
9
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. Out side the body
2. At site of absorption
3. During drug distribution
4. During drug metabolism
5. During drug excretion.
6. On receptor or body system.
10
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.
11
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
•
.
PHARMACOKINETIC INTERACITONS
AT THE ABSORPTION LEVEL:
EXAMPLES:
DRUGS MECHANISM EFFECT
A) TETRACYCLINE +
Ca2+
, Fe2+
, AL3+
, Mg2+
SALTS
CHELATION MUTUALLY
REDUCED
ABSORPTION
A) B) ANTICOAGULANTS
OR THYROXINE
OR DIGOXIN
OR THIAZIDES
+
CHOLESTYRAMINE
BINDING TO
RESIN
REDUCED
ABSORPTION
13
• 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
14
DURING DISTRIBUTION
Displacement from plasma proteins binding
e.g. Sodium valproate displaces Phenytoin and
Sulphonamides displaces bilirubin (in
neonates)
15
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.
Or chronic use of alcohal shows tolerance to general
anesthetics.
EXAMPLES INCLUDE:
PRIMARY DRUG INDUCING DRUG EFFECT OF INTERACTION
ORAL
ANTICOAGULANTS
e.g. WARFARIN
BARBITURATES
RIFAMPICIN
DECREASED
ANTI-COAGULATION
TOLBUTAMIDE PHENYTOIN
CHLORPROMAZINE
DECREASED
HYPOGLYCAEMIA
ORAL CONTRA-
CEPTIVES
PHENOBARBITONE FAILURE OF
CONTRCEPTION
PREDNISONE
DEXAMETHASONE
BARBITURATES REDUCED STEROID
LEVELS
DOXYCYCLINE BARBITURATES REDUCED DOXYCYCLINE
LEVELS
QUINIDINE PHENYTOIN
BARBITURATES
REDUCED
QUINIDINE LEVELS
17
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
INTERACTIONS OF LIVER ENZYME INHIBITORS
PRIMARY DRUG INHIBITING DRUG INTERACTION
PHENYTOIN ISONIZID
AZAPROPAZONE
CHLORAMPHENICOL
PHENYTOIN
INTOXICATION
ORAL
ANTICOAGULANTS
e.g. WARFARIN
ALLOPURINOL
NORTRIPTYLINE
QUINIDINE
HAEMORRHAGE
TOLBUTAMIDE
CHLORPROPAMIDE
PHENYLBUTAZONE
CHLORAMPHENICOL
DISCOUMAROL
HYPOGLYCAEMIA
6-MERCAPTOPURINE
AZATHIOPRINE
ALLOPURINOL BONE MARROW
SUPPRESSION
ANY DRUG
CIMETIDINE
KETOCONAZOLE
FLUOXETINE
RAISED PLASMA
LEVEL OF DRUG
19
Enzyme inducers
Phenobarbital
Rifampin
Grisofulvin
Phenytoin
Ethanol
Carbamazepine
20
Enzyme inhibitors
• Phenylbutazone
• Metronidazole
• Cimetidine
• Omperazole
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)
BEST ELIMENATED IN ACIDIC URINE
PRIMARY DRUG COMPETING DRUG EFFECT OF INTERACTION
PENICILLIN PROBENECID INCREASED
PENCILLIN LEVELS
METHOTREXATE SALICYLATES
SULPHONAMIDES
BONE MARROW
DEPRESSION
LITHIUM THIAZIDES LITHIUM TOXICITY
HYPERNATRAEMIA
DIGOXIN SPIRONOLACTONE INCREASED PLASMA
DIGOXIN LEVELS
SALICYLATES
INDOMETHACIN
PROBENECID INDOMETHACIN OR
SALICYLATES TOXICITY.
Some drugs compete for excretion with other drug in combination
23
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.
24
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).
25
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
THANK YOU
26

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Drugs Interactions.ppt

  • 1. 1 DRUG – DRUG INTERACTIONS By Dr. Faraza Javaid
  • 2. 2 DRUG – DRUG INTERACTION When one drug is administered, a response occurs, if a second drug is given and response to the drug is altered ,a drug interactions is said to have occurred This 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
  • 3. Undesired or harmful (toxicity is ↑ed with ↓in efficacy) • Aspirin and Warfarin • Propranolol + Salbutamol • Paracetamol + Alcohol • Gentamycin + loop diuretics 3
  • 4. 4 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
  • 5. 5 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
  • 6. 6 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
  • 7. SYNERGISTIC PHARMACODYNAMIC DRUG INTERACTIONS DRUG INTERACTS WITH RESULTS IN TUBOCURARINE AMINOGLYCOSIDES QUINIDINE PROCAINE PROLONGED PARALYSIS ORAL HYPOGLYCAEMICS SALICYLATES PROPRANOLOL EXCESSIVE HYPOGLYCAEMIA DIGITALIS PROPRANOLOL GUANETHIDINE VERAPAMIL BRADYCARDIA ANTIHYPERTENSIVES DIURETICS ENHANCED HYPOTENSION
  • 8. DRUG INTERACTIONS MAY BE ANTAGONISTIC PRIMARY DRUG INTERACTS WITH RESULTING IN SALBUTAMOL -PROPRANOLOL ANTIAGONISM OF BRONCHODILATION ANTIHYPER- TENSIVES -NSAIDS ANTAGONISM OF HYPOTENSIVE EFFECT (Na+ - RETENTION) - SELECTIVE COX 2 INHIBITORS NO SIGNIFICANT EFFECTS ON Na SULPHONAMIDES -L. ANAETHETICS -(PABA) ANTAGONISM OF ANTIMICROBIAL EFFECTS WARFARIN OESTROGENS WARFARIN EFFECT ANTAGONIZED BY INCREASED CLOTTING FACTOR SYNTHESIS OPIOIDS NALOXONE ANTAGONISM
  • 9. 9 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. Out side the body 2. At site of absorption 3. During drug distribution 4. During drug metabolism 5. During drug excretion. 6. On receptor or body system.
  • 10. 10 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.
  • 11. 11 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 • .
  • 12. PHARMACOKINETIC INTERACITONS AT THE ABSORPTION LEVEL: EXAMPLES: DRUGS MECHANISM EFFECT A) TETRACYCLINE + Ca2+ , Fe2+ , AL3+ , Mg2+ SALTS CHELATION MUTUALLY REDUCED ABSORPTION A) B) ANTICOAGULANTS OR THYROXINE OR DIGOXIN OR THIAZIDES + CHOLESTYRAMINE BINDING TO RESIN REDUCED ABSORPTION
  • 13. 13 • 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
  • 14. 14 DURING DISTRIBUTION Displacement from plasma proteins binding e.g. Sodium valproate displaces Phenytoin and Sulphonamides displaces bilirubin (in neonates)
  • 15. 15 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. Or chronic use of alcohal shows tolerance to general anesthetics.
  • 16. EXAMPLES INCLUDE: PRIMARY DRUG INDUCING DRUG EFFECT OF INTERACTION ORAL ANTICOAGULANTS e.g. WARFARIN BARBITURATES RIFAMPICIN DECREASED ANTI-COAGULATION TOLBUTAMIDE PHENYTOIN CHLORPROMAZINE DECREASED HYPOGLYCAEMIA ORAL CONTRA- CEPTIVES PHENOBARBITONE FAILURE OF CONTRCEPTION PREDNISONE DEXAMETHASONE BARBITURATES REDUCED STEROID LEVELS DOXYCYCLINE BARBITURATES REDUCED DOXYCYCLINE LEVELS QUINIDINE PHENYTOIN BARBITURATES REDUCED QUINIDINE LEVELS
  • 17. 17 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
  • 18. INTERACTIONS OF LIVER ENZYME INHIBITORS PRIMARY DRUG INHIBITING DRUG INTERACTION PHENYTOIN ISONIZID AZAPROPAZONE CHLORAMPHENICOL PHENYTOIN INTOXICATION ORAL ANTICOAGULANTS e.g. WARFARIN ALLOPURINOL NORTRIPTYLINE QUINIDINE HAEMORRHAGE TOLBUTAMIDE CHLORPROPAMIDE PHENYLBUTAZONE CHLORAMPHENICOL DISCOUMAROL HYPOGLYCAEMIA 6-MERCAPTOPURINE AZATHIOPRINE ALLOPURINOL BONE MARROW SUPPRESSION ANY DRUG CIMETIDINE KETOCONAZOLE FLUOXETINE RAISED PLASMA LEVEL OF DRUG
  • 20. 20 Enzyme inhibitors • Phenylbutazone • Metronidazole • Cimetidine • Omperazole
  • 21. 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) BEST ELIMENATED IN ACIDIC URINE
  • 22. PRIMARY DRUG COMPETING DRUG EFFECT OF INTERACTION PENICILLIN PROBENECID INCREASED PENCILLIN LEVELS METHOTREXATE SALICYLATES SULPHONAMIDES BONE MARROW DEPRESSION LITHIUM THIAZIDES LITHIUM TOXICITY HYPERNATRAEMIA DIGOXIN SPIRONOLACTONE INCREASED PLASMA DIGOXIN LEVELS SALICYLATES INDOMETHACIN PROBENECID INDOMETHACIN OR SALICYLATES TOXICITY. Some drugs compete for excretion with other drug in combination
  • 23. 23 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.
  • 24. 24 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).
  • 25. 25 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