DRUG

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DRUG DRUG INTERACTIONS

• Dr.Abdul latif Mahesar
• King Saud University
• May 2009

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DRUG DRUG INTERACTION

• when one drug is administered, a response
  occurs, if a second drug is given and response to
  1st drug is altered ,a drug interactions is said
  to have occurred
• This may be
• Desired or beneficial
• e.g. Multi drug treatment of T.B
• Naloxone to treat Morphine overdose
• Undesired or harmful
• aspirin and warfarin

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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
  changes 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
• 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.
• eg alcohal benzpdiazepines (sedation)
• Morphine Naloxone ( to reverse opioid
  overdose)
• Rifampicin INH ( effective anti TB
  combination.)

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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
• 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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• 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
• 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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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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Enzyme inducers.

• Phenobarbital
• Rifampin
• Grisofulvin
• Phenytoin
• Ethanol
• Carbamazepine

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Enzyme inhibitors

• Phenylbutazone
• Metronidazole
• Cimetidine
• Omperazole

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Interaction during excretion

• this occurs in kidney
• by latering binding and hence filtration
• by inhibitin tubular secretion
• eg probenecid and pencillins
• by latering urine flow and or urine PH.

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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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• Pharmacodynamics synergism/ antagonism
• interaction may lead to toxicity (concurrent
  administration of 2 nephrotoxic drugs can produce
  kidney damage)
• In vitro due to their chemistry.
• As thiopental suxamethonium, must not be mixed
  in same syringe because of formation of insoluble
  complex. (called incompatibility)

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• Drug interaction can make medications more
  effective or may decrease the effectiveness or
• they can cause unexpected potentially dangerous
  (harmful) Side effects OR
• can be useful as multi drug Treatment as in (TB,
  AIDS).

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• If one drug changes RATE at which other drugs
  move from stomach to small intestine, their
  rate of absorption into blood will be affected.
• If one drug changes level of ACIDITY in stomach,
  absorption of other drugs may change.
• If one drug binds to another, neither may be
  absorbed at all.

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Atropine opiate inhibit the gastric emptying
and hence slows the absorption of the drugs from
GIT
Antacids, Ca Iron form an insoluble complex
Tetracyclin retard its absorption thereby
reducing effectiveness of the drug in fighting
infection.
Colestyramine, a bile acid-binding resin, binds
to warfarin/ digoxin/ diuretics, prevent their
abs.???
Adrenaline LA slow its abs prolongs its
local effect.
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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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• Renal excretion
• - Renal excretion of weak acid/base may be
  influenced by drugs that affect urinary pH
  ionization
• ex. Antacids (Mg/ Al- OH) alkalinize urine thus
  increase renal Clearance of salicylates.

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• Inhibition of active tubular secretion of some
  drugs inhibition of renal transporter
  (P-glycoproteins ) can inhibit renal excretion
  increase serum drug concentration.
• Ex. Probenecid inhibit renal tubular secretion of
  penicillin increase its blood level
• Other drugs may be directly toxic to kidneys,
  reducing their function resulting in higher
  levels of drugs.

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• Pharmacodynamic interactions ! 2 drugs may / may
  not act on the same R to produce DI.
• ß-adrenoceptor antagonists diminish !
  effectiveness of ß - agonist (salbutamol)
• Many diuretics causes hypokalemia, w predispose
  digoxin tox??
• MAOIs increase ! amounts of adrenaline
  aggravate ! effect of ephedrine/ tyramine
• Bleeding increase in GIT if warfarin aspirin
• NSAID inh biosynthesis of PGs that cause renal
  vasoD/ natriuretics HTN.

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• OTC medications can also interact e Rx
  medication. Some examples of this type of
  interaction include
• Antihistamines, often used for allergies colds,
  can increase ! sedative effects of barbiturates,
  tranquilizers, some Rx pain relievers.
• Decongestants in cold cough medications can
  interact e antihypertensive drugs to aggravate
  high BP.

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• Mixing antidiabetic medication (e.g., oral
  hypoglycemics) ß blockers (e.g., Inderal) can
  decrease ! response of ! antidiabetic drug??
  increase frequency severity of hypoglycemia
  episodes.
• Bec (increase in heart rate in BP are masked e
  prop).

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• Other types of drug interactions
• Drug effects can be additive (effect effect
  double effect) Potentiation means that drug A
  boosts ! effects of drug B, often by increasing !
  levels of drug B in ! blood.
• Synergism (effect effect gt than double
  effect) 2 2 5. can be beneficial
• Antagonistic (effect vs effect lt than double
  effect).