1. Drug Interaction and Adverse Drug reaction (ADR)
DR A.A BUSARI
(MB.BS, M.Sc., MMCP, FWACP)
Department of Pharmacology, Therapeutics and Toxicology.
College of Medicine, University of Lagos.

2. Drug interation

3. DRUG INTERACTIONS
It is the modification of the effect of one drug (the object drug ) by the prior or concomitant administration of another drug or agent
(precipitant drug).

4. Outcomes of drug interactions
undesired (Harmful Effects)
Desired (Beneficial Effects)

5. Outcome of Interactions:
Enhancement in drug action/ improved therapeutic benefits
Reduction in desired drug effects
Neutralization of drug effects (therapeutic failure)
Increased risk of adverse reactions

6. Forms of DI Drug interaction include - Drug – drug Interactions
Drug – herbal Interactions
Drug – food Interactions
Drug – Chemical Interactions
Drug – laboratory test Interactions
Pharmacogenetic Interactions.

7. Risk Factors for Drug Interactions
High Risk Patients
Elderly, young, very sick, multiple disease
Multiple drug therapy, Renal, liver impairment
High Risk Drugs
Narrow therapeutic index drugs e.g.(digoxin, warfarin, theophylline)
Recognized enzyme inhibitors or inducers

8. Classification of DDI

9. Site of interaction
Outside the body.
Inside the body.

10. Outside the body:
Incompatibilities: reaction of IV drugs given together in solutions after mixing that are not longer safe for the patient. This results in an alteration of the structure and stability of the drug combinations (in the solution) leading to:
Loss of drug activity.
Formation of precipitates.
Development of toxic product.

11. Drug Interactions Inside the body
Pharmacokinetic drug interactions
Pharmacodynamic drug interactions

12. PHARMACOKINET IC INTERACTIONS

13. Pharmacokinetic drug interactions
Involve the interactions between drugs leading to alterations in the following:
Absorption.
Distribution.
Metabolism.
Excretion.

14. Interaction at the site of absorption
Formation of drug Chelates or complexes.
Altered gut Flora
Altered GIT Motility.
Altered PH.
Drug induced Mucosal damage.
Malabsorption caused by other drugs.
Interaction other than in the Gut.

15. Absorption
Direct chemical interaction in the gut and formation of drug Chelates or complex
Calcium (milk), iron, anti acid (Al or Mg hydroxide) + Tetracyclin insoluble complex.
levothyroxine , digoxin and some acidic drugs e.g warfarine + Colestyramine decrease their absorption.

16. PHARMACOKINETIC INTERACTIONS
Absorption – Drug interaction can affect the rate and extent of systemic drug absorbtion (bioavailability) from the absorption site resulting in increased or decreased drug bioavailability.
Antacids/milk (Ca) + tetracycline
Cholestyramine + digoxin, etc
Reduced bioavailability of tetracycline and digoxin due to the formation of complexes that are not absorbable)

17. Absorption Altered intestinal bacterial flora
Antibiotics kill a large number of the normal
flora of the intestine
Antimicrobials may potentiate Oral Anticoagulant by reducing bacterial synthesis of vitamin K.
In 10% 0f patients receiving Digoxin…..40% or more of the administered dose is metabolized by the intestinal flora which Increases digoxin conc.
and increases its toxicity

18. Antibiotics and Oral Contraceptives
Antibiotics kill bacteria in gut
Oestrogen conjugates not hydrolysed
Conjugates not re-absorbed
Less oestrogen - loss of contraceptive effect
(No effect on progestogen component)

19. CONT’D Altered gut motility OR
Slowing of gastric emptying by drugs like antimuscarinic drugs and opiate analgesics
anticholinergics + acetaminophen
Impact: delay in absorption of acetaminophen OR
Accelerated by drugs e.g metclopromide which hasten gastric emptying

20. CONT’D
Altered PH.
The non-ionized form of a drug is more lipid soluble and more readily absorbed from GIT than the ionized form.

21. H-2 blockers, anti acid + ketoconazole Decrease gastric acid, dissolution of ketoconazole is decreased, resulting in reduced absorption Therefore, These drugs must be separated by at least 2h in between administration.

22. CONT’D Drug-induced mucosal damage:
Colchicine (which cause local Mucosal damage) can decrease absorption of poorly absorbed drugs e.g. (phenytoin)

23. CONT’D Malabsorption caused by other drugs:
Orlistat (Xenical) Inhibits pancreatic lipases, preventing hydrolysis of ingested fat)
Orlistat (Xenical) + fat soluble vitamins
(A,D,E,K)
malabsorption of Fat-soluble vitamins

24. Interaction at the site of drug distribution
Displacement from plasma protein binding
It depends on the affinity of the drug for the plasma protein.
The most highly bound drug(s) is capable of displacing others.
The concentration of the free drug (the drug displaced) is increased.
Sodium valproate displaces phenytoin from its binding site on plasma albumin.

25. CONT’D Displacement from tissue bindings
Quinidine displaces digoxin from its binding site in tissues and cause increase concentration of free digoxin.

26. PHARMACOKINETIC INTERACTIONS
Adsorption
Antacids/Charcoal + Paracetamol
Antacids/Charcoal + H2 blockers
(Reduced bioavailability of the drugs)There is always the possibility of antacid and charcoal adsorbing other drugs
Increased GIT transit time
Antimuscarinics + Paracetamol
Antimuscarinics + Levodopa
(Takes longer time for the drugs to reach the small intestine for absorption due to inhibition peristalsis by the antimuscarinic)

27. Altered drug Metabolism
Changes in drug metabolism are the most important causes of unexpected drug interactions.
There are several enzyme families involved in drug metabolism, and the cytochrome P450 (CYP) enzyme family is the most important.

28. CONT’D
Inhibition of a cytochrome P450 enzyme increases the concentration of some drugs by decreasing their metabolism. For example, clarithromycin is a strong inhibitor of CYP3A-catalysed simvastatin metabolism, thus increasing the risk of myopathy.

29. CONT’D
Drug inhibition of cytochrome P450 enzymes is also used therapeutically.
For example, ritonavir, a strong inhibitor of CYP3A, reduces metabolism of other protease inhibitors thus increasing their effectiveness in treating HIV (so called ‘ritonavir-boosted’ regimens).

30. CONT’D
Induction of a cytochrome P450 enzyme decreases the concentration of some drugs by increasing their metabolism.
For example, carbamazepine is a strong inducer of CYP3A that increases the metabolism of the combined oral contraceptive, thus increasing the risk of unwanted pregnancy.

31. CONT’D
Prodrugs
Some drugs rely on cytochrome P450 enzymes for conversion to their active form.
As this is usually dependent on a single enzyme pathway, prodrugs are particularly vulnerable to changes in metabolism.
Inhibition of conversion from prodrug to active drug may lead to inadequate concentrations of the active drug and therapeutic failure.
For example, tamoxifen is metabolised by CYP2D6 to its active form endoxifen, and concomitant therapy with the strong CYP2D6 inhibitor paroxetine has been associated with increased mortality in breast cancer.

32. CONT’D Enzymes Inhibitors CYP1A2 CYP2C9 CYP2C19 CYP2D6 CYP3A
Inducers
Inhibitors
CYP1A2
ciprofloxacin, fluvoxamine,
ethinyloestradiol, interferon-alfa
phenytoin, rifampicin
CYP2C9
fluconazole
carbamazepine, rifampicin
CYP2C19
fluconazole, fluvoxamine, ticlopidine, fluoxetine, clarithromycin, voriconazole, moclobemide
lopinavir/ritonavir, rifampicin, St John’s wort
CYP2D6
bupropion, fluoxetine, paroxetine, perhexiline, cinacalcet, doxepin, duloxetine, flecainide, moclobemide, quinine, terbinafine
CYP3A
erythromycin, clarithromycin
voriconazole, itraconazole, ketoconazole, indinavir, ritonavir, saquinavir, diltiazem, verapamil, grapefruit juice
, aprepitant, cimetidine, ciprofloxacin, cyclosporin, fluvoxamine, imatinib
carbamazepine, modafinil, phenytoin,
phenobarbitone, rifabutin, rifampicin,
St John’s wort

33. Alterations in renal clearance
Increase in Renal Blood Flow.
Inhibition of Active Tubular Secretion.
Alterations in Tubular Reabsorption.

34. hydralazine increases the renal clearance of digoxin
Increase in Renal Blood Flow
hydralazine + digoxin
hydralazine increases the renal clearance of digoxin

35. probenecid + penicillin Decreases tubular secretion of
Active tubular secretion:
It occurs in the proximal tubules.
The drug combines with a specific transporter protein to pass through the proximal tubules.
When two drugs compete for the transporter protein for excretion, one of the drugs will be secreted thus reducing the excretion of the other drug and increasing its plasma concentration.
probenecid + penicillin
Decreases tubular secretion of
Penicillin

36. Passive tubular Reabsorption
Acidification of urine increases reabsorption and decreases excretion of weak acids, and, in contrast, decreases reabsorption of weak bases.
Alkalinization of urine has the opposite effect.
In some cases of overdose, these principles are used to enhance the excretion of weak bases or acids
e.g. sodium bicarbonate + salicylates(weak acid)
decrease reabsorption and Increase excretion of salicylates

37. Pharmacodynamic drug interactions
Pharmacodynamics are related to the pharmacological activity of the interacting drugs .
Both drugs act on the target site of clinical effect.
Synergism
Summation or Additive.
Potentiation.
Antagonism

38. Syn- together ; ergon- work
Drug Synergism
Syn- together ; ergon- work

39. Drug Synergism: This is the facilitation of the effects of one drug by another when given together Types: a. Additive (summation) b. Supra-additive (Potentiation)
Synergism: sharma-AB>A+B, Additive and summation diff entity,doesnot talk about potentition/supraadditive
Tripathi says synergism as facilitation of the effects of one drug by another when given together, and classifies synergism as additive and supraadditive

40. Addition/Summation
Summation /Addition
Effect of drugs A + B = Effect of drug A + Effect of drug B
Final effect is same as the algebraic sum of the
magnitude of individuals drugs
Side effects do not add up
Examples of Summation: Different MOA
Aspirin : (-) PG synthesis  analgesia +
Codeine : Opioid agonist  analgesia +
Examples of Addition: Same MOA
Ibuprofen: (-) PG synth  analgesia +
Paracetamol: (-) PG synth  analgesia+
Pg. 496 sharma opioid Recptors mu and delta, inhbn of ad. cy.—dec camp—dec cell excitablity, activation of K channels-hyperpolarisation,decrease ca conductance

41. Other Additive Drug Combinations
Effect
Amlodipine + Atenolol
Antihypertensive
Glibenclamide + Metformin
Hypoglycemic
???additive/???summative
NO & Halothane: 373 tripathi
Amlo-268 sharma
Gli+Met=kdt 274,fig 19.6

42. Supra-additive/Potentiation
SEffect of drug A + B > Effect of drug A + Effect of drug B
When two drugs are given together, the final effect is much
more than the simple algebraic sum of the magnitude of
individuals drugs.
Examples:
Sulphamethoxazole & Trimethoprim--- sequential blockade
of two steps in synthesis of folic acid in micro-organisms.

43. Pharmacodynamic beneficial combinatoin
Other eg. Beta blocker and frusemide

44. Synergism by altering the pharmacokinetics of the other
Synergism by altering Pharmacokinetics
of the other:
Levodopa + Carbidopa

45. Other supraadditive drug combinations
DRUG PAIR
BASIS OF POTENTIATION
Ach + Physostigmine
Inhibition of break down
Adrenaline + Cocaine
Inhibition of neuronal uptake
Tyramine + MAO inhibitors
Increasing releaseable CAT store
Ach-105 kdt
Adrenaline cocaine-sharma 157,158,159
Mao=sharma 464-tranylcypromine, moclobemide, selegiline iproniazid,
Tyramine: 178 sharma mao present liver git metabolise tyramine rapidly-in presence of mao- inhb tyramine met- concof tyr increases and inc releseable cat stores----cheese reaction

46. Drug Antagonism

47. DDefinition: Drug Antagonism
Combined effect of two drugs is less than the sum of the effects of the individual drugs
Effect of drugs A + B < Effect of drug A + Effect of drug B
One drug decreases / opposes / reverses / counters
the effect of other drug by different mechanisms

48. Types of Antagonism
a. Pharmacological Antagonism : i. Competitive (Reversible) ii. Non-competitive (Irreversible) b. Chemical Antagonism c. Physiological Antagonism d. Physical antagonism

49. CONT’D B) Chemical Antagonism A) Physical Antagonism
Based on physical property of drugs, e.g. charcoal (adsorb alkaloid) in alkaloidal poisoning
B) Chemical Antagonism
Chemical reaction between two drugs
e.g., NaHCO HCl

50. C) Physiological/Functional Antagonism
CONT’D
C) Physiological/Functional Antagonism
Opposite effects of two drugs on same function
Two drugs act on two diff. types of receptors & antagonize action of each other, e.g. histamine & adrenaline (adrenaline for treatment of anaphylactic shock); Adrenaline & insulin on blood sugar level

51. D) Pharmacological Antagonism
Opposite effect of two drugs binding to same receptors
Receptor antagonism is specific,e.g. atropine  spam of intestine by acetylcholine not by Histamine.or 5-HT (serotonin)
Types
Competitive Non-competitive
Equilibrium Non-equilibrium
(Reversible) (Irreversible)

52. i) Competitive Antagonism (equilibrium or reversible)
Competition between agonist & antagonist for specific site or receptor
Action of agonist is blocked if conc. of antagonist is 
Antagonism can be overcome (surmount) by  conc. of agonist
Cont.

53. CONT’D

54. II) Non-Equilibrium(irreversible) Antagonist
Antagonist binds to receptor with covalent bond
Irreversible blocking
e.g. adrenaline & phenoxybenzamine

55. iii) Non-competitive (non-surmountable Antagonist
CONT’D
iii) Non-competitive (non-surmountable Antagonist
Antagonist binds to another site of receptor
DRC is flattened + max. response is 
e.g., verapamil (noradrenaline)

56. CONT’D

57. ADVERSE DRUG REACTIONS

58. DEFINITION
WHO’s definition of an adverse drug reaction, which has been in use for about 30 years, is “a response to a drug that is noxious and unintended and occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease, or for modification of physiological function

59. DEFINITION CONT’D
Lawrence and Aronson in an article published in lancet proposed the following as a definition of ADR: “An appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product.”

60. CONT’D
The terms “adverse reaction” and “adverse effect” are interchangeable, except that an adverse effect is seen from the point of view of the drug, whereas an adverse reaction is seen from the point of view of the patient.

61. Epidemiology
4% of hospital admissions 1 in 1000 deaths in medical wards 10 to 20 % of in-patients 5% of patients in general practice

62. CONT’D More frequent in elderly: erratic drug taking
multiple pathology
altered pharmacokinetics
increased sensitivity of CNS and CVS

63. CLASSIFICATION OF ADVERSE DRUG REACTIONS

65. Prevention of Adverse drug reactions
Never use any drug unless there is good indication. If the patient is pregnant do not use the drug unless the need is imperative.
Allergy and idiosyncrasy are important causes of ADRs. Ask if the patient had previous reactions.
Ask if the patient is already taking other drugs including self medication

66. CONT’D
Age, hepatic and renal disease may impair clearance of drugs so smaller doses may be needed. Genetic factors may also predispose to certain ADRs
Prescribe as few drugs as possible and give clear instructions
Where possible use familiar drugs. With new drugs be particularly alert for ADRs and unexpected event.
If serious ADRs are liable to occur warn the patient

67. QUESTIONS Explain the mechanism(s) of drug antagonism
Describe the mode of drug interactions between the following concomitantly administered drugs:
Calcium supplements and tetracycline
Adrenaline and phenoxybenzamine
Levodopa and Carbidopa
Define Adverse Drug Reactions according to the W.H.O.
Briefly discuss with named examples the clinical applications of drug synergism.
Briefly discuss factors that could predispose to drug interactions.