2. Topics covered
• Introduction
• Drugs likely to be involved
• Drug food interaction
• Drug alcohol interaction
• Drug drug interaction
1. Pharmacokinetic
2. Pharmacodynamics
• Drug interaction during drug development
• Drug disease interaction
• Drug herb interaction
3. Drug interaction can be defined as the modifications of
the effects of one drug by the prior or concomitant
administration of another drug
Drug that precipitates the interaction - Precipitant drug
Drug whose action is affected - Object drug
6. Drugs likely involved in interactions
• Drugs highly bound to plasma
proteins
• Used for long term
• Enzyme inducers or inhibitors
• Two drugs simultaneously given
for same disease
Precipitating drugs
• Narrow therapeutic index
• Zero order kinetics
• Steep dose response curves
Object Drugs
8. Useful Interactions
• Adrenaline with lignocaine
• Probenecid wid penicillin
Increase duration of
action
Synergistic effects
• Atropine in organophosphate poisoning
• Naloxone in opiod poisoning
Reverse toxic
symptoms
• Protamine with heparin
• Desferroxamine with iron
Neutralise the action
• Sulfamethoxazole with trimethoprim
10. How drugs effect food???
Food intake
Alteration
in gut flora
Nutrient
absorption
Nutrient
metabolism
Nutrient
excretion
11. How food can effect drugs
Increase
absorption
Decrease
absorption
Irritation
of
digestive
tract
No effect
• Rifampicin- without food
• Rifabutin- with food
• Rifapentin- no effect of
food
12. Milk Fruit juice
Tea/coffee Alcohol
Swallowing of
the medicine
• Erythromycin
• Ketoconazole
• celiprolol
• Grapefruit
juice
• Tetrcayclines
• Bisacodyl
• Iron
supplements
• Mercaptopurin
• Wine-
tyramine
reaction
• iron
absorbtion
• theophylline
18. Interactions outside the body
• Mixing of the drugs in the same syringe
1. Thiopentone and succinylcholine
2. Carbenicillin inactivate aminoglycosides
3. Hydrocortisone inactivates penicillins
19. Interactions outside the body
• Mixing of the drugs in the same syringe
• Giving drug in i.v infusion
1. Quinopristin and Dalfopristin
2. Ampicillin, sodium salts of phenytoin, heparin
20. Unstable
Infuse within
2-4hrs
Stable for
6-8 hrs
Stable for
12 hrs
Photosensitive
drugs
Not infused
after 6 hrs
Ampicillin Benzylpenicillin Fluoxacillin Amphoterecin Cephaloridine
Erythromycin Diazepam Tetracycline Dacarbazine colistin
Stability of drugs in Saline or Dextrose
solution
21. Prevention of Pharmaceutical Interactions
1. Give iv drugs by bolus
2. Do not add infusion solutions
3. Avoid mixing of drugs in the same infusion
4. Mix the drug thoroughly in the infusion
5. Use 2 separate infusion sites if drugs administered simultaneously
26. Absorbtion
• Chemical Interaction
1. Chelation
2. Alteration in pH
3. Forming an absorbtive layer
Cholestyramine inhibits absorbtion of Digoxin,warfarin
Sucralfate interferes with absorbtion of Phenytoin
27. Absorbtion
• Chemical Interaction
1. Chelation
2. Alteration in pH
3. Forming an absorbtive layer
• Altered Gut flora
Broad spectrum antibiotics potentiate anticoagulants
28. Absorbtion
• Chemical Interaction
1. Chelation
2. Alteration in pH
3. Forming an absorbtive layer
• Altered Gut flora
• Altered gastric emptying
29. Absorbtion
• Chemical Interaction
1. Chelation
2. Alteration in pH
3. Forming an absorbtive layer
• Altered Gut flora
• Altered gastric emptying
Atropine/opiods reduce absorption of drugs
Purgatives decrease absorbtion of digoxin
30. Absorbtion
• Chemical Interaction
1. Chelation
2. Alteration in pH
3. Forming an absorbtive layer
• Altered Gut flora
• Altered gastric emptying
• Presence of food
31. Absorbtion
• Chemical Interaction
1. Chelation
2. Alteration in pH
3. Forming an absorbtive layer
• Altered Gut flora
• Altered gastric emptying
• Presence of food
• Alteration of drug transporters
32. Oral drug inhibitor transporter
Digoxin quinidine P gp
Paclitaxel Cyclosporin P gp
methotrexate Omeprazole BCRP
irinotecan gefitinib BCRP
Effect on Transporters
36. Distribution
1. Displacement from tissue binding sites
2. Displacement from plasma protein binding
Can be clinically important if 2 criteria are fulfilled
1. Drug should be highly protein bound (>90%)
2. Low apparent volume of distribution
Precipitant drugs involved
1. Sulfonamides
2. Salicylates
3. Phenylbutazone
45. Pharmacodynamic Interactions
A) Direct Pharmacodynamic Inteactions
1. Antagonism at same site
2. Synergism at same site
● Effects of depolarising skeletal muscle relaxants potentiated by
antibiotics like aminoglycosides, polymixin B
46. Pharmacodynamic Interactions
A) Direct Pharmacodynamic Interactions
1. Antagonism at same site
2. Synergism at same site
3. Summation of similar effects at different sites
● Effect of alcohol as a depressant potentiated by other
centrally acting drugs
● Effect of trimethoprim and sulfamethoxazole
47. Pharmacodynamic Interactions
A) Direct Pharmacodynamic Interactions
1. Antagonism at same site
2. Synergism at same site
3. Summation of similar effects at different sites
B) Indirect Pharmacodynamic Interactions
1. Cardiovascular system
Loss of Antihypertensive action of ACEI with NSAIDS
Bradycardia- beta blockers + verapamil
48. Pharmacodynamic Interactions
A) Direct Pharmacodynamic Interactions
1. Antagonism at same site
2. Synergism at same site
3. Summation of similar effects at different sites
B) Indirect Pharmacodynamic Interactions
1. Cardiovascular system
2. Fluid and electrolyte imbalance
Thiazide and loop diuretics - hypokalemia
49. Pharmacodynamic Interactions
A) Direct Pharmacodynamic Interactions
1. Antagonism at same site
2. Synergism at same site
3. Summation of similar effects at different sites
B) Indirect Pharmacodynamic Interactions
1. Cardiovascular system
2. Fluid and electrolyte imbalance
3. CNS
Sedation- BZD+ Alcohol
50. Drug Interaction studies during drug developement
• Main objectives:
1. Any interaction large enough to require dose adjustment
2. Any interaction calls for therapeutic monitoring
3. Contraindication to concomitant use of any medication
• Interactions between
1. new drug and existing drug
2. metabolic enzymes (CYP1A2, CYP2B6, CYP3A4)
3. metabolites of the investigational drug
4. Transporter based interactions
51. Conduct in vitro metabolism and drug
drug interaction studies
Conduct in vivo studies with specific
substrate
Label as such based on vitro
studies
Presence of significant interactions??
Conduct in vivo studies with other
drugs based on co administration
Dose adjustment required or not?
-+
52. Drugs in Liver Diseases
1. Pharmacokinetic level
• Decrease the activity of drug metabolising enzymes
• Changes in the blood flow
1. Drugs undergoing extensive hepatic first pass metabolism
2. Drugs which are inactivated in the liver
3. Drugs which are activated in the liver
4. Drugs which are partly metabolised
5. Due to reduced synthesis of albumin
53. Drugs in Liver Diseases
1. Pharmacokinetic level
2. Pharmacodynamic level
• CNS sensitivity of sedatives, opioids is increased
• Effect of anticoagulant is enhanced
• Altered fluid and electrolyte balance
54. Drugs in Renal Disease
• Drugs which are excreted unchanged
• Drugs which are partly metabolised, partly excreted unchanged
• Drugs which are completely metabolised and then excreted
59. Alteration in gut flora
• Antibiotics can effect normal flora and cause vitamin B depletion
• Antibiotics like cefamendole, cefoperazone, cefotetan can
interfere with vit K producing bacteria
60. Interfere with absorbtion
of Fe, Ca, fat
Loss of fat-soluble
vitamins,
Ex. Vit A and E
Antacids decrease the
absorbtion of Ca 2+,vit C
Alteration in absorption
61. Alteration in nutrient metabolism
• Eg.
Anticoagulant drug warfarin and vitamin K
Statins inhibit HMG –CoA Reductase inhibitor – precursor for
cholesterol and coenzyme Q10
62. Alteration in nutrient excretion
• D- penicillamine & EDTA binds metals Zn2+ and eliminates it via urine
• Diuretics cause loss of ions such as Mg 2+ ,K+ ,Na+ , Ca 2+
63. OAT
Increase duration of action
• Increases duration of
action
• Bloodless field
• Lesser systemic S/E
• Increase
concentration at site
A drug interaction is a situation in which a substance affects the activity of a drug, i.e. the effects are increased or decreased, or they produce a new effect that neither produces on its own.
There are hundreds of reactions..however incidence of such reactions is diff to guage since there are certain distinctions to make
Incidence of reactions also varies geographically
There are hundreds of reactions..however incidence of such reactions is diff to guage since there are certain distinctions to make
In
critically ill pts, its difficult to distinguish btwn adverse effect of drug n due to disease
Dec bioav treatment failure
Increase toxicity
Milk dissolves the coating of bisacody leading to pain and gastritis Mercaptopurine is a purine analog used for acute lymphoblastic leukemia and chronic myelogenous leukemias. Since it is inactivated by xanthine oxidase (XO), concurrent intake of substances containing XO may potentially reduce bioavailability of mercaptopurine. Cow’s milk is known to contain a high level of XO. This interaction may be clinically significant. Therefore most patients should try to separate the timing of taking mercaptopurine and drinking milk.
Fruit juice dec abs of erythromycin Orange juice inreases abs of ketoconazole dec tht of celiprolol Grapefruit juice- enzyme inhibitor
Hesperidin, present in orange juice, is responsible for the decreased absorption of celiprolol
quinopristin and dalfopristin- givn wid 5% dextrose
Ampicillin, sodium salts of phenytoin, heparin-unstable in acidic ph of 5% dextrose
Adrenaline, erythromycin, cephalothin- inactivated at alkaline ph. Therfore avoided in aminophylline infusion solution
Broad spectrum antibiotics potentiate anticoagulants by reducing synthesis of vitamin K
Broad spectrum antibiotics potentiate anticoagulants by reducing synthesis of vitamin K
Broad spectrum antibiotics potentiate anticoagulants by reducing synthesis of vitamin K
atropine/opiods reduce absorption of drugs by delaying gastric emptying
Food can effect the rate of gastric emptying. For example fatty food can slow gastric emptying and retard drug absorption. Generally the extent of absorption is not greatly reduced. Occasionally absorption may be improved. Griseofulvin absorption is improved by the presence of fatty food. Apparently the poorly soluble griseofulvin is dissolved in the fat and then more readily absorbed.
Propranolol plasma concentrations are larger after food than in fasted subjects. Th
Generally drugs are better absorbed in the small intestine (because of the larger surface area) than in the stomach, therefore quicker stomach emptying will increase drug absorption. For example, a good correlation has been found between stomach emptying time and peak plasma concentration for acetaminophen. The quicker the stomach emptying (shorter stomach emptying time) the higher the plasma concentration, Figure 11.3.1.
Also slower stomach emptying can cause increased degradation of drugs in the stomach's lower pH; e.g. l-dopa.
Charcoal binds certain drugs and prevents their initial reabsorbtion. Treatment of poisoning with drugs such as carbamezapine, phenobarbital
Drugs enter the vascular compartment and get distributed into various tissues
Warfarin (99% bound v-9l), phenytoin (90% v-35l)
Ths displacement reactions hav bn highly exaggerated
Cos drugs like warfarin phenytoin and tolbutamide hav a low extraction ratio. Therefore rate of total clearance is proportional to fraction of the unbound drug
Interaction in whcich one drugs inhibits or induces the metab of the other drug can occur btween 2 drugs being metabolised by d same enzyme. However it doesn preclude d possibility of interaction btwen 2 drugs bein metabolised bybdiff enzymes
Theo inhibited by diltiazem
increase the amount of endoplasmic reticulum in hepatocytes
increases the content of CYP450
Interactions r stereoselective-phenylbutazone inhibits the metab of S isomer of warfarin but increases d clearance of d R isomer. However no effect on the racemic mixture
new drug and existing drug should be defined
2. metabolic enzymes (CYP1A2, CYP2B6, CYP3A4) should be ascertained
3.. metabolites of the investigational drug should be considered
4. Transporter based interactions to be evaluated
Decrease the activity of metab ezymes thereby decreasing the plasma clearance of drugs is reduced
Decrease the activity of metab ezymes thereby decreasing the plasma clearance of drugs is reduced
Betel nuts contain arecoline which is a natural cholinergic alkaloid n therefore causes exacerbation of symptoms with flupenthixol and fluphenazine which presents as rigidity, bradykinesia, akithesia
Ginko biloba interacts wid drugs such as aspirin and warfarin and causes an inc in INR leading to post op bleeding
Garlic interacts with warfarin n causes an increase in INR leading to in post op bleeding
St Johns wort may lead to serotonin syndrome whn taken along wid sertraline , tca, maoi
It also causes a decrease in conc of OCPs, antiretroviral drugs such as protease inhibitors, BZD such as alprazolam, and statin such as lovastatin
Liiqorice inhibits d enzyme 11 beta …….. Which is responsible for degradation of steroids thereby leading to steroid toxicity such as wt gain, inc glucose, HTN, oedema
Serotoninergic drugs, such as fenfluramine and dexfenfluramine, inhibit the reuptake of serotonin, stimulate satiety, and therefore reduce food intake
Methylphenidate- This medication is often prescribed for hyperactive young children who are in their rapid growth phase. Long-term use of this drug may cause growth retardation in these children
An orexigenic, or appetite stimulant, is a drug, hormone, or compound that increases appetite. This can be a naturally occurring neuropeptide hormone such as ghrelin, orexinor neuropeptide Y,[1][2] or a medication which increases hunger and therefore enhances food consumption. Usually appetite enhancement is considered an undesirable side effectof certain drugs as it leads to unwanted weight gain,[3][4][5] but sometimes it can be beneficial and a drug may be prescribed solely for this purpose, especially when the patient is suffering from severe appetite loss or muscle wasting due to cystic fibrosis, anorexia, old age, cancer or AIDS.[6][7][8][9][10] There are several widely used drugs which can cause a boost in appetite, including tricyclic antidepressants (TCAs), tetracyclic antidepressants, natural or synthetic cannabinoids, first-generation antihistamines, most antipsychotics and many steroid hormones.
Normal flora involved in the production of B5, b2,b2,b6 ..howeve rmay not be clinically important if they r getting vit b thru diet
Cephalosporins have methylthiotetrazole side chain tht can interfere with vit k activity
Drugs can damage the intestinal absorptive surfaces including villi, microvilli, brush border enzymes, and the transport systemdamage can come from over-the-counter drugs such as aspirin and other acidic drugs, or from antibiotic neomycin or laxatives. The resulting changes in the mucosal lining interfere with optimum absorption of nutrients such as iron, calcium, fat (including some fat-soluble vitamins), protein, sodium, and potassium. Many laxatives, mineral oil, and cathartic agents reduce transit time in the GI tract and may cause steatorrhea and loss of fat-soluble vitamins, A and E, and possibly calcium and potassium
Inhibiton of Q10 may be responsible for statin induced myopathy
2 molecules of deferasirox binding an atom of iron
