Transcript Drugs affecting Renal Elimination

Drug-Drug Interactions (DDI)
What's our plan today
 Introduce Drug-Drug Interactions (DDI)
 Study different mechanisms resulting in DDI
DDI , what's the problem ?
 Most of patients these days are on multiple drugs (Poly-Pharmacy),
especially OLD patients
 There is strong possibility that drugs INTERACT with each other
affecting Safety, Efficacy
 Harmful drug–drug interactions cause 10–20% of the adverse drug
reactions requiring hospitalization and they can be avoided
Rational drug use
DDI
D-Food Interact
Drugs used for
Older people,
Children,
Expecting Women
Irrational Drug
Combination
ADR
Detection &
prevention of ADR
Dose adjustment
in special pop
Categories of ddi based on mechanism
DDI
PK
PD
Pharmacokinetic interaction
Typical Journey that the drug takes
ORAL
Absorption
IV
Distribution
Metabolism
Elimination
Any OTHER drug that affects any of above, WILL result in change in CONCENTRATION
Ddi affecting absorption
Absorption
• CHELATION:
 Heavy metal ions (Zn, Fe, Ca, Mg) can bind
anionic drugs (Tetracycline, Cipro)
 Results in poor soluble salts, lower
absorption
 Ion exchange resins bind drugs prevent
absorption
 Ion exchange resin bind to bile salts & drugs
such as
Digoxin, Thyroxine, Warfarin
 IV drugs (Adrenaline) lowering absorption of
local
anesthetics
Ddi affecting absorption
• Affect on GI Motility:
Absorption
 Drugs affecting GI motility affect overall
absorption
 Metclopramide improves Gastric Emptying
as a result drug reaches fast, quick onset
 Migraine slows gastric emptying, delays
onset of action
 Digoxin has poor solubility, 20-30% excreted
out unabsorbed
 Drugs (Anti-cholinergic) slowing GI motility might
improve absorption or have toxic effect
 Metclopramide might reduce therapeutic effect
Ddi affecting absorption
• Affect on GI Microrganism (Bacteria):
Absorption
 Broad spectrum antibiotics affect bacteria in long
intestine
 Some drugs require bacterial activation for effect
 Ex. Oral contraceptives; Bacterial enzymes break
bonds to release free estrogen to be absorbed in body
 If estrogen levels are low, contraceptive effect
(ovulation, conception) might not occur
 Bacteria involved in synthesizing Vit K
 Vit K antagonize effect of courmarin (anticoagulants), low
vitamin K levels might increase
effect of Coumarin (Bleeding risk)
Ddi affecting distribution
Distributio
n
• Drugs affecting Protein binding:
 Highly protein bound drugs affected
 Increase in free fraction due to displacement
from
protein sites
 Increase in conc might result in increased
activity, higher
elimination rate
 Ex. Methotrexate, warfarin highly protein
bound
 NSAIDS, Aspirin might displace these
drugs from
sites
Ddi affecting metabolism
Metabolis
m
• Drugs affecting Metabolism of Drugs:
 Majority of drugs metabolized by CYP
enzymes
 CYP3A4, 2D6 are major enzymes
 Drugs can inhibit or induce these
enzymes leading to increase or decrease in
metabolism

Ddi affecting metabolism
• Drugs Inducing CYP enzymes:
Metabolis
m
 Induction of CYP might lead to increase in
metabolic capacity of liver
 Might result in decrease conc
 Ex. Rifampicin is a strong inducer

Ddi affecting metabolism
Metabolis
m
Ddi affecting metabolism
Metabolis
m
Ddi affecting metabolism
• Drugs Inhibiting CYP enzymes:
Metabolis
m
 Inhibition of CYP might lead to decrease in
metabolic capacity of liver
 Might result in increased conc
 Ex. Cipro inhibits CYP leading to increase in
Theophylline conc
 Inhibition can also be used to lower
Dose/Cost
 Diltiazem inhibits CYP, lower dose
Cyclosporin
Ddi affecting metabolism
• Genetic Polymorphism:
Metabolis
m
 Different ethnic groups sometimes have
different enzymatic capacities
 Ex. Some groups are extensive, some
poor metabolisers
 2-5 % of Indians are poor CYP2D6
metabolisers
 11 % North Indians are poor CYP2C19
metabolisers
Ddi affecting metabolism
• Genetic Polymorphism:
Metabolis
m
 Diazepam is CYP2C19 substrate
 Some patients “Extensive”, some “Poor”
metabolisers
 “Extensive” patients respond normally
while “Poor” have long sedation
 Omeprazole (CYP2C19 Inhibitor) will
convert both category to “Poor
Metaboliser”
Ddi affecting renal excretion
• Drugs affecting Renal Elimination:
Elimination
 Drugs primarily eliminated by Kidney can
get affected by
1. Change in Urine flow
2. Change in Urine pH
3. Change in Tubular secretion
Ddi affecting renal excretion
• Drugs affecting Renal Elimination:
Elimination
 Lithium primarily eliminated by Kidney
1. Lithium not bound to proteins, freely filtered
2. Thiazide diuretics INCREASE tubular
reabsorption (More Lithium back in plasma)
leading to toxicity (25 – 30 % decrease in
clearance)
3. NSAID reduce blood flow, less Lithium
filtered, levels in plasma increase
Ddi affecting renal excretion
• Drugs affecting Renal Elimination:
Elimination
 Change in Urine pH:
 Sodium Citrate used to increase pH (7-8),
reduce symptoms of urinary tract
infections
 Acidic Drugs: Cephalosporins, Acyclovir,
Penicillins MORE IONISED , less reabsorbed
 Basic Drugs: Cimetidine, Ranitidine MORE
UN-IONISED, More reabsorbed
Ddi affecting renal excretion
• Drugs affecting Renal Elimination:
Elimination
 Drugs affect pH of URINE affect reabsorption
of drugs
 If we make pH more AlKALINE (>7) then
 Acidic drugs are MORE in IONISED form
 LESS reabsorption, DECREASE of Plasma
levels
 Basic drugs are MORE in UN-IONISED form
 MORE reabsorption, INCREASE of plasma
levels
Categories of ddi based on mechanism
DDI
PK
PD
Pd based drug interactions
 Drugs can have affect pharmacological actions of other drugs
 Drugs can add (Synergistic) or decrease (Antagonistic ) effects of other co-administered
drug
 If MOA of drug is known, we can predict effect of other drug on it’s MOA
Pharmacological synergism
 Combinations used to increase
therapeutic effect
 Sometimes may cause toxicity

ACE inhibitors + Aldosterone
antagonist

MOA inhibitor (Phenelzine) + sertraline = High
levels of SERTONIN, leading to serotonin
syndrome
Pharmacological antagonism
A
B
 Drug A prevents/Blocks effect of
Drug B
 Ex.
Antagonistic effect on
effect of B by A

NSAID lowers diuretic effect of Thiazides

Affects prostaglandins levels, lower rate of
filtration, low sodium excretion

Metoclopramide (Dopamine antagonist) lowers
effect of Levodopa = Increased signs of
Parkinsonism (Ataxia, dyskinesia)
Sources of information on ddi
 Information on DDI can be obtained from various sources
1. In vitro and animal data:
1. In vitro studies looking at effect on CYP enzymes (Enzymatic studies)
2.
Animal studies evaluating interaction (Ex. Effect of CYP inhibitor on conc of CYP substrate in
mice)
2. Case Reports:
1. Case reports or letters published in medical journals
2. Useful source for identifying rare DDI, infrequent combination's of drugs
3. Case reports however need to carefully studied for verification
Sources of information on ddi
 Information on DDI can be obtained from various sources
1. Clinical Trials:
1.
2.
3.
4.
Most reliable source of info
However the sample size is small, study population is healthy volunteers
Studies conducted after single dose may not reflect results after multiple dosing
Results should be evaluated for clinical significance
2. Reviews, Monographs and Handbooks:
1.
2.
Various journals report reviews, Pharmaceutical journal, Annals of Pharmacotherapy
Books , a good source but needs to be verified for current information
Sources of information on ddi
 Information on DDI can be obtained from various sources
1. DDI websites:
1.
2.
3.
Some a specific
Some provide comprehensive data base
Permit to look for combination
Identifying DDI in clinics

Identifying DDI in clinics
Evaluating
Medication & AE
history
Literature
Assessment
Managing an
Adverse Reaction
Reporting
new or rare
interactions
Asses medication and adverse reaction
history
 List of all medicines, therapeutically active agents taken by patients
 Entire dosing history (When, how long, how many doses etc )
 If drugs stopped, restarted , then results should be documented
 Interaction timing depends on several factors
 Some drugs interact at steady state after reaching certain conc
 DDI involving Enzyme induction takes time
Literature evaluation
 Look for literature sources for potential DDI
 Cross check reference
 Medical literature or case reports
Managing adverse reaction
 Management depends on severity of risk
 Is the event dose related ?, then consider changing dose
 Ex. Miconazole increases bleeding time of warfarin. Lower warfarin dose
 Some sever case needs stoppage of drugs
 Ex. Erythromycin + Terfenadine = High levels of terfenadine = Cardiac arrhythmias
 Change antihistaminic or change antibiotic
 In some case , dose spacing might be useful.
 Ex. To avoid chelation of Cipr by Fe salts, avoid coadministration
Reporting new or rare reactions
 Rare, new reactions should be reported to WHO, Pharmacovigilance
 If possible , publish in reputed medical journal
 Ideally re-challenge should be done but typically doctors/patient not comfortable
THANK YOU
-PHARMA STREET