DR. S. PARTHASARATHY MD., DA., DNB, MD (ACU), DIP. DIAB.DCA, DIP. SOFTWARE STATISTICS PHD (PHYSIO)

MAHATMA GANDHI MEDICAL COLLEGE AND RESEARCH INSTITUTE , PUDUCHERRY – INDIA

Drug interactions

OBJECT + PRECIPITANT = ???

An interaction is said to occur when the

effects of one drug are changed by the

presence of another drug

OBJECT ?? PRECIPITANT ??

Fentanyl and propofol Object precipitant

Fentanyl morphine Object , precipitant

WHY SHOULD WE KNOW ABOUT THIS

As anaesthesiologists

COMBINING DANGEROUS DRUGS

Anesthesiologists usually combine drugs to get better action and benefits

Yes -- we combine drugs -- but what’s the problem ??

TYPES

pharmaceutical interaction pharmacokinetic interaction pharmacodynamic interaction (direction and intensity)

1. antagonistic 1 + 1 = 0 2. additive 1+1 = 2 3. synergic 1+1 = 3

DEFINITIONS

A pharmaceutical interaction is a chemical or physical interaction that occurs before a drug is administered or absorbed systemically.

A pharmacokinetic interaction occurs when one drug alters the absorption, distribution, metabolism, or elimination of another.

A pharmacodynamic interaction occurs when one drug alters the sensitivity of a target receptor or tissue to the effects of a second drug.

HISTORY

WTG morton Ether day ether by itself could produce hypnosis,

reasonable levels of analgesia, and muscle relaxation

Guedel’ s stages

NOW PATIENTS WANT

No mask induction Pain free Quick recovery No delirium No vomiting

WHAT NOW ??

IV Agents

Narcotics

Muscle relaxants

So what happened to Guedel stages ??

PROBLEMS CREATED BY DRUG–DRUG INTERACTIONS Agents with low safety margins warfarin, digoxin, and theophylline

Conscious sedation Pethidine and MAOI

Can we think like this ?? If a drugs fails to act - is it due to a

drug interaction ??

WHY TO COMBINE ??

Combination therapy can reduce toxicity

atenolol and hydralazine

Drugs for Malignancy

Drugs for Seizures

PHARMACEUTICAL INTERACTION

Thio and scoline in the IV line

Fortwin and taxim

Bupivacaine and sodabicarb

Adrenaline and soda bicarb

PHARMACEUTICAL INTERACTION

Heparin and hydrocortisone Inactivation of heparin

Gentamicin and hydrocortisone Inactivation of gentamicin

INHALATIONAL AGENTS

Older anaesthetists

Trilene and sodalime

Younger ones

Sevoflurane and sodalime

PHARMACOKINETIC INTERACTIONS

Absorption distribution, metabolism, elimination of another drug

ABSORPTION

Oral tetracycline can be inactivated by chelation if it is given together with antacids containing polyvalent cations such as Mg2+, Ca2+, or Al3+.

Morphine delays gastric emptying Small gut drugs like para ??

ABSORPTION

Adrenaline and local anaesthetics

Second gas effect

DISTRIBUTION

Possible depression of cardiac function

Propofol

Agent

VRG

PLASMA PROTEINS

Thyrotoxicosis

Fever

aspirin

ENZYME INDUCTION

METABOLISM

Neostigmine and scoline

Ecothiophate and scoline

MAO INHIBITORS

sympathetic neurotransmission:

CNS transmission

Separate topic

HEPATIC BIOTRANSFORMATION

Hepatic blood flow Agents decrease hepatic blood flow

Extraction High Lidocaine and propranolol

Low-extraction drugs such as diazepam, alfentanil, or mepivacaine have ERs of 0.3 or less.

etomidate, blocks the synthesis of cortisol and aldosterone by inhibiting the P450-dependent mitochondrial enzymes, 17α-hydroxylase and 11β-hydroxylase.

Protease inhibitors such as saquinavir and ritonavir can inhibit the metabolism of midazolam and fentanyl,

ENZYME INDUCTION

propofol competitively inhibits CYP3A4, and it

can reduce the clearance of midazolam by 37%

Co administration of cimetidine and diazepam

causes clinically significant elevations in

diazepam

Alfentanil and erythromycin are both

metabolized by CYP3A4, and the antibiotic

greatly prolongs the effect of the opioid.

DRUG ELIMINATION

Probenecid and penicillin

Quinidine and digoxin

The cation system handles the elimination of atropine, isoproterenol, neostigmine, and meperidine

ACIDIC AND ALKALINE URINE

PHARMACODYNAMIC INTERACTIONS-

PHARMACODYNAMIC INTERACTIONS-

Direction and intensity

1. antagonistic 1 + 1 = 0 2. additive 1+1 = 2 3. synergic 1+1 = 3

ADDITIVE (1 +1 = 2)

Rocuronium and vecuronium Nitrous oxide with volatile anesthetics

is additive Two benzodiazepines

likely to occur when drugs with identical mechanisms are combined

SYNERGY

potentiation of opioids by NSAIDs potentiation of nondepolarizing

relaxants by the various volatile anesthetics

supra-additive interaction occurs between aminosteroid and benzylisoquinolines

ANTAGONISTIC DRUG INTERACTIONS neostigmine, naloxone, or flumazenil. An antagonistic interaction occurs between

succinylcholine and the nondepolarizing relaxants.

drug combination may simultaneously be synergistic and antagonistic for different effects.

When butorphanol is combined with midazolam, the mixture increases sedation but has less anterograde amnestic effect than midazolam alone

CLINICAL SCENARIO

Pharmacodynamic

Interactions Affecting

Hemodynamics

PATIENTS WITH BRONCHOSPASM

Rapid-acting β2 agonists (albuterol, terbutaline),

anticholinergics (ipratropium)

phosphodiesterase inhibitors (theophylline).

increased risk for tachydysrhythmias and ectopic

rhythms.

Similar considerations apply to the patient receiving the

IV β2 agonist, ritodrine, for premature labor.

TCADS

minimize the use of pancuronium, halothane, ketamine

Prone for arrhythmias

TCADs induced hypotension ???

COCAINE

Patients with chronic cocaine intoxication are less of a

problem, (THAN ACUTE) but they are still at risk for

dysrhythmias (avoiding halothane, pancuronium,

atropine, and sympathomimetics)

Increase MAC – halothane

Pharmacodynamic Interactions Affecting

Analgesia or Hypnosis

THIOPENTONE – FENTANYL – THEN THIPENTONE

fentanyl and midazolam are combined for conscious sedation, the opioid is producing sleep as well as analgesia.

Thiopental–midazolam interaction has been studied in humans, and the combination was found to have 1.8 times the expected potency of the individual agents

PROPOFOL AND MIDAZ

DECREASE MAC OF AGENTS

IV lignocaine Clonidine. Midaz

Α2-AGONIST INTERACTIONS

Opioid

Benzodiazepines

Agents

BUPRENORPHINE AND MORPHINE

Agonist and antagonist

Three-Way Interactions

PHARMACODYNAMIC INTERACTIONS-

SEPARATE TOPIC

Herbal Agents Opioids

SOME EXAMPLES

Adrenaline and local anaesthetics

Prevent absorption----- pharmacokinetic

Alpha 2 agonist action --- pharmacodynamic

Sodabicarb and local anaethetics

Precipitation = pharmacoceutical

Increased absorption – pharmacokinetic

PETHIDINE AND PROMETHAZINE

Sedation

Antanalgesic effect

Pharmacodynamic

THE DESIRABLE BUT UN??WANTED INTERACTION

Thank you all