Drug drug

interaction
mainly in dentistry

By : Yusra Al-jabery

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Drug interaction

An alteration in the duration & magnitude of pharmacological

effects of one drug produced by another drug, food, or any other
substance ( such as herbs & pollutions ) .
However, not all drug interactions are clinically significant or undesired,
and some are actively sought in pharmacotherapeutics to increase drug
effectiveness, decrease toxicity, or both .

** So two or more drugs administered at same time may :

A. Act independently .
B. interact to increase or diminish magnitude or duration.
C. interact to cause an unintended reactions.

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• Drug interactions and drug effects are:

Dose-dependent & duration- dependent .

• Higher the dosage and the longer the administration, the greater is the
chance that an interaction occurs.

• Many drugs have a long biologic half-life, and effective concentrations may
be present in the blood or tissue for many days after the cessation of
therapy.

• Interactions may occur days and weeks after discontinuation of therapy

with one of the interacting drugs.
• Genetic-based differences

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Risk Factors For Drug Interactions:
• High Risk Patient: • High Risk Drugs:

- Elderly and Young people. - Narrow therapeutic index drugs

- Very sick patient. ( digoxin, Warfarin ,Theophylline
- Multiple disease with multiple & Aminoglycosides).
drugs (Polypharmacy)
- Renal Impairment - Recognized enzyme inhibitors or
_ Liver Impairment inducers.

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Risk Rating Classification of D-D interaction

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 Classification of Drug
Interactions

Unexpected
Antagonism Potentiation Summation Synergism
drug effect

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 Antagonism
• Antagonism indicates that the biologic or clinical response to a drug is
reduced by administering a second agent.
• Depending on the mechanism involved:

1) Physical antagonism: based on physical property of drug

E.g. charcoal adsorbs alkaloids and can prevent their absorption—used in
alkaloidal poisonings.
2) Chemical antagonism: The two drugs react chemically (neutralization)
and form an inactive product (not binding to receptor).
E.g. Dimercaprol as chelating agent, for lead & mercury poisoning.
- Heparin + penicillin/hydrocortisone in same syringe.

3) Physiological/functional Antagonism: The two drugs act on different

receptors or by different mechanisms, but have opposite overt effects on
the same physiological function,
E.g. Glucagon and insulin on blood sugar level.
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 Antagonism

• 4) Receptor antagonsim: One drug (antagonist) blocks the receptor

action of the other (agonist)

Receptor antagonism can be:

• Competitive:
The antagonist is chemically similar to the agonist, competes with it
and bind to the same site to the exclusion of the agonist molecules.
E.g. (Acetylcholine & Atropine) , (Morphine & Naloxon)

• Noncompetitive:
The antagonist is chemically unrelated to the agonist, binds to a
different allosteric site ,altering the receptor in such a way that it is
either unable to combine with the agonist.

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 Potentiation
• when a combination of two drugs that do not share
similar pharmacologic activities results in an effect
of one of the drugs that is greater than expected.
Although not active in producing the effect by itself

• Examples :
Amoxicillin + Clavulanic acid (Clavulanic not active)

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 Summation
•Refers to the combined activities of two or more drugs that elicit identical
or related pharmacologic effects.

However, the maximum effect that can be obtained is no greater than

what can be achieved by sufficient doses of a single drug
Side effects of components of an additive pair may be different—do not
add up, So combination is better tolerated than higher dose of one
component.

Aspirin + paracetamol : as analgesic/ antipyretic.

- Nitrous oxide + ether : as general anesthetic.

- Amlodipine + atenolol : as antihypertensive.

- Glibenclamide + metformin : as hypoglycaemic.

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 Synergism

• The combination of two or more agonists produces an effect

that is greater quantitatively than what can be achieved by
maximally effective doses of any one drug given alone
• The combination of alcohol and carbon tetrachloride
provides an example of synergism leading to acute toxicity.
Here, hepatotoxicity is much greater than what is typically
associated with either drug given alone.

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 Unexpected drug effect

• On occasion, the combination of two or more drugs can result in a

response typically not observed when any of the drugs is given singly,
even in overdose .
• Example :
For instance, disulfiram inhibits the intermediary metabolism of
alcohol, resulting in the accumulation of acetaldehyde if alcohol is
ingested by the patient. The symptoms of acetaldehyde intoxication—
throbbing headache, blurred vision, pronounced hypotension, chest
pain, dysphoria, and mental confusion—constitute a syndrome that
does not normally occur with either drug administered alone .

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 Mechanism of drug interaction

• Drug interactions can occur at any point along the pharmacologic

pathway of the agonist

Before the drug is Period when it is in

contact with its site Point at which it is
administered eliminated
of action

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 Mechanisms of drug interaction
Drug interactions can be broadly divided into:

• Pharmaceutical Interaction: ( outside the body)

Called as incompatibility.
It’s a physicochemical inteaction that occurs when drugs are mixed in
IV Infusions causing precipitation or inactivation of active principles.

Examples:
• Hydrocortisone +Heparin (in same syringe)  Inactivate the Heparin.
• Aminoglycosides (as Amikacin or Gentamicin) are INCOMPATABLE with
Penicillins (Ampicillin)  Inactivation the Aminoglycoside

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• Pharmacokinetic ( ADME)

A. Absorption ( drugs with small molecular weight , nonpolar un-

ionized OR in high concentration , will diffuse across biological
membranes more readily).

B. Distribution ( Protein binding).

C. Metabolism ( Enzyme Induction\ inhibition).

D. Excretion (Altered pH, Ionization, Entero-hepatic recirculation).

• Pharmacodynamic ( At receptor or tissue level).

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 (A) Interaction at the site of
absorption
• Formation of drug chelates or complexes.
• Altered gut flora.
• Altered GIT motility.
• Altered pH.
• Drug induced mucosal damage.
• Mal-absorption caused by other drugs.
• Interaction other than in gut.
• First pass effect.

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 Formation of drug chelates or complexes
• Calcium (milk and dairy product), iron, antacid (Aluminum or
Magnesium hydroxide) + Tetracyclin
 Insoluble complex.

• Ferrous + Fluoroquinolones (ciprofloxacine)  preventing

fluoroquinolone absorption.

• Zinc + Fluoroquinolones  inactive complexs and decrease absorption.

It is minimized by administering the two drugs with gap

of 2-3 hours.
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Altered gut flora

• Antibiotics kill a large number of the normal flora of the intestine.

Example:

Antibiotics may potentiate oral Anticoagulant; by reducing bacterial

synthesis of Vitamin K Increase bleeding.

 <40% of Digoxin is metabolized by Intestine flora. So if taken with

Antibiotics  increased toxicity risk of Digoxin.

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Altered GIT motility

• Antimuscarinic drugs ( Atropin) and opiate analgesics  Slowing of

gastric emptying.

Example:
Atropin / Opioids + Acetaminophen
 Delay in absorption of acetaminophen.

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Altered pH

• When one drug elevate gastric pH ; the concomitant drug ( weak acid)
absorption will be prevented or decreased.

Examples :
 Ketoconazole absorption is decreased by H2 blockers and proton
pump inhibitors.

 Antacid ( Gaviscon) + Aspirin  decrease absorption of Aspirin.

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Drug induced mucosal damage

• Cholchicin
( which cause local mucosal damage) can
decrease absorption of poorly absorbed drugs
“e.g. Phenytoin”

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 Mal-absorption caused by other drugs

• Orlistat inhibits pancreatic lipases preventing hydrolysis of ingested

fat)  Decrease Weight.

Orlistat + Fat soluble vitamins (K,A,D,E)

Mal-absorption of vitamins

Administer vitamins at least 2 hours before or

after Orlistat administration.
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Interaction other than in gut

• Addition of vasoconstrictors (e.g. Adrenalin)

to local anesthetics  Delay absorption and
prolong local anesthesia effect.

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First pass effect

• Hepatic metabolism of a pharmacological agent when it is

absorbed from the gut and delivered to the liver via the
portal circulation.

• ONLY part of drug is circulated systemically, so bioavailability

of drug is reduced.

Bioavailability :the fraction of the dose of a drug that

enters the systemic circulation from a given dose
commonly used for orally drugs.

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 First pass effect

 So drugs with high pass effect have higher oral dose than other
routes, e.g : Nitrate.

 This can be bypassed by giving drug sublingual, buccal,

intravenous, intramuscular, suppository, inhalation or transdermal.

 IV administration of drugs bypasses GI absorption and gets directly

into systemic circulation  100% bioavailable.

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 ( B )Distribution
• After a drug is absorbed, a reversible interaction may modify it’s
distribution or the rate of transfer from one location to another.

• Drug distribution can be affected by plasma protein binding &

distribution across cellular membranes.

• Interaction occurs due to displacement of one drug from it’s binding

sites on plasma proteins by another drug.

• The Unbound form of drug is active (becomes more leading to toxic

level in the blood), while the bound form works as temporary storage.

• Drugs highly bound to plasma proteins like oral anticoagulants,

sulfonylureas, certain NSAIDs and anti-epileptics are particularly liable to
displacement interactions.

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 Distribution
1) Sulfamethoxazole (antibiotic) increase level of:
Tolbutamide (sulfonylurea for DM)  Increase Hypoglycemia effect.
 Warfarin  Increase Bleeding.
 Phenytoin  Increase Toxicity.

2) Aspirin + Sulfonylureas drugs  increase effect of sulfonylureas 

Increase Hypoglycemia effect.

• Some plasma proteins bind many different drugs, whereas other

proteins bind only one or a limited number.
 serum albumin tends to bind many acidic drugs.
 Alpha 1-acid glycoprotein tends to bind many basic drugs.

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 ( C ) Metabolism
(Biotransformation)
• It converts lipophilic chemical compound into more readily excreted
hydrophilic products.

• The liver is the major site of biotransformation, although specific drugs

may undergo biotransformation primarily or extensively in other tissues.

• Most drugs are metabolized in the liver by the microsomal enzyme

system and drugs that alter these enzymes can affect drug
concentrations.

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 Metabolism

• Many drug metabolites maintain a degree of pharmacological activity

, so if drug metabolite are active , termination of drug action takes
place by further biotransformation or by excretion.

• Examples :
A) Codiene is active , and it`s metabolite ( Morphine ) is also active.
B) Prednisone is inactive , but it`s` metabolite Prednisolone is active.

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Chemical reactions associated with
biotransformation
• Phase I (nonsynthetic) reactions : enzyme-catalyzed
biotransformation of the drug without any conjugations, so drug
becomes more polar.

• Include: Oxidations, Reductions, and Hydrolysis.

• They introduce or expose a functional group

(e.g: - OH) that serves as the active center for sequential conjugation in
a phase II reaction.

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 Chemical reactions associated with
biotransformation
Phase II (synthetic) reactions: endogenous substance is conjugated to the
drug to further increase compound`s solubility.

 Takes place if phase I is insufficient to clear a compound OR if phase I

generate reactive metabolite.

 Require a functional group—an active center—as the site of conjugation.

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 Phase II reactions
Examples Type of Conjugation

Morphinne, Acetaminophen, Glucuronidation

Diazepam
Sulfonamide, Isoniazid, Dapsone Acetylation

Acetaminophen, Bromobenzene Glutathione conjugation

Salicylic acid, Benzoic acid, Nicotinic Glycine conjugation

acid

Methyldopa, Acetaminophen, Estrone Sulfation

Dopamine, Epinephrine, Histamine Methylation

Carbamazepine Water conjugation

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 Metabolizing enzymes

Microsomal enzyme Non-microsomal enzyme

• Present in smooth endoplasmic • Present in cytoplasm,
reticulum . mitochondria.
• Catalyze glucuronide • Non-specific , catalyze few
conjugation, most oxidative & oxidative, reductive& hydrolytic
some reductive & hydrolytic reactions& not all conjugative
reactions reaction.
• Include CYP450 , glucuronyl • Not usually inducible.
transferase. • Occurs mainly in liver, GIT,
• Occurs in liver & other tissues. plasma & other tissues.

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 Cytochrome P-450

• Superfamily of monooxygenase , found in all kingdoms of

life(mammalian, plant, bacterial).

• In mammals, high concentration of it in membrane of ER within

liver cells, but also found throughout body ( small intestine, lungs,
placenta & kidneys).

• Use haem iron to oxidise molecules, making them more water

soluble for clearance.

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 Cytochrome P-450
• A large number of families of cytochrome P-450 enzymes exists
( more than 50 enzymes).

• drugs may be metabolized by only one CYP450 enzyme or by

multiple enzymes.

• They oxidise xenobiotic(drugs & toxins) & endogenous compounds

like hormons, cholesterol & Vit D (to control their level ).

• It is the one most frequently involved in phase I reactions

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• The CYP3A subfamily is most abundant one , and responsible for many
reactions in drug metabolism.
• CYP3A4 is a particularly abundant enzyme.

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 Cytochrome P-450

• CYP450 enzyme system can be induced to increase or decrease rate of

drug`s metabolism & is responsible for many adverse drug effects.

• Mechanism of metabolism interactions are:

Enzyme inhibition: Decrease rate of metabolism. Macrolide antibiotics
( Erythromycin ,Clarithromycin), Omeprazole, Azole antifungals ,
Grapefruit juice, Ciprofloxacin, cimetidine , chloraphenicol , propranolol
Enzyme induction: Increase rate of metabolism. (Barbiturates.
Phenytoin, Carbamazepine ,Rifampin ,Cigarette moking, Chronic
alcoholism, pollutants)

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 Enzyme inhibitors

Example :

• 1.Risk of statin-induced myopathy is increased by (fibrates, niacin,

erythromycin, azole antifungal and HIV-protease inhibitors) due to
inhibition of statin metabolism.
(Note : statins are used for treatment of dyslipidemia).
2.Miconazole oral gel (inhibitor) will increase warfarin effect  warfarin
dose should be reduced.

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 Enzyme inducers

Examples:
• Phenobarbital + Warfarin  increase warfarin metabolism  increase
thrombosis incidence & decrease INR ( monitor therapy ).

• Phenytoin increases hepatic metabolism of Oral Contraceptive 

decrease OC’s level  Unplanned pregnancy.

• Prolonged Phenytoin enhances Vit D3 metabolism causing it’s

deficiency(Osteomalacia).

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 Enzyme inducers
• Instances of failure of antimicrobial therapy with metronidazole,
doxycycline or chloramphenicol have occurred in patients who are on long-
term medication with an inducing drug.

• Metronidazole and alcohol > disulfiram like reaction ( nausea, vomiting,

flushing, tachycardia, and shortness of breath).

• Exception: The toxic dose of Paracetamol is lower in

chronic alcoholics and in those on enzyme inducing medication ,because
one of the metabolites of paracetamol is responsible for its overdose
hepatotoxicity.

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• Carbamazepine (Inducer) + Verapamil (Inhibitor)

Decrease level/effect Increase level/effect

of Verapamil.
of
Carbamazepine
• The effect of the inhibitor is more prominent.

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• It takes 1–2 weeks of medication with the inducer to produce
maximal effect because it involves protein synthesis.

• It regresses gradually over 1–3 weeks after discontinuation of the

inducer.

• In contrast the inhibition of metabolism develops quickly.

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 ( D ) Excretion

• Increasing or decreasing the rate of excretion, renal or biliary clearance

of a drug also alters its Elimination Rate Constant( K value ; rate of drug
is removed from system)

Alter the amount of drug available in the

circulating plasma

Affecting the duration and the degree of

activity of the drug

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 Excretion
• Kidney most important organ for elimination of drug.

• Some metabolites formed in liver, excreted via bile into intestinal

tract , then if subsequently hydrolyzed &reabsorbed from gut  their
action is prolonged.

• Pulmonary excretion  important mainly for elimination of

anesthetic gases & vapors.

• drugs excreted in milk  are potential sources of unwanted

pharmacological effects in nursing infants.

• other routs: Saliva, Tears & Sweat are quantitavely unimportant.

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 Excretion

• Renal excretion is influenced by:

1. Urinary pH.
2. Tubular re-absorption.
3. Inhibition of active tubular transport

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 Excretion

1 ) Urinary pH:

 Change in the pH of urine can also affect excretion of weakly acidic

or weakly basic drugs.

 This has been utilized in the treatment of poisonings.

 Acidic drugs will be excreted more in alkaline urine

 Basic drugs will be excreted more in acidic urine

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 Excretion

2 ) Tubular re-absorption :

 Acetylsalicylic acid & Probenecid inhibits tubular secretion of

penicillins and cephalosporins and prolongs their plasma t½.

 Aspirin decreases tubular secretion of Methotrexate.

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 Excretion
3 ) Inhibition of active tubular transport :
 Diuretics and to some extent tetracyclines, ACE inhibitors and certain
NSAIDs have been found to raise steady-state blood levels of lithium by
promoting its tubular re-absorption and decrease its clearance.

Lithium Toxicity  Monitor its level

• Interactions affecting biliary excretion :

Phenobarbital ( increase bile flow & synthesis of proteins which

function in biliary conjugation mechanisms ) will decrease plasma level
of many drugs .

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Pharmacodynamic Interactions

• These interactions derive from modification of the action of one drug

at the target site by another drug, independent of a change in its
concentration.

• This may result in an enhanced response (synergism), an attenuated

response (antagonism) or an abnormal response.

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• Several drug interactions are deliberately employed in therapeutics, like :

o Clavulanate in Amoclan  Inhibit beta-lactamase –producing bacteria 

allowing amoxicillin extended spectrum of action.

o ACE inhibitors + Diuretics  Treat Hypertention.

o Furosemide + Spironolactone  To prevent hypokalemia

o Levodopa + Carbidopa  For Parkinson disease.

- Carbidopa inhibits peripheral breakdown of levodopa,
 increase availability of levodopa at BBB  allowing lower levodopa
dose. And it reduces nausea & vomiting

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Examples on beneficial
antagonism:
• Naloxon for Morphine (Opioids) overdose.
• Protamine Sulphate for Heparin toxicity.
• Physostigmine for Atropine toxicity.
• Ethanol for Methanol poisoning.
• Deferoxamine for Iron poisoning.
• Flumazenil for benzodiazepine(diazepam) overdose.

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 Drug-Food Interaction
• Nutrients may protect the gastric mucosa from irritants, but they
may also act as mechanical barrier that prevents drug access to
mucosal surfaces and reduces or slows the absorption of some drug.

• Component in Grapefruit juice inhibit CYP450 3A4 isoenzyme &

increase bioavailability of drugs like : calcium channel-blocking
agents, Benzodiazepines, and Warfarin .

• Changes in the pH of kidney fluids can inhibit excretion of some drug.

Example : large doses of Vitamin C may cause acidic drugs to be
reabsorbed ,delaying excretion & increasing plasma levels of drug.

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 Drug – disease interaction
• A drug prescribed for the treatment of one disease may have
an adverse effect on a different condition that has been
generally well controlled.

• Examples :
1) Nonselective beta 1-adrenergic receptor antagonist
(Propranolol), used for treatment of chronic stable angina,
hypertension, or cardiac arrhythmia , can induce asthma attack
by blocking beta 2-adrenergic receptors and increasing airway
resistance.
2) COX-1 inhibitors ( Aspirin) can lead to GI bleeding in patients
with preexisting peptic ulcer.

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3) COX-1, COX-2, COX-3 inhibitors & Amoxicillin may induce renal
toxicity in patients with preexisting renal dysfunction.
4) Hypothyroidism increase the sensitivity of patients to
sedative/anxiolytic agents & Opioids.

So generally, patient with hepatic dysfunction, renal insufficiency or

cardiac disease can lead to elevated plasma concentration of drugs &
associated adverse drug effects.

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 Preventing adverse drug events

I. Accurate Diagnosis.
II. Critical assessment of the need for pharmacotherapy.
III. Benefits versus risks of drug therapy.
IV. Individualization of drug therapy.
V. Patient education.
VI. Continuous reassessment of therapy.

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