Drug Interactions- Wargo

Terms in this set (105)

6 questions total on EXAM

He will ask us a minimum of 2 questions on inducers and inhibitors: Will ask questions like: "What enzyme is inhibiting or inducing?"

Drug Type & Age Group

Children: infectious agents, asthma

Adolescence: ADHD and stimulants

Older: Antidepressants, analgesics, cholesterol

What is a Drug Interaction?

A modification of the expected drug response as a result of exposure to another

1. Drug
2. Herbal/natural product
3. Drink
4. Environmental/chemical change

*An unexpected response

A drug interaction can cause

1. Increased or decreased action of either substance

2. Adverse effect not normally associated with either substance

3. Improved therapeutic responses

4. Decreased adverse effects

Types of drug interactions

1. Pharmacokinetic
2. Pharmacodynamic

Pharmacokinetic

Absorption
Distribution
Metabolism
Excretion

Pharmacodynamic

Additive
Antagonist
Synergistic

Which type of drug interaction is easier to know the expected interactions

Pharmacodynamic

Pharmacokinetics are harder (effects are more transient)

Precipitant Drug

Drug that causes the altered action of the other drug

*He will ask a question using the terms precipitant/object drug so KNOW THESE

Drug whose action is altered by the interaction

*He will ask a question using the terms precipitant/object drug so KNOW THESE

Drug A increases the serum concentration of Drug B. Which drugs is the Precipitant? The Object?

Precipitant Drug: Drug A

Object Drug: Drug B

Would a substrate be considered your precipitant or object drug?

Substrate = Object drug = Drug whose action is altered by the interaction

Would an inhibitor/inducer be your precipitant or object drug?

Inhibitor/Inducer = Precipitant drug = Drug that causes the altered action of the other drug

Drug-Drug Interaction: Severity of interaction

Clinical importance (ORCA- Organization of Regulatory and Clinical Associates )

Likelihood of morbidity and mortality

Likelihood of intervention

What kind of interventions are available? Is it life-threatening? Easily managed and monitored?

Drug-Drug Interaction: Probability of interaction

Likelihood of the adverse reaction

Timing of administration

Consideration of the PK properties of the DDI

Dose and duration of therapy

Route of administration

Sequence of administration

Therapeutic window of the object drug

Monitoring planned for the patient

Drug-Drug Interaction: Clinical implications

Management burden

Awareness of the intervention

Drug-Drug Interactions: Patient characteristics

EtOH, diet, smoking & drug use

Age

Gender

Concurrent disease

Other active medications

Drug-Drug Interactions: Evidence supporting interaction

Quantity of evidence

Quality of evidence

Biological plausibility

Potentially Significant versus Clinically Significant

Pomegranate Juice example

Lack of data on clinical importance
Often missing patient-specific information that makes the occurrence of DDI likely

Lack of information on risk factors
Clinical outcome can range from harmless to fatal

What are the major metabolizing enzymes in the liver

CYP450

If I'm inhibiting an enzyme, I inhibit it's functions so I can't break down the medication efficiently

Classic Classification Criteria

Potential severity of the adverse outcome
Particularly difficult to assess
NSAID example

Adequacy of documentation in literature
Less of a problem today
Many times we can predict interaction potential

ORCA System for Classification

Contraindicated

Provisionally Contraindicated

Conditional

Minimal Risk

No Interaction

NEED TO KNOW THIS **************
Second thing he said that will be on test
Need to know these potential classifications
On exam he will give us potential harms, risks, etc.

ORCA—Contraindicated

No situation have been identified where the benefit of the combination outweighs the risk

Contraindicated example

*Monoamine oxidase inhibitor +
pseudoephedrine*

The risk? Life-threatening HTN-Hypertension reaction

Risk is unacceptable given the potential benefit (possible improvement in cold symptoms)

ORCA—Provisionally Contraindicated

The combination increases the risk of Adverse Drug Events (ADEs)

Avoid concurrent use unless interactions is desired or no alternative is available

If used, increase monitoring required

Provisionally Contraindicated example

Warfarin + aspirin

Acceptable if aspirin is used intentionally for anticoagulant effects after assessment of risk/benefit

Not acceptable if aspirin used for pain management

ORCA—Conditional

Risk may be increased, depending on the clinical situation

Assess risk and take action as needed

Conditional example

Ciprofloxacin + antacids: Binding in the GI tract can be minimized by giving ciprofloxacin 2 hours before or 4-6 hours after antacid

Warfarin + thyroid: Risk is minimal if warfarin is started in patients stabilized on thyroid, monitor INR any time change in clinical thyroid status occurs

Warfarin + thyroid is a really weird interaction
High thyroid (energetic), Low thyroid (sluggish). If a patient is on thyroid medication b/c of hypothyroidism, it will ramp up the clotting factors that warfarin acts upon.

ORCA—Minimal Risk

Risk of adverse outcome appears small

No special precautions appear necessary

Minimal Risk example

Caffeine + oral contraceptives:

Serum caffeine concentrations may increase somewhat, but adverse effects are unlikely

ORCA—No Interaction

Evidence suggests that drugs do not interact

No Interaction example

Cyclosporine + ofloxacin:

Ofloxacin does not appear to affect cyclosporine PK

Pharmacokinetic Drug Interactions: ADME

His expectation in terms of Exam purposes is to classify what type of interaction it is

For example, is it an absorption interaction?

Is it a metabolism interaction?

Pharmacokinetic Drug Interactions: Absorption

Complexation/chelation

Increased GI motility

Decreased GI motility

Alteration of gastric pH

Alteration of intestinal flora

Absorption example #1

Antacids are complexing (cation and anion binding) and no absorption ability at this point we lose our efficacy of our antibiotics

Change our dosing to fix

Absorption example #2

We have a medication like Metoclopramide (Reglan) which speeds up the GI tract, so your body has less time to absorb

To fix, we can space out the medications

Absorption example #3

Anticholinergics -> dry, slowing things down

DUMBBELL mneumonic
Diarrhea
Urination
Mydriasis (dilation)
Bradycardia
Bronchoconstriction
Emesis
Lacrimation
Lethargy

Absorption example #4

In order for ketoconazole to be broken down, it needs it's acidity, so if we are decreasing pH we are decreasing dissolution and absorption

Absorption example #5

Pharmacokinetic Drug Interactions: Distribution

Protein binding

For medications to be active, they need to be unbound from proteins

So when a medication is hanging on to a protein, it's stored

Distribution example

Clinical Importance of Protein Binding

Displacement from protein binding sites produce transient increases in unbound drug concentrations

May alter the PD effect
-Important for drugs with narrow therapeutic indexes

May alter the clearance

Dosage adjustments may be required

Pharmacokinetic Drug Interactions: Metabolism

Uhoh

Involves lots of memorization but is the most clinically useful for our career

What is the major site of drug metabolism

What are the two main types of hepatic drug metabolism

1. Phase I oxidative metabolism
-Initial step in drug biotransformation
-Mediated by cytochrome P450 (CYP) enzymes

2. Phase II metabolism
-Drug metabolites are converted into more water-soluble compounds that can be more easily eliminated

What type of hepatic drug metabolism is much less of a concern in terms of potential interactions

Phase II metabolism

Drug Metabolizing Enzymes Function

Transform lipid-soluble drugs into more water-soluble metabolites -> excretion into bile and urine

Appear to enhance survival by eliminating the undesirable chemicals

Know this Definitions: Exam Question!

1. Substrate
2. Inducer
3. Inhibitor

A drug that is normally metabolized by the enzymes

May be influenced by inhibitors and/or inducers

Up-regulate amount or activity of enzyme leading to enhanced metabolism of substrate

What medication can cause auto-induction

Competes successfully for enzyme site blocking or delaying substrate access

If he gives us a CYP3A4 inducer, it will ______ the metabolism for that substrate

If he gives us a CYP3A4 inhibitor, it will ______ the breakdown of the substrate

inhibit or reduce

Enzyme-inhibition interactions slide #1

Enzyme-inhibition interactions slide #2

Exam Question from red. Precipitant acts on Object drug (substrate) and inhibits metabolism, therefore concentration of object drug is high. Take away Inhibitor Precipitant, metabolism higher and concentration of drug lower

What happens if you discontinue the inhibitor (precipitant) acting on a substate (object drug)

The inhibitor of the substrate was inhibiting metabolism

If you take away the inhibitor of metabolism, metabolism will resume to normal

Therefore, there will be a lower concentration of the substrate (object drug)

What happens if you discontinue the inducer (precipitant) acting on a substate (object drug)

The inducer of the substrate was inducing metabolism

If you take away the inducer, metabolism will be lower in the substrate (object drug)

Therefore there will be a higher concentration of the substrate (object drug)

Enzyme-inhibition interactions slide #3

The time course tends to be more gradual. Can't set watch to it, more of a watch and wait approach

Are there more inducers or inhibitors

more inhibitors (200) where there is only around 10 inducers

T/F If you know someone is on an inhibitor, you can preemptively make adjustments knowing interactions may occur within a 24hr window

Is inducers or inhibitors less predictable

Induction is less predictable

If he gives us an inducer, we increase metabolism of the object drug, so we need to ______ the dose of the object drug to account for that

CYP450 Interactions:Inhibition

Itraconazole vs Eryhtromycin vs Verampil are common inhibitors but notice the potency in their inhibition.

CYPs And Metabolism

Vast majority we will see in our career are 3A4+3A5

2D6, 2C9, 2C19, 2C1, AND 2E1 will be required to know***

For Each Proceeding Enzyme slide

Note that inhibitors he lists are STRONG inhibitors same thing with STRONG inducers

EXAM: KNOW YOUR INHIBITORS AND INDUCERS

CYP1A2 Inhibitors

Cimetidine
Ciprofloxacin
Fluvoxamine

CYP1A2 Typical Inducers

Barbiturates
Carbamazepine
Phenytoin
Rifampin

CYP1A2 Atypical Inducers

Hydrocarbons (tobacco)
Char-grilled meats

CYP2C9 Anti-infective Inhibitors

Fluconazole
Metronidazole
Sulfamethoxazole

CYP2C9 Anti-infective Other Inhibitors

Amiodarone
Valproic acid
Alcohol (Acute)

CYP2C9 Typical Inducers

Barbiturates
Carbamazepine
Phenytoin
Rifampin

CYP2C9 Atypical Inducers

Alcohol (Chronic)
Grisiofulvin

CPY2C19 PPIs Inhibitor

Esomeprazole
Omeprazole
Cimetidine (H2)

CPY2C19 SSRIs Inhibitor

Fluoxetine
Fluvoxamine

CPY2C19 Anti-infective Inhibitor

Fluconazole
Isoniazid

CPY2C19 Typical Inducer

Barbiturates
Carbamazepine
Phenytoin
Rifampin

CPY2C19 Atypical Inducer

St Johns Wort
Norethindrone

CPY2D6 Antidepressants
Inhibitor

Bupropion
Fluoxetine
Paroxetine

CPY2D6 Antihistamines
Inhibitor

Diphenhydramine
Chlorphiniramine

CPY2D6 Antiarrythmics
Inhibitor

Quinidine
Amiodarone
Dronedarone
Flecainide
Propafanone

CPY2D6 Inducer

CPY3A4 HIV Antivirals Inhibitor

Indinavir
Ritinovir
Sequinavir

CPY3A4 Antibiotics Inhibitor

Ciprofloxacin
Clarithromycin
Erythromycin
Itraconazole
Ketoconazole
Fluconazole

CPY3A4 CCBs Inhibitor

Diltiazem
Verapamil

CPY3A4 Other Inhibitor

Grapefruit juice
Cimetidine
Amiodarone
Dronedarone
Fluvoxamine
Cyclosporine

CPY3A4 Typical Inducer

Carbamazepine
Barbiturates
Phenytoin
Rifampin

CPY3A4 Atypical Inducer

St. John's Wort

What happens to the object drug when...
An enzyme inducer is added to therapy?

Induced metabolism of the object drug, therefore decreased concentration of the object drug

What happens to the object drug when...
An enzyme inhibitor is added to therapy?

Inhibits metabolism of the object drug, therefore increased concentration of the object drug

Pharmacokinetic Drug Interactions: Elimination

Methods of drug elimination

Renal (most common)
Hepatic
GIT
Breast milk
Pulmonary
Bodily fluids (sweat, tears, etc.)

*Probably wont ask question elimination. Look at slides 54-61...

Pharmacodynamic Drug Interactions

Pharmacodynamic Interactions:Additive Interactions

Alcohol and benzodiazepines make us sleepy -> CNS depressant effects. If I take them together, I increases this effect. If at toxic levels -> bad

Pharmacodynamic Drug Interactions:Antagonistic Interactions

Drug-Drug interactions

Drug food interactions like Coumadin and broccoli (vitamin K)

Warfarin works against vitamin K, so more factors opposing it

Pharmacodynamic Drug Interactions:Synergistic Interactions

Metolazone (diuretic) and furosemide (diuretic), if given together, their synergistic effect is basically 1+1 = 3. This is an enhanced interaction. We want this substantially enhanced effect.

Two drugs with similar pharmacological effects. The effect can be from the drugs intended effect or adverse effects

Pharmacodynamic- Additive

Two drugs with opposite pharmacologic effects given concomitantly are antagonistic. This effect can also be a result of food intake

Pharmacodynamic- Antagonistic

Two drugs with different mechanisms that result in a beneficial pharmacological result

Synergistic Interactions

Drug Elimination: Renal

Stepwise Approach to DDIs

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