Drug Interactions

How would we get a ligand-gated ion channel to open more?

we would use an agonist

How does a ligand-gated ion channel work?

When the ligand fits into the receptor, the channel opens

How are new chemicals formed in enzymes?

Two substrates bind together and create a new chemical

Most enzyme drugs ___

block

Route of administration

way to get the drug into the body

Examples of enteral administration

• mouth

• stomach

• small intestine

• rectal

What organ does not have a great absorptive surface?

stomach

Site of administration increases ____ and decreases ___ ___

efficacy, side effects

What does “enteral” mean

lips to anus

Where does most drug absorption happen?

small intestine

Parenteral

bypassing the digestive system

Advantages of parenteral administration

• used for poorly absorbed drugs

• immediate onset of action

• longer lasting effect

• concentrates drug at a specific location

• more predictable response

• titratable dosage

Disadvantages of parenteral administration

• pain

• irreversible

• not useful for self-administration

• contamination/infection risk

• extravasation/phlebitis

Extravasation

drug leaves the vein and goes into the surrounding tissues

Phlebitis

inflammation of the veins

Examples of parenteral administration

• intravenous

• intra-arterial

• intramuscular

• epidural

• intrathecal

• subcutaneous

• intra-articular

Why don’t we inject into arteries most of the time?

They are a higher pressure system

Intra-articular injection

right into the capsule

Examples of topical administration

• skin

• eyes

• ears

• intranasal

• inhalation

• vaginal

Topical

medicine applied directly to a specific part of the body

Which of the topical routes of administration are local only?

eyes and ears

Disintegration

one big chunk of drug is broken into smaller chunks

Dissolution

molecules are pulled off so they can diffuse across the membrane

Dissolved liquid

elixir, syrup, inconvenient, fast-acting

Why is a dissolved liquid fast-acting?

it has already gone through disintegration and dissolution

Suspension

chunks of drug floating in a liquid, thicker liquid, shake it up

Why are powders not used commonly?

they aren’t very accurate

Why are capsules useful?

you can control how much is in there

Enteric-coating

ensures that the drug breakdown does not happen until the drug reaches the small intestine

Sustained-release drug

dissolves slower so there is a longer-lasting effect

Oral dosage forms from fastest to slowest

• dissolved liquid

• suspensions

• powders

• capsules

• tablets

• coated tablets

• enteric-coating

• sustained-release

How do pharmacokinetic drugs work?

One drug causes a change in the concentration of another

What three things do pharmacokinetic drugs do to cause a concentration of another drug?

• inc/dec absorption

• inc/dec metabolism

• changes where the drug is at in the body

Rate of drug absorption can determine

• onset of action

• duration of action

• intensity of response

Variables affecting absorption

• nature of absorbing surface (intestinal epithelium vs. skin)

• surface area (small vs. large intestine)

• blood flow to site of administration (peripheral IV in shock patient)

• pH at the site of absorption

Drug elimination

removal of the drug’s activity

Biotransformation

body changes the drug into something with no activity

Two types of drug elimination

biotransformation & excretion

Two types of biotransformation

hepatic metabolism & tissue enzymes

Excretion

gets the drug out of the body

Examples of excretion

• kidneys

• lungs

• sweat glands

• salivary glands

• mammary glands

• GI tract

What is the most common form of excretion?

kidneys (urine)

Therapeutic range

safe and effective range for a drug

Toxic level

Reproduceable negative consequences

Minimum effective concentration

how much of the drug do we need to see an action occurring?

Onset of action

how long it takes the drug to work

Duration of action

measurable effect of the drug

What does the duration of action dictate?

how frequently we give the drug

Variables affecting dose/response relationship

• body weight

• age

• gender

• genetics

• tolerance

• psychological factors/beliefs

• comorbid medical conditions

Why do young patients need to have a smaller dose of drugs?

their metabolic systems are not fully developed

Why do elderly patients need altered dosages of drugs?

their liver and kidneys have broken down so they will need a smaller dose because it is eliminated at a slower rate

Drug-drug interaction

the pharmacologic or clinical response different from that anticipated from the known effects of the two drugs

Antagonistic drugs

cancel each other out

Synergistic drugs

add each other up

Why are drug-herbal medicine interactions of concern?

there are biologically active chemicals in herbal medicine that interact with the drug

Types of drug interactions

• drug-drug

• drug-food

• drug-herbal

• drug-laboratory

Pharmacodynamic drug interaction

one drug induces a change in a patient’s response to a drug without altering the object drug’s kinetics

Pharmaceutical drug interaction

physical and chemical incompatibilities so one of the drugs is no longer dissolved

Types of patients with greatest risk for a drug-drug interaction

• multiple medications

• multiple prescribers/pharmacies

• elderly

• obese patients

• critically ill patients

Are most drug-drug interactions dangerous?

no

Object drug

drug that the concentration is going up or down

Characteristics of important object drugs

• have a narrow therapeutic range

• steep dose-response curve

• are metabolized by hepatic enzymes

• typically used chronically

Why can a narrow therapeutic range be dangerous?

a small change will push you outside of this range which will have poor consequences

How does the dose-response curve work?

steeper the curve, bigger the response

What is the most common characteristic of object drugs?

they are metabolized by hepatic enzymes

Chronic drug use

if you take the drug for a while, the drug interaction will reach its full potential

Clinical significance

something happened that was big enough to cause a measurable and meaningful change

Result of drug-drug interaction in terms of absorption

• changes in extent of absorption

• changes in rate of absorption

Mechanisms of altered absorption

• complexation

• changes in pH

• changes in GI motility

Complexation

drugs bind to each other and cannot be absorbed

Changes in pH

drugs that can change gastric pH

What is the hardest form altered absorption to predict?

changes in GI motility

drugs that slow GI motility

• opioids

• anticholinergics (antidepressants)

Why is increased GI motility dangerous?

it changes the absorption time available for other drugs which would be a problem for sustained-release drugs

Cytochrome P-450 enzyme

responsible for drug metabolism, biotransformation, biochemical degradation, and/or detoxification

CYP2D6 shows genetic ___

polymorphism

What does genetic polymorphism for CYP2D6 mean?

you are predisposed to have a lot or a little of these

Factors affecting drug metabolism

• age

• disease state

If you cannot tell how well someone’s liver works (elderly) how would you dose the drug?

escalation strategy

Escalation strategy

guessing but you start with a really low dose

In what patients would you use the escalation strategy?

• elderly patients

• disease state

____ ____ in the liver account for the most clinically significant drug-drug interactions

enzyme changes

What does enzyme induction lead to?

ineffective treatment and disease state worsening

Enzyme induction

certain drugs are capable of increasing metabolic enzymes in the liver

If you recognize enzyme induction what should you do?

increase the dose

Enzyme induction onset and offset

• onset- 5 days

• offset- 3 or more weeks

Enzyme inhibition

one drug causes a change in the plasma concentration and in the pharmacologic response of the object drug

What is the most common drug-drug interaction that is significant?

enzyme inhibition

Prodrug

drug that is not active when swallowed, but is activated in the liver through hepatic metabolism

What happens in the liver with enzyme inhibition?

it is accumulated

What does enzyme inhibition lead to?

drug toxicity

Onset and offset period for enzyme inhibition

• onset- max intensity within 24 hours

• offset- 24 hours after discontinuation of the precipitant

Pharmacodynamic drug interactions

levels don’t change but effects add up or cancel out

synergistic therapeutic effects

the drugs both do something we like

synergistic adverse side effects

both drugs cause a negative outcome (GI upset)

Are herbal medications FDA regulated?

no

If you are taking these two types of medications you should always check with a prescriber before starting herbal medication

antiplatelet or anticoagulant