Principles of Pharmacology III

Whenever a patient is taking more than one drug

When can drug-drug interactions occur?

1. Multiple drugs for one disorder

2. Multiple disorders requiring different drugs

3. OTC meds, caffeine, nicotine, alcohol

Why might patients be taking more than one drug? [3]

Intensification of effects

When the effects multiply when drugs are together

Warfarin is a blood thinner.

Aspirin has bleeding as a side effect.

Combined, there is an increased risk of hemorrhage and bleeding.

What happens when warfarin and aspirin interact?

Sulbactam is a surfactant.

Ampicillin is an antibiotic.

Together they have increased therapeutic effects and can effectively fight infection.

What happens when sulbactam and ampicillin are combined?

1. intensification of effects

2. reduction of effects

3. Creation of a unique response

Types of drug reactions: [3]

Reduction of effects

When two drugs interact and have an inhibitory effect. They reduce effects, good or bad.

Propranolol is a blood pressure medication

Albuterol is an asthma medication

Propranolol will cause bronchoconstrition. Albuterol will cause bronchodilation. They counteract each other.

What happens when propranolol and albuterol interact?

Patient gets very projectile vomit sick

What happens when alcohol and disulfiram interact?

1. Direct chemical/physical interaction

2. pharmacokinetic interaction

3. Pharmacodynamic interaction

4. combined toxicity

Four basic mechanisms of drug interactions

Check their compatibility

What is important to do before putting two medications in a cup/ IV bag?

1. gastric pH

2. Laxative

3. Drugs that depress peristalsis

4. Drugs that induce vomiting

5. Adsorbent drugs

6. Drugs that reduce blood flow

Things that can alter absorption: [6]

Some drugs require stomach or blood pH to be absorbed properly

How can gastric pH affect drug interactions?

If the drug is absorbed in the intestine, laxatives speed up the process so LESS is absorbed

How do laxatives alter absorption?

Slower peristalsis increases absorption, because there is slower movement in the GI tract. More contact with walls of the bowel.

How do drugs that depress peristalsis affect absorption?

Vomiting would decrease the absorption of the drug

How do drugs that induce vomiting affect absorption?

Adsorbent drugs

Drugs that absorb other drugs

Metabolism

Most important and most complex mechanism in which drugs interact (certain enzymes involved)

P-glycoprotein

Transmembrane protein that transports a wide variety of drugs out of cells.

Transport across membranes can either get enhanced or decrease. If there is not enough, there is not a lot of movement across membranes

What happens if there is too much/not enough p-glycoprotein?

Combined toxicity

Drugs with overlapping toxicities should not be used together (monitored closely if they are)

Potentitive

Pharmacodynamic interaction where drugs at the same receptor have an additive effect

They both increase sedation and euphoria. Have a potentiative interaction

What happens when morphine and diazepam interact?

inhibitory or potentiative

When drugs interact at the same receptor, they can either be…

Low therapeutic index

Little window between minimum and toxic concentration

The number of drugs a patient is taking, especially ones with a low therapeutic index

Risk for serious drug interaction is directly proportionate to what?

1. Minimize # of drugs a patient receives

2. Throrough drug history

3. Adjust dosage when metabolizing inducers are added or needed

4. Adjust timing to minimize interference wth absorption

5. Monitor for early signs of toxicity

6. Vigilant when patients are taking drugs with low therapeutic index

How to minimize adverse drug-drug interactions? [6]

grapefruit juice inhibits metabolism of certain drugs, raising the blood lovel of the drug.

Example: felodipine, lovastatn, cyclosporine, midazolam

How does the Grapefruit Juice effect alter metabolism of certain drugs?

Foods rich in vitamin K

Warfarin should not be taken with which foods?

Tyramine. drug toxicity

MAOIs should not be taken with what foods containing what?

Salt substitutes. toxicity.

potassium sparing diuretics should not be taken with what?

citrus beverages

Aluminum-containing antacids should not be taken with what?

taken with food

Nausea dugs should be taken on what stomach?

It induces drug metabolizing enzymes (such as for some antidepressants) and reduces the blood levels of the drug

Effect of St. Johns wart on many drugs

They may decrease platelet aggregation and enhance the effects of anticoagulants

effect of cod liver capsules on platelets

Adverse drug reaction

Any noxious, unintended, or undesired effect that occurs at normal drug doses.

1. the elderly

2. the very young

Adverse drug reactions are common in what age groups? [2]

Risk increased by severe illness

What increases the risk of drug reactions?

1. drowsiness

2. nausea

3. itching

4. rash

Mild drug reactions include: [4]

1. respiratory depression

2. neutropenia

3. hepatocellular injury

4. anaphylaxis

5. hemorrhage

Severe drug reactions (potentially fatal) include: [5]

Side effect

A nearly unavoidable secondary drug effect produced at therapeutic doses

toxicity

Adverse drug reaction caused by excessive dosing

1. neutropenia (risk for infection)

2. anti-cancer medications

When can toxicity occur at normal dosing? [2]

Penicillins

most common drugs that cause anaphylaxis

Primarily the degree of sensitization of the immune system, NOT by the drug dosage

Allergic reactions are determined primarily by what?

Sulfonamides

1. diuretics

2. antibiotics

3. oral hypoglycemic agents

Besides penicillin, what drugs may also induce allergies?

Idiosyncratic effect

An uncommon drug response resulting in succinycholine-induced paralysis. usually brief, may last for hours in genetically predisposed patient.

Iatrogenic disease, sometimes called drug-induced disease

Disease produced by a physician, usually to refer to a disease produced by drugs

Drugs for antipsychotic disorders that can cause Parkinson’s-like symptoms

Example of iatrogenic disease:

Physical dependence

Develops during long-term use of certain drugs. A state in which the body has adapted to drug exposures in such a way that abstinence syndrome will result if drug use is discontinued

1. opioids

2. alcohol

3. barbiturates

4. amphetamines

Drugs that can lead to physical dependence: [4]

Teratogenic effect

Drug-induced birth defects

IT may take decades for evidence of carcinogenesis after exposure

Why is it difficult to evaluate drugs for carcinogenic effects?

Several drugs used to treat cancer

Which drugs are among those with the greatest carcinogenic potential?

Amphotericin B (antifungal)

drug that is commonly toxic to kidneys

Doxorubicin (anticancer)

Drug that is commonly toxic to the heart:

Amiodarone (antidysrhythmic)

Drug that is commonly toxic to the lungs:

Aminoglycoside (antibiotic)

Drug that is commonly toxic to the inner ear

Hepatotoxicity

As soe drugs undergo metabolism, they are converted to toxic products that can injure liver cells.

Combining hepatotoxic drugs, ex: acetaminophen and alcohol

What about heptatotoxic drugs can increase the risk for liver damage?

1. jaundice

2. dark urine

3. light-coloured stool

4. nausea

5. vomiting

6. malaise

7. abdominal discomfort

8. loss of appetite

Signs of liver injury [8]

Aspartate amniotransferase (AST) and alanine amniotransferase (ALT)

Two drugs to monitor for liver injury (example that is not alcohol and tylenol)

QT interval

Measure of the time required for the ventricles to repolarize after each contraction

QT drugs

The ability of some drugs to prolong the QT interval on electrocardiography

Creates serious risk of life-threatening dysrhythmias (ex: v-fib)

QT drugs cause serious risk of what?

1. women

2. the elderly

3. patients with bradycardia

4. congestive heart failure

5. congenital QT prolongation

6. low potassium

7. low magnesium

Patients at higher risk for life-threatening dysrhythmias on qt drugs:

1. body weight and composition

2. body surface area (BSA) vs. weight

3. age

Individual variation in drug responses often depends on [3]

reduced excretion and increased toxicity

How would someone with kidney disease have a variation in drug responses?

Reduced metabolism and increased toxicity

How would someone with liver disease have a variation in drug responses?

pH changes that alter absorption, distribution, metabolism, and excretion of drugs

How would someone with an acid-base imbalance have a variation in drug responses?

Tolerance

Decreased responsiveness to a drug as a result of repeated drug administration

higher doses required

Dosing considerations for increased tolerance

1. pharmacodynamic tolerance

2. metabolic tolerance

3. tachyphylaxis

Three categories of drug tolerance

pharmacodynamic tolerance

Drug tolerance associated with long-term administration of drugs such as morphine and heroin

Metabolic tolerance

Drug tolerance resulting from accelerated drug metabolism

Tachyphylaxis:

Reduction in drug responsiveness brought on by repeated dosing over a short time

Bioavailability

abaility of the drug to reach the systemic circulation from its site of administration.

1. tablet disintegration time

2. enteric coatings

3. sustained-release formulations

Variability in bioavailability is often caused by: [3]

1. change in gastric pH

2. diarrhea

3. constipation

4. food in stomach

Causes of variable absorption: [4]

Pharmacogenomics

Study of how genes affect individual dru responses

1. altered drug metabolism

2. changes in drug targets

How genes may affect individual drug responses [2]

Genetic variations alter the structure of the drug receptor

How can genetics alter drug targets?

Slower by women

Alcohol is metabolized more slowly in which sex?

More effective in women than men

Certain opioid analgesics are much more effective in which sex?

Starvation reduces the protein binding of drugs, which increases the level of free drugs

what can reduce the protein binding of drugs, causing variation in the drug response?