Drug interactions Flashcards
Tell me the 3 types of drug interactions
- Drug-Drug
- Drug-Food
- Drug-Condition (condition is the type of people who take the drugs)
LO
By the end of this session, you should be able to:
- describe, with examples, how drugs interact at both the pharmacodynamic and pharmacokineticlevels
When can drug interactions occur?
Whenever 2 or more drugs are given
What is a drug interaction?
The modification of the effect of one drug (the object drug) by the prior or concomitant administration of another
What is the pharmacologic or clinical repsonse to the administration of a drug combination different from?
That, that is anticipated from the known effects of the 2 or more agents when given alone
Why may drug interactions be harmful?
- toxicity
- reduced efficacy
Why may drug interactions be beneficial?
- synergistic combinations
- pharmacokinetic boosting
- increased convenience
- reduced toxicity
- cost reduction
What are the reasons for multiple drug therapy?
- combination is better than a single agent
- Patients have more than one disease
- Drug B may reduce/ block the side effects of Drug A
Give an example where combination drug therapy is better than a single agent
Chemotherapy
- cancer
- infections
Give an example of why multiple drug therapy may be used for Drug B to reduce/ block the side effects of drug A
Antiemetics – cancer chemotherapy
What are the risk factors for drug interactions and provide examples for each
1. High risk patients
- E.g., Elderly, young, very sick, patients with multiple disease (especially with liver and/or renal impairment as effects drug metabolism and clearance) that require multiple drug therapy
2. High risk drugs
- Narrow therapeutic index drugs so limited therapeutic window for the patient e.g. (digoxin, warfarin, theophylline these drugs are highly possible to have adverse reactions)
- Recognised enzyme inhibitors or inducers e.g., Cytochrome P450
What age group is most at risk from adverse drug reactions (ADR)?
the elderly
Why is the elderly most at risk of ADR? What is this?
Due to polypharmacy
(the use of multiple medications at the same time by one person)
Are men or women more likely to be given polypharmacy?
Women
Why is the risk of adverse effects of drugs higher with polypharmacy?
Due to the numerous drug-drug interactions
Give examples of medications that are taken by a ‘healthy’ 75-year-old and what they are used for
- Antihypertensive - High blood pressure
- Diuretic – High blood pressure
- Steroids – inflammatory condition of the muscles
- Pain killers – Osteoarthritis
- Iron – Anaemia of chronic disease
- Proton pump inhibitors – prevent stomach ulcers due to the pain killers
- Bulking agent – counteract the constipation caused by the iron tablets
- Slow-release sodium – to counteract the loss of sodium caused by the diuretics
State the 4 different effects which drug can have on one another during drug-drug interactions
- additivity
- antagonism
- potentiation
- synergism
Whats Additivity?
A combination of two or more chemicals is the sum of the expected individual response
Whats antagonism?
Exposure to one chemical results in a reduction in the effect of the other chemical
Whats potentiation?
Exposure to one chemical results in the others chemical producing an effect greater than if given alone
NB. With potentiation one drug won’t have an effect but would increase the effect of another
Whats synergism?
Exposure to one chemical causes a dramatic increase in the effect of another chemical
Tell me about the method of Isoboles to establish interactions
- The lines join doses giving the same response e.g. ED25
- The theory underlying the Isobole involves the calculation of doses of drug A that are effectively equivalent to doses of drug B with that equivalence determining whether the Isobole is linear or nonlinear
Whats Synergism/ synergy?
The interaction or cooperation of two or more organisations, substances or other agents to produce a combine effect greater than the sum of their separate effects
Name the 3 types of drug interactions and a brief description of what each is?
- Chemical interactions – drugs combine chemically
- Pharmacodynamic interactions – drugs interact at the receptor
- Pharmacokinetic interactions – altering the concentration of the drug that reaches the receptor
Do the chemical interaction occur inside or outside of the body?
Outside the body
Tell me about chemical interaction incompatibilities, what does this lead to?
Incompatibilities: reaction of iv drugs resulting in solutions after mixing that are no longer safe for the patient due to altering stability (change the PH) or structure, leading to:
- Loss of drug activity
- Formation of precipitates
- Development of toxic product
Give an example of a chemical interaction incompatibility
Penicillin and aminoglycoside should never be placed in the same infusion fluid because of formation of inactive complex.
Tell me about Heparin and the chemical interactions with this drug
Heparin -
- an anticoagulant sometimes used to keep iv lines open and free from blood clots
- it is highly negatively charged and will combine with basic drugs
- IV lines are therefore often flushed with saline before a drug is given.
Are the pharmacodynamics of drugs usually predictable?
yes
In pharmacodynamics, when the drugs compete for the same receptor site, what type of interactions may this involve?
- agonist- antagonist interactions
- agonist – partial agonist interactions
Whats cross tolerance in pharmacodynamics?
Altered receptor numbers or affinity due to one drug affecting the actions of another
Give an example of cross tolerance
Propranolol or atenolol (ß-blockers used to treat hypertension and angina) interfere with the actions of ß-receptor agonists such as salbutamol or terbutaline (used as bronchodilators in asthma)
Give some more examples of cross tolerance
- Thiazide diuretics affect with plasma ion concentrations (reduce potassium) and enhance the actions of cardiac glycosides (digoxin)
- Sildenafil (Viagra) inhibits phosphodiesterase type V, raising the levels of cGMP. This can potentiate the action of drugs such as glyceryl trinitrate (used to treat angina) which activate guanylate cyclase. The combination can produce fatal hypotension.
- Warfarin (anticoagulant, antagonizing vitamin K) can cause bleeding – exacerbated by aspirin (anti-inflammatory) which blocks the production of prostaglandins and can cause bleeding in the stomach.
What are the pharmacokinetic interactions and where do they occur?
- ABSORPTION (into blood stream)
- DISTRIBUTION (in blood stream)
- METABOLISM (in liver)
- EXCRETION/ELIMINATION (in kidney)
Pharmacokinetic interaction
What are the variable that influence absorption?
- Altered concentration of free drug in gut lumen
- Competition for active transport
- Food (not really a drug - drug interaction)
- Gastro-intestinal motility
- Gut microflora – antibiotics
- First - pass metabolism in the gut wall
Give two examples of interactions that decrease the concentration of free drug in the gut lumen (formation of drug Chelates or complexes)
Tell me about them
- Tetracyclines + di- or tri-valent cations e.g., calcium (milk), magnesium and aluminium (anti acid), iron –> insoluble complex
- CHOLESTYRAMINE (ANION EXCHANGE RESIN, bile acid binding) interacts with acidic (anionic) drugs such as warfarin –> decrease absorption
Tell me about the interactions that result in competition for active uptake processes
- Most drugs are absorbed by simple passive diffusion
- Both drugs must compete for the same transporter system
- Relevant transporters exist for amino acids, for purines and for pyrimidine bases
A theoretical example would be levodopa (for Parkinson’s disease_ and tryptophan (for depression)
In reality this type of interaction is most important in relation to drug- food interactions
With interactions with food, what factors are effected?
- Interaction affecting absolute bioavailability- for example milk (Ca2+) and tetracyclines (see above)
- Interactions affecting the shape of the plasma concentration- time curve (due to altering gastric emptying)
Tell me about the absorption rate of drugs that are taken after a meal
Drugs taken after a meal are more slowly absorbed as progress to the small intestine is delayed
Name 2 drugs that alter gastrointestinal motility
- Anticholinergics
- Metoclopramide
Tell me about the effects of anticholinergics
- Slow gastric emptying
- Decrease G.I. motility
- Increase Tmax
- Decrease Cmax
- AUC not altered (usually)
Tell me about the effects of Metoclopramide
- D2 antagonist used as antiemetic
- Increase gastric emptying
- Increase G.I. motility
- Decrease Tmax
- Increase Cmax
- AUC not altered (usually)
What does the lower bowel contains vast numbers of?
The lower bowel contains vast numbers (1012 per g) of largely anaerobic bacteria
What is the major metabolic reactions that occur in the Liver and gut bacteria?
How are substrates that are poorly absorbed generally given?
Orally
How are conjugates excreted?
In bile
What does poorly absorbed broad-spectrum oral antibiotics decrease?
- Decrease gut flora numbers
- Decrease gut flora metabolism
What does Warfarin compete with and why?
Warfarin competes with vitamin K to prevent synthesis of coagulation factors. If vitamin K production in the intestine is inhibited by antibiotics, then the anticoagulation effect is increased
Whats the flow diagram for antibiotic and oral contraceptives?
WIth biliary excretion, what does the main interaction involve?
The main interaction involves interference with entero-hepatic circulation of the drug in lower bowel
Drug As effect is 20% and Drug Bs effect is 30%. If the combined effect from Drug A+B is 80%, which is the correct description of Drug A and Drug B’s interactions:
A. Addivitiy
B. potentiation
C. Synergism
D. antagonism
E. None of the above
C. Synergism
Drug A’s effect is 20% and Drug B’s effect is 30%. If the combined effect from Drug A+B is 10%, which is the correct description of Drug A and Drug B’s interactions
A. Addivitiy
B. potentiation
C. Synergism
D. antagonism
E. None of the above
D. antagonism
Drug A’s effect is 0% and Drug B’s effect is 30%. If the combined effect from Drug A+B is 80%, which is the correct description of Drug A and Drug B’s interactions
A. Addivitiy
B. potentiation
C. Synergism
D. antagonism
E. None of the above
B. potentiation
What is the type of drug-to-drug interaction which is the result of interaction at the receptor level?
A. Pharmacodynamic interaction
B. physical and chemical interaction
C. Pharmaceutical interaction
D. pharmacokinetic interaction
E. None of the above
A Pharmacodynamic interaction
Penicillin and aminoglycoside should never be placed in the same infusion fluid because of the formation of an inactive complex. This drug reaction is a:
A. Chemical interaction
B. Pharmacodynamic interaction
C. Pharmacokinetic interaction
D. None of the above
A. Chemical interaction
What is the type of drug-to-drug interaction which is connected with processes of absorption, biotransformation, distribution and excretion?
A. Pharmacodynamic interaction
B. Physical and chemical interaction
C. Pharmaceutical interaction
D. Pharmacokinetic interaction
E. None of the above
D. Pharmacokinetic interaction
Give an example of when a drug affects first-pass metabolism in the gut wall
The Cheese and wine reaction
- Important interactions are when inhibition of an enzyme increases the bioavailability
Tell me about distribution in the fat and lean tissue when drugs are inhaled
Shows drugs given by ventilation. Only a small amount of drug can reach target tissue
Tell me the rough percentages of drug distribution within the body
Tell me about the interactions affecting the extent of drug distribution
Tell me any necessary formulas
What do acidic drugs bind to?
What do basic drugs bind to?
- Acidic drugs bind to albumin e.g. warfarin
- Basic drugs bind to acid glycoprotein e.g. propranolol
With interactions affecting the extent of drug distribution, when is the interaction only important?
- Displaced drug has a narrow therapeutic index e.g., warfarin
- Displaced drug is highly protein bound e.g., >98%
Displaced drug has a low apparent volume of distribution, what does this mean for plasma content?
Displaced drug has a low apparent volume of distribution-
so that plasma contains a significant proportion of the body load and so that the extra free drug “liberated” in the plasma produces a significant increase in drug at the site of action
Give an example of a drug affecting first-pass metabolism in the liver
How does it affect the process?
CYP450 (cytochrome P 450) family is the major metabolising enzyme in the oxidation process
Tell me the effects of the following…
- CYP substrate and CYP inhibitor
- CYP substrate and CYP inducer
Tell me the effect of the following on metabolism and bioavailability
- P450 inducer
- P450 inhibitor
What does CYP450 increase the synthesis of?
Haemoprotein
How long is required for change to be seen with CYP450
Takes a number of days to produce a significant change
In regard to CYP450, what do some inducers bind to?
Some inducers bind to cytosolic receptors and enter the nucleus to affect DNA transcription
Give examples of therapeutic drugs which are also Cytochrome P450 enzyme inducers
- Barbiturates
- Glutethimide
- Phenylbutazone
- Phenytoin
- Rifampicin
- Griseofulvin
- Carbamazepine
Give examples of some environmental chemicals which are also Cytochrome P450 enzyme inducers
- Polycyclic aromatic hydrocarbons e.g., cigarette smoke burned steaks etc
- Organochlorin pesticides and dioxins
- Certain foods e.g., brassica
- Wood oils e.g., eucalyptol
Tell me the possible mechanism for enzyme induction
NB. Enzyme induction can be defined as the increase in the biosynthesis of catalytically active enzyme following exposure of the organism to chemical agents or physiological conditions.
P450 induction
Give examples of some drugs which induce CYP450
Phenobarbital
ethanol
rifampicin
What does the drug Rifampicin reduce the effect of?
Warfarin
What is paracetamol usually metabolised to?
Glucuronide or sulphate
What happens to drugs like paracetamol when these enzymes are saturated at high doses?
What can induce these enzymes?
- Paracetamol (normally metabolised to glucuronide or sulphate)
- When these enzymes are saturated (at high doses) it is metabolized by a cytochrome P450 to N-acetyl-p-benzoquinone imine (NAPQI, toxic)
- Chronic use of alcohol induces this enzyme.
Who can Phenobarbital be given to and what does this help with?
Phenobarbital can be given to premature babies to induce glucuronyl transferase, increasing bilirubin conjugation (Neonatal Jaundice).
Why are clinical effects of enzyme induction in things like Cytochrome P450 slow to develop?
Clinical effects are slow to develop as more enzyme is synthesised and persist after treatment during which time the additional enzyme is slowly degraded
When are clinical effects of a drugs most important and give examples of drugs that meet this criteria
- Clinical effects are most important when the drug has a narrow therapeutic index e.g., WARFARIN- ANTICOAGULANT
- TOLBUTAMIDE – HYPOGLYCEMIC
Whats meant by a drugs therapeutic index?
The Therapeutic Index ( TI ) is used to compare the therapeutically effective dose to the toxic dose of a pharmaceutical agent.
The TI is a statement of relative safety of a drug.
It is the ratio of the dose that produces toxicity to the dose needed to produce the desired therapeutic response.
Herb-drug interactions
What is St. John’s Wort: CYP3A4 inducer?
St John’s wort: a herbal medicine that is used to treat symptoms of mental health problems, such as mild and moderate depression, mild anxiety and sleep problems.
Tell me about the results of St. John’s Wort reducing Simvastatin (Zocor) levels
St. John’s Wort Reduces Simvastatin (Zocor) Levels
16 subjects took 10mg simvastatin alone and after St. John’s Wort 900 mg/day X 14 days
AUC of Simvastatin & its active metabolite substantially reduced
Induction of CYP3A4 and P-glycoprotein?
No effect on Pravastatin
St. John’s Wort: Increases CYP3A4 Activity
12 subjects took probe drugs with St. John’s Wort 900mg/d X 14d
- Caffeine (1A2)
- Tolbutamide (2C9)
- Dextromethorphan (2D6)
- Midazolam (3A4)
Only midazolam was affected (PO > IV)
Garlic Supplements Decrease Saquinavir (Invirase) Levels
Garlic Supplements Decrease Saquinavir (Invirase) Levels
- 9 subjects took 1200 mg saquinavir TID alone and after garlic capsules BID X 20 days
- Allicin content of garlic capsules confirmed
- Garlic associated with 51% decrease in AUC of saquinavir
Examples of P450, substrate, inducer and inhibitor
Graph for P450 inhibitors
Give 3 examples of enzyme inhibitors
- Slidenafil
- Disulfiram
- Methanol
Tell me about Slidenafil
Sildenafil (Viagra) metabolised by CYP3A4 - induced by barbiturates and rifampicin; inhibited by erythromycin and cimetidine
Tell me about Disulfiram
Disulfiram – inhibitor of aldehyde dehydrogenase, used to produce an adverse reaction to ethanol – also inhibits metabolism of other drugs e.g. warfarin which it potentiates
Tell me about Methanol
Methanol metabolised to formaldehyde – toxic. Poisoning treated with ethanol, which competes for aldehyde dehydrogenase and slows its metabolism
Tell me the effects of enzyme inhibition of P450? Where and what effects are caused?
- Direct action at the P450 active site
- IMMEDIATE EFFECT
- RAPID RECOVERY (depends on half-life of inhibitor)
Tell me some inhibitors of P450
- Cimetidine
- Isoniazid
- Chloramphenicol
- Disulphiram
- Allopurinol
- MAOI
Tell me the clinical uses of P450
- Gastric Ulcers
- Tuberculosis
- Antibiotic
- Alcoholism
- Gout
- Depression
Tell me the physiological effects causes by the inhibition of P450
- Decreased clearance
- Increased blood levels
- Increases effect (parent active)
- Decreased effect (prodrug)
What are the three types of renal excretion?
- Glomerular filtration
- pH dependent reabsorption
- Renal tubular secretion
Tell me about Glomerular filtration
- Depends on cardiac output
- Interaction would be due to toxicity
Tell me about pH dependent reabsorption
- interaction possible if drug alters urine pH
Tell me about Renal tubular secretion
- PROBENECID blocks renal tubular secretion of anions
- Used to be given with penicillins to reduce their renal excretion and increase blood levels
Tell me about biliary excretion
- The main interaction involves interference with entero-hepatic circulation of the drug in lower bowel
Summary
- Drug interactions are common
- Interactions are most important when
a. Drug has a narrow therapeutic index
b. Any quantitation of response
- Interactions can occur whenever drugs compete for the same protein site (transporter, enzyme, carrier etc.)
- Interactions can:
a. Increase effect toxicity
b. Decrease effect loss of benefit
c. Alter shape of concentration – time curve
d. Alter shape of effect – time curve
