Interactions COPY Flashcards
Name the enzyme inhibitors (SICKFACES.COM)
Sodium valproate Isoniazid / itraconazole Cimetidine Ketoconazole Fluconazole / fluoxetine Alcohol (acute, binge) / Amiodarone Chloramphenicol Erythromycin + clarithromycin Sulphonamides (co-trimoxazole) Ciprofloxacin Omeprazole Metronidazole
Also:
Grapefruit juice
Name the enzyme inducers (SCRAP GPSS)
Sulphonylureas Carbamazepine Rifampicin Alcohol (chronic) Phenytoin
Griseofulvin
Phenobarbital
St John’s Wort
Smoking
What are the main interactions with amiodarone?
- Amiodarone inhibits warfarin metabolism- enhanced anticoagulant effect
- Increased risk of bradycardia, AV block, myocardial depression with beta blockers
- Risk of ventricular arrhythmias with lithium
- Plasma concentration of digoxin increased by amiodarone
Amiodarone has a very long half life so there is potential for drug interactions to occur weeks/months after stopping treatment
What are the common interactions with digoxin?
- Plasma conc of digoxin increased by amiodarone (enzyme inhibitor)
- Plasma conc of digoxin increased by erythromycin (enzyme inhibitor)
- . Plasma conc of digoxin reduced by rifampicin (enzyme inducer)
- Plasma conc of digoxin reduced by St John’s Worst (enzyme inducer)
- Increased toxicity of digoxin if hypokalaemia occurs with loop and thiazide diuretics
- Plasma conc of digoxin increased by CCBs
What are the common interactions with lithium?
- Risk of lithium toxicity with ACEi (excretion reduced)
- Risk of lithium toxicity with NSAIDs (excretion reduced)
- Sodium depletion with loop and thiazide diuretics (excretion of lithium reduced)
- Risk of ventricular arrhythmias with amiodarone
What are the common interactions with methotrexate?
- Increased risk of infection with vaccines
- PPIs at high doses reduce clearance of methotrexate increasing risk of toxicity
- Penicillins increases risk of methotrexate toxicity
- Trimethoprim- both folate antagonists, increased risk of side effects and nephrotoxicity
What are the common interactions with phenytoin?
- Effects of phenytoin enhanced by NSAIDs
- Amiodarone inhibits phenytoin metabolism
- Phenytoin accelerates metabolism of warfarin
- Cimeditine inhibits metabolism of phenytoin
- Plasma conc of phenytoin increased by fluoxetine
- St John’s Wort reduces plasma conc of phenytoin
- Ciprofloxacin affects the concentration of phenytoin
- Decreases efficacy of combined contraceptive pill
- Phenytoin decreases exposure to NOACS
What are the common interactions with theophylline?
- Increased risk of convulsions with quinolones e.g. ciprofloxacin
- Plasma conc of theophylline reduced by St John’s Wort
- Plasma conc of theophylline reduced by rifampicin
- Plasma conc of theophylline increased by cimetidine
- Plasma conc of theophylline increased by fluconazole
- Smoking can increase theophylline clearance and increased doses of theophylline are therefore required
What are the common interactions with warfarin?
- Anticoagulant effect increased by NSAIDs
- Anticoagulant effect increased by fluconazole
- Anticoagulant effect increased by statins
- Anticoagulant effect increased by ciprofloxacin, erythromycin, metronidazole
- Anticoagulant effect reduced by griseofulvin
- Anticoagulant effect reduced by antiepileptics
- Alcohol effects anticoagulant control
- Anticoagulant effect antagonised by Vitamin K
- Anticoagulant effect enhanced by cranberry juice
What is the risk of consuming tyramine based food and drink e.g. cheese if on MAOIs?
Hypertensive crisis
How does alcohol interact with TCAs and mirtazapine?
Increased sedative effect
What are the main interactions with combined oral contraceptives?
- Enzyme inducing drugs increase metabolism of contraceptives. Additional contraceptive precautions should be taken for 4-8 weeks after stopping treatment
- Some ABX may reduce efficacy of the pill by impairing bacterial flora responsible for recycling ethinylestradiol e.g. ampicillin, amoxicillin, doxycycline. Additional precautions are required for duration of treatment and for 7 days after stopping
What are the main interactions with progesterone only contraceptives?
Efficacy reduced by enzyme inducers
Additional protection is needed for duration of treatment and 4 weeks after
What are the main interactions with sympathomimetics e.g. pseudoephedrine?
- MAOI- hypertensive crisis
- Beta blockers- hypertension risk
What are the main interactions with Orlistat?
- Orlistat reduces plasma conc of amiodarone
- Anticoagulants- monitor
- Acarbose for diabetes due to its GI effects
- Reduces absorption of ciclosporin
What is a pharmacokinetic interaction?
These occur when one drug alters the absorption, distribution, metabolism, or
excretion of another drug, thus increasing or reducing the amount of drug available
to produce its pharmacological effects.
What is a pharmacodynamic interaction?
This is where effects of one drug are changed by the presence of another drug at its
pharmacological site of action.
e.g. electrolyte imbalance, combined toxicity, antagonising effects
What PPI does clopidogrel interact with and what would be an alternative?
Omeprazole and esomeprazole
Lansoprazole would be an alternative
What drug can cause blue vision and which drug can cause yellow vision in overdose
Blue vision can be cause by slidenafil and yellow vision is a sign of digoxin toxicity alongside nausea and vomiting
Which SGLT is not licensed to be used with pioglitazone for triple therapy
Dapagflozin
What is drug interaction?
the modifications of effects of one drug by another drug (poly-pharmacy)
What is drug interaction? Pharmacodynamics (PD)
(“what the drug does to the body”)
related to the pharmacological activity of the interacting drugs leading to either:
synergistic effect, 1+1 > 2
or antagonistic effect, 1+1 < 2
What is drug interaction? Pharmacokinetic (PK)
(“what the body does to the drug”) related to the effect of a drug on another on physical disposition of the drug, i.e. movement of drug thru the body absorption distribution metabolism elimination
Effects of drug interaction
Increased effect: Additive or Synergistic
effect
BAD - Increased toxic effect GOOD - Increased therapeutic effect to produce synergistic therapeutic effects e.g. several antibiotic combinations Penicillin-Streptomycin
PD interactions arise when one drug changes the response of target or non-target tissues to another drug:
• Synergism
– Penicillin-Streptomycin
– Digoxin toxicity with diuretic induced potassium wasting
PD interactions arise when one drug changes the response of target or non-target tissues to another drug:
• Antagonism
– Beta adrenoceptor antagonist diminish the effectiveness of b-adrenoceptor agonists such as salbutamol
– Antidote: agents with a specific action against the activity or effect of drugs involved in poisoning cases
PK absorption eg. Altered pH; The non-ionized form of a drug is more lipid soluble and more readily absorbed from GIT than the
ionized form does.
-Ex1., antacids (aluminum or magnesium
hydroxide) Increase the pH and Reduce absorption of acidic drugs
digoxin (heart conditions), phenytoin (epilepsy), chlorpromazine (schizophrenia) isoniazid (tuberculosis) Therefore, these drugs must be separated by at least 2h in the time of administration of both.
PK absorption eg H2 antagonists increase the pH and Reduce absorption of acidic drugs:
digoxin (heart conditions), phenytoin (epilepsy), chlorpromazine (schizophrenia) isoniazid (tuberculosis) Therefore, these drugs must be separated by at least 2h in the time of administration of both.
Altered motility: Atropine (non-selective muscarinic blocker) Increase absorption of cyclosporine due to the increase of stomach emptying time and Increase the toxicity of cyclosporine example of - PD - PK absorption - PK excretion - PK metabolism - PK distribution
PK absorption
Chelation - Iron may chelate ciprofloxacin, resulting in decreased absorption example of - PD - PK absorption - PK excretion - PK metabolism - PK distribution
PK absorption
PK interactions (2): Distribution
• Drugs in bloodstream often bound to plasma proteins;
• Only unbound drugs can leave blood to affect target organs;
• Low albumin levels can increase availability of drugs and potentiate their effects;
• Competitive: drugs with higher affinity to albumin are capable to displace others, leading to increase concentration of free
drug (therefore yield more drug response):
Phenytoin (90%)
Tolbutamide (96%)
Warfarin (99%) –>
Aspirin
Sulfonamides
Phenylbutazone
PK interaction (3):Metabolism
the most drug-drug interactions are metabolism based (diagram)
Phase I metabolism: involves oxidative metabolism via the Cytochrome P450 (CYP) family of enzymes
Enzymatic induction
Inducer: Drug that will increase the synthesis of CYP450 enzymes
e.g. barbiturates, bzd, hydantoin antiepileptics, glucocorticoids, rifampicin, griseofulvin, St. John´s wort, smoking, grilled meat, chronic alcohol
intake – increase
SCRAP GPSS
-Decrease the effect of several drugs, e.g.
cardiotonics, steroid hormones, coumarin
anticoagulants
N.B enzyme induction involves protein synthesis. Therefore, it needs time up to 3 weeks to reach a maximal effect
Enzymatic inhibition
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Inhibitor: Drug that will decrease the metabolism of a substrate
e.g. some macrolides, quinolones, sulfonamides, some antimycotics (e.g. ketoconazole, fluconazole), isoniazid, metronidazole, chloramphenicol,
amiodarone, verapamil, diltiazem, quinidine, SSRI, proton pump inhibitors, cimetidine, garlic, ginkgo, grapefruit juice
-Increase the effect of several drugs
Inhibition of the enzyme may be due to the competition on its binding sites , so the onset of action is short may be within 24h.
When an enzyme inducer (e.g.carbamazepine) is administered with an inhibitor (verapamil) -> the effect of the __________ will be predominant
inhibitor
Omeprazole Inhibits oxidative metabolism of A. aspirin B. diazepam C. sertraline D. clarithromycin
B. diazepam
Omeprazole has actual adverse influences on the pharmacokinetics of medications such as diazepam, carbamazepine, clozapine, indinavir, methotrexate, tacrolimus, mycophenolate mofetil, clopidogrel, digoxin, itraconazole, posaconazole, and oral iron supplementation.
PK interaction (4): Excretion
Drugs are eliminated from the body as an unchanged drug or metabolite
– Renal excretion is the major route of
elimination;
– affected by renal function and urinary pH
Drug-Food
interactions
Tetracycline interacts with Milk (Ca2+ ) -> Unabsorpable complex
Warfarin (diagram)
Vitamin K-containing foods
Drug-Disease interactions
HEART : b1 adrenergic receptors - Heart rate & Contractility
SMOOTH MUSCLE -airway & vasculature:
b2 adrenergic receptors -> Relaxation & dilation
Drug ADR: homologous targets
•Non-selective b antagonists, e.g. Propranolol, are contraindicated in patients with asthma
Drug-Disease interactions:
Contraindications of atropine
1- Patients with angle closure glaucoma
2- Patients with shallow anterior chamber
3- Senile hyperplasia of the prostate
4- Patients with gastric ulcer
(increase symptoms due to slowing gastric emptying)
Changes in absorption
Alteration -GI motility
Alteration/ action
GI motility - Increased GI motility caused by metoclopramide may decrease cefprozil absorption (2nd gen cephalosporin)
GI alkalinization by omeprazole may decrease absorption of A. amantadine B. dapsone C. metronidazole D. ketoconazole
D. ketoconazole
changes in absorption PK
GI flora - Decreased GI bacterial flora caused by an antibiotic admin could decrease bacterial production of vitamin K augmenting anticoagulant effect of
warfarin
Changes in absorption
Alteration -Drug metabolism in wall of intestine
Drug metabolism in wall of intestine -
certain antidepressants is that phenylephrine could potentiate a spike in blood pressure; TCAs and MAOI
MAO acts to break down neurotransmitters like norepinephrine (and dopamine and serotonin); thus, MAOIs act to increase the amount of these chemicals in our synapses. Monoamine oxidases (MAO) are in the wall of GI tract. NE = main neurotransmitter of SNS and works to immediately increase our BP. Thus, a sympathomimetic like phenylephrine + MAOI, which is also stimulating the sympathetic system, has the potential to elevate BP into a hypertensive crisis.
Incidentally, MOA is involved in other body processes including the breakdown of tyramine, an amino acid involved in BP regulation. Tyramine helps release more NE. Thus, to prevent hypertensive crises, patients who take MAOIs should stay away from..
foods rich in tyramine like strong/aged cheeses, cured meats, yeasts, beers and dried fruits.
Phase II metabolism
conjugates the previously oxidized molecule with a water soluble weak acid (glucouronic acid, tauric acid, etc) enhancing overall water solubility
How to do drug-drug interactions occur
Drug-drug interaction always due to interaction at phase I enzymes (i.e. cytochrome P450)
Passive tubular reabsorption example
Sodium bicarbonate. Increases lithium clearance and decreases its action
Antacids Increases salicylates clearance and decreases its action
What happens when pH increases
Ionisation doesn’t occur as it only occurs at acidic pH
PK interactions: Absorption a) b) c) d)
a) altered pH
b) altered motility
c) altered intestinal bacteria flora
d) chelation
which drugs have strong affinity to protein binding
Phenytoin (90%)
Tolbutamide (96%)
Warfarin (99%)
which drugs have weak affinity
Aspirin
Sufonamides
Phenylbutazone
Non selective antimuscarinic drugs should never be used to
Non selective antimuscarinic drugs should never be used to treat acid-peptic disease.
Active tubular secretion
-It occurs in the proximal tubules. The drug combines with a specific protein to pass through the proximal tubules.
-When a drug has a competitive reactivity to the protein that is responsible for active transport of another drug, this drug will reduce such a drug excretion increasing
its con. and hence its toxicity.
-Probenecid decreases tubular secretion of methotrexate.
Passive tubular reabsorption
- Excretion and reabsorption of drugs occur in the tubules by passive diffusion which is regulated by concentration and lipid solubility.
- N.B., Ionized drugs are reabsorbed lower than non-ionized ones
Pharmacokinetic drug interactions
• Changes in GI absorption • Displacement from plasma protein binding • P450 Mediated – Enzyme inhibition – Enzyme induction • Decreased renal elimination
Drug-Herb interactions
• St John’s Wort e.g. cyclosporin • Ginkgo biloba • Kava • Garlic
Clinically significant to pharmacist perspective for interactions – what to look for
1. Vulnerable patient groups – Elderly – Multiple drug therapies (poly-pharmacy) – Renal or hepatic impairment – Chronic or serious illness 2. Particular groups of drugs: • Narrow therapeutic index • Enzyme inducers • Enzyme inhibitors
Sirolimus & grapefruit juice
Plasma concentration of sirolimus increases by grapefruit juice
Clozapine & cytotoxics
Avoid use of cytotoxics with clozapine due to possible increased risk of ventricular arrhythmias
Theophylline & phenobarbital
Metabolism of theophylline accelerated by phenobarbital
Tetracyclines & zinc
Absorption of tetracyclines possibly reduced by zinc (give atleast 2-3 hours apart)
Lithium & metronidazole
Increased risk of lithium toxicity when given with metronidazole
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Narrow therapeutic index
digoxin, theophylline, warfarin, ciclosporin, phenytoin, carbamazepine
Enzyme inducers out of the following: A. Carbamazepine B. Ciprofloxacin C. Warfarin D. Amiodarone E. Ketoconazole F. Phenytoin G. Diltiazem H. Rifampicin
carbamazepine
phenytoin
rifampicin
Enzyme inhibitors out of the following: A. Amiodarone B. Ciprofloxacin C. St Johns Wort D. Verapamil E. Fluoxetine F. Omeprazole G. Ketoconazole H. Diltiazem
amiodarone, ciprofloxacin, diltiazem, fluoxetine, verapamil, ketoconazole
Phenytoin and Amiodarone
Amiodarone increases phenytoin concentration
NB: Amiodarone is an enzyme inhibitor.
Due to amiodarones long half life: potential for interaction several months after discontinuation
Phenytoin and Warfarin
Phenytoin (p450 enzyme INDUCER) induces warfarins metabolism, decreases warfarin concentration, reduced anti-coagulation effect, decreases INR
Phenytoin and COC
Phenytoin (a p450 enzyme inducer) accelerates metabolism of Oestrogens, reducing their effectiveness
Patient should be changed to an IUD
Phenytoin and Fluoxetine
Fluoxetine increases phenytoin concentration
Phenytoin and Theophylline
Theophylline decreases phenytoin concentration
Phenytoin and St Johns Wort
St Johns Wort decreases phenytoin concentration
St Johns Wort is an enzyme inducer
Phenytoin and Fluconazole
Fluconazole increases phenytoin concentration (Fluconazole enzyme inhibitor part of SICKFACES)
Phenytoin and Cimetidine
Cimetidine increases phenytoin concentration (Cimetidine enzyme inhibitor part of SICKFACES)
Phenytoin and Diltiazem
Diltiazem increases phenytoin levels, and diltiazems own effects are decreased by phenytoin
Phenytoin and Rate limiting CCB’s
Phenytoin decreases effects of Verapamil and Diltiazem and also Felodipine
Amiodarone and Grapefruit Juice
Grapefruit Juice increases levels of Amiodarone
Grapefruit Juice is an enzyme inhibitor
Amiodarone and warfarin
Amiodarone increases warfarin levels
Enhances anti-coagulant effects, increased bleed risk
Amiodarone is an inhibitor of some of the CYP450 enzymes.
Amiodarone and Simvastatin
Increased risk of Myopathy
Max dose of Simvastatin: 20mg
This is not the same with Atorvastatin etc but still monitor for mypopathy
Amiodarone and beta blockers and Rate-limiting CCB’s diltiazem and verapamil
Increased risk of
Bradycardia
Myocardial depression
AV block
When given with beta blockers/ rate limiting CCB
Amiodarone and Lithium
Increased risk of Ventricular Arrhythmias
(poss associated with QT prolongation)
Also both effect THYROID function
Theophylline + enzyme inhibitors:
Cimetidine, Fluconazole, Ketoconazole, Ciprofloxcin, Erythromycin
Theophylline levels increased as it is metabolised by the CYP450 enzymes
Theophylline + enzyme Inducers:
Carbamazepine, Alcohol, Phenobarbital, Phenytoin, Rifampicin, St Johns Wort
(SCRAP GP’s)
Theophylline levels decreased
Theophylline and Quinolone antibiotics e.g. Ciprofloxaxin, Levofloxacin
Increased risk of SEIZURES
These BOTH lower seizure threshold
What do diltiazem and Verapamil (rate limiting CCBs) do to Theophyllines concentration?
Increase it
these are CYP3A4 enzyme inhibitors!
NSAIDs and warfarin/ phenindione
NSAIDs increase warfarin levels- increased anticoagulant effect
NSAIDs, like warfarin, have a high affinty for Albumin. They displace warfarin off the protein= more free warfarin
So remember the interaction is not because both drugs can increase bleed risk- NSAIDs actually increase the levels of warfarin
SSRI’s and TCA’s and warfarin
SSRI’s and TCA’s will increase warfarin levels- increased anticoagulant effect
Statins and warfarin
Only statin that interacts: Rosuvastatin
Increased effects of warfarin
Clopidogrel and warfarin
Anti-coagulant effect enhance (both thin blood)- increased risk of bleeds
Orlistat + Antiepileptics
Possible increased risk of convulsions- orlistat lowers seizure threshold
Methotrexate and Phenytoin
Do not use together- both deplete Folate
Methotrexate and Trimethoprim/ Co-trimoxazole (trimethoprim + Sulfamethoxazole)
Do not use together- both deplete folate- haematological blood toxicity risk
Sulfamethoxazole also increases methotrexate toxicity
Methotrexate and Ibuprofen
Methotrexate toxicity increased by NSAIDs due to decreased renal excretion
Methotrexate and Flucloxacillin
Methotrexate toxicity increased by all penicillins due to decreased renal excretion
Methotrexate and Clozapine
Neutropenia risk increased
PPI’s and Methotrexate
Increased risk of Methotrexate toxcity as excretion decreased
ALOT of antibiotics interact with Methotrexate. Can you think of any?
Trimethoprim/ co-trimoxazole (folate depletion)
The following increase methotrexate toxicity: Ciprfloxacin Doxycycline Tetracycline Sulfonamide (Sulfamethoxazole)
If in doubt, whats that ONE DRUG that seems to have interactions with everything?!
CICLOSPORIN
an immunosuppressant
Which OTC medication can possibly interact with ANTI-EPILEPTICS and increase the risk of CONVULSIONS?
ORLISTAT (Alli)
Carbamazepine is an enzyme inducer, but is itself metabolised by the CYP450 system. Which other enzyme inducers may reduce the concentration of carbamazepine?
Phenytoin (May also reduce phenytoins conc)
Rifabutin
St Johns Wort
What drugs, used in hypertension, can increase the risk of Myopathy?
Diltiazem
Verapamil
Amlodipine
Ranolazine
MAX SIMVASTATIN DOSE= 20mg for all of these!!
Drugs interacting with Gentamicin/ Vancomycin?
NEPHROTOXIC DRUGS:
Ciclosporin (immunosuppressant)
Tacrolimus (immunosuppressant)
Cephalosporins
OTOTOXICITY: Loop diuretics (furosemide)
What kind of OTC products should patients with high BP avoid?
SOLUBLE preparations e.g. effervescent
Due to high SODIUM content
Spironolactone + ACEi/ARB
Potassium sparing diuretic given with postassium elevating drugs: HYPERKALEAMIA
Spironolactone + Tacrolimus
Potassium sparing diuretic given with postassium elevating drug Tacrolimus: Hyperkaleamia
Furosemide + Vancomycin
Increased risk of Ototoxicity
Digoxin + Diuretics
Diuretics (thiazides and loops) can cause Hypokaleamia
Digoxin toxicity is precipitated by low potassium!!
Give potassium sparing diuretics/ potassium chloride to manage
Eplerenone (potassium sparing diuretic) is metabolised by the CYP450 enzyme system
Its concentration is increased by clarithromycin and itraconazole only
Its concentration is reduced by all the enzyme inducers
What drugs may cause hypoglyceamia and therefore reduce the amount of insulin a patient needs?
ACE inhibitors!
Other oral antidiabetics
NSAID + quinolone (ciprofloxacin, Levofloxacin)
Possible increased risk of seizures
NSAID + Diuretics
Increased risk of nephrotoxicity
NSAIDs will also antagonise the diuretic effects: Fluid retention! Can cause ankle swelling and high blood pressure with chronic use
NSAIDs + anti-hypertensives (beta-blockers, CCB’s, ACE inhibitors, alpha-blockers [tamsulosin, doxazosin] nitrates)
NSAIDs themselves can cause high BP
They antagonise the hypotensive effects of these drugs
Which opioid can enhance the anticoagulant effect of coumarins (warfarin)
Tramadol
Which antibiotic can reduce the effectiveness of most of the opioids, including fentanyl, morphine, codeine, methadone?
RIFAMPICIN!! (enzyme inducer)
Opioids can reduce BP (hypotensive)
Their hypotensive and sedative effects are increased by alcohol. What happens if given with MAOIs?
Possible CNS excitation or depression
Hypotension or hypertension can occur
(remember MAOIs can cause hypotensive crisis)
Clopidogrel + enzyme inhibitors
Some of the enzyme inhibitors (erythromycin, cimetidine, ciprofloxacin, fluconazole, ketoconazole) actually REDUCE clopidogrels antiplatelet effect!- dont get confused in exam!
Clopidogrel + PPI’s
Antiplatelet effect REDUCED by omeprazole and esomeprazole
Pantoprazole safest PPI to use, or H2 antagonist
Sotalol + loop or thiazide diuretics
risk of ventricular arrhythmias caused by sotolol is increased by diuretics due to their hypokaleamia effect
Lithium + ACE inhibitors
ACE inhibitors will decrease the excretion of lithium!
Nothing to do with electrolyte disturbance
Lithium + Beta blockers
No interaction!
Lithium + Aminophylline/ Theophylline
These will increase the excretion of lithium, reducing its levels
NSAIDs + Lithium
Excretion of lithium reduced by NSAIDs so increased risk of Lithium Toxicity!
Lithium + SSRIs
Increased risk of CNS effects, lithium toxicity
think SSRI’s cause hyponatreamia- sodium levels effect lithium
Methotrexate and Aspirin
Methotrexate toxicity increased
As Aspirin and NSAIDs decrease methotrexate excretion
Doxycycline + Isotretinoin
Severe headache/ visual disturbance due to cranial (brain) hypertension
Atorvastatin and clarithromycin
increased risk of myopathy
Co-trimoxazole + Spironolactone
Increased risk of hyperkaleamia
Metronidazole + Mebendazole
severe skin reaction
Baclofen + ACE inhibitors
Baclofen enhances hypotensive effect
Baclofen + beta blockers
Baclofen enhances hypotensive effect
Alpha blockers (sildenafil) + nitrates (isosorbide mononitrate)
Enhanced hypotension effects
