illustrated drug interaction by mohie al-dien elsayed (md) file4 4 mtc mec time n need to keep...
TRANSCRIPT
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Illustrated Drug interaction
By
Mohie Al-Dien Elsayed (MD)
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Definitions and Terms:
-Adverse Event (AE): untoward, unintended, Effect or Experience possibly causing harm
-ADE (AE associated with a Drug): an AE which happens in a patient taking a drug
-ADR (Adverse Drug Reaction): ADE with Drug/event suspected causal association.
-Drug Interactions: “The pharmacologic or clinical response to the administration of a drug combination
different from that anticipated from the known effects of the two agents when given alone ”. Drug
interactions represent 3–5% of preventable in-hospital ADRs.
Drug-Drug Interactions classification:
I) According to effect: A-Harmful Effects (potentiating/antagonism)
B- Beneficial Effects (Additive or Synergistic)
II) According to site of interaction:
A) In-vitro: 1-Drug-laboratory tests interaction:
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2) Mixing 2 drugs prior injection:
B) IN-VIVO: ♣ Underlying factors; A) Patient factors:
Old age changes: e.g. ↓ liver metabolism, kidney function, nerve transmission or the functioning of bone marrow.
↓sensation→ ↑ the chances of errors being made in the administration of drugs.
Genetic factors: e.g enzyme genetic variability.
Serious diseases that could worsen if the dose of the medicine is reduced.
at High Risk for Drug Interactions e.g. Hepatic/renal diseases.;Autoimmune disorders.Cardiovascular
disease.;Gastrointestinal disease; Infection ; Psychiatric disorders; Respiratory disorders.;Seizure disorders.
pregnant women , Smoking ;Alcohol
Diet/Nutrition ;Environment
B) Drug dependent factors: *Polypharmacy:
*Narrow therapeutic index = LD50 (Lethal dose in 50% of animals) / ED50 (Effective dose in 50% of animals) e.g.
Aminoglycoside antibiotics (gentamicin, tobramycin) Anticoagulants (warfarin, heparins), Aspirin, Carbamazepine,
Conjugated estrogens,Cyclosporine ,Digoxin,Esterified estrogens,Hypoglycemic agents, Levo-thyroxine Na,Lithium
,Phenytoin,Procainamide,Quinidine sulfate/gluconate,Theophylline,Tricyclic antidepressants ,Valproic acid.
2-Steep dose-response curve (Phenytoin, Aminoglycoside Vancomycin): Small changes in the dosage of a drug
produce large changes in the drug's concentration in the patient’s blood plasma.
3-Saturable hepatic metabolism: In addition to dose effects the capacity to metabolize the drug is greatly decreased.
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MTC
MEC
Time
Plasm
a drug
conce
ntratio
n
Need to keep concentration of drug withinthe therapeutic range
MEC=Minimum effective concentration MTC=Maximum therapeutic concentration
♣ Classified according to underlying mechanisms into:
A) Pharmacokinetic drug-drug interaction:
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1) Altered Absorption:
a)Altered pH:
*Gastric acidity: * Infection Absorption of weak acid drugs eg Aspirin & Phenobarbitone.
* Antiacids ,H2 antagonists , PPIs, atazanavir, itraconazole (gastric alkalinity) →↓ Absorption of weak Acid
(Aspirin,barbiturate,Ketoconazole ,quinolones & fluoroquinolones , tetracyclin)& ↑ absorption of weak base .
*Intestinal Alkalinity Absorption of weak base drugs e.g. Ephedrine
b) Altered Efflux Transporter (P-gp, MDR1) to intestinal lumen(↓ by Quinidine →↑digoxin plasma concentration .
c) Altered motility; Gastric Emptying Time,GET (stomach emptying time):
* GET ↓by food,morphine,Metoclopramide (antiemitic)→ ↑absorption of rapid dissolution drugs ( Paracetamol &
Propranolol) & ↓ absorption of delay dissolution drug( Digoxin).
*GET ↓by fasting ,antacids, opioid, antimuscarinic (propantheline atropine), antidiarrhoeal →↓ absorption of
paracetamol & ↓ bioavailability of drugs that are degraded in the intestine (levodopa) and ↑Increased bioavailability
of lipid soluble drugs .
NB: The Reverse; Laxatives will cause drugs to move through the intestine so rapidly that they are poorly absorbed.
d) Interactions during absorption.
1- Chelation : (Chelating agent forming a stable complex with a toxic metal):
*Antacids (Ca2+
, Mg2+
, Al3+
), iron salts (Fe2+
) and milk (Ca2+
) inhibit the absorption of tetracyclines
*Bile acid binding resins: cholestyramine, cholestipol adsorps and inhibits the absorption of thyroxine , cardiac
glycosides (digoxin, digitoxin), warfarin, corticosteroids, thiazides .
*Kaolin-pectin decrease the absorption of digoxin
*Tetracyclines and Quinolones chelate metals and form an insoluble complex that ↓their absorption.
* EDTA chelates toxic metals such as lead and reduces toxicity.
2- Adsorption: nonspecific, physical,binding of a drug to another agent:
-Cholestyramine adsorbs dicumarol,methotrexate and digitoxin and decreases their absorption.
-Antacids decrease digoxin and iron absorption by adsorption.
d) Altered intestinal bacterial flora:
Antibiotics (Chloramphenicol, tetracyclines) kill a large number of the normal flora of the intestine,
* →↓synthesis of vit K by bacteria, →↑the efects of oral anticoagulants which compete with vit K.
* →↓ enterohepatic recycling of estrogens, → the efficacy of oral contraceptives
* →↑ absorption of drugs that are metabolized by gut bacteria e.g.digoxin. (In 10% 0f patients receive digoxin 40% or more of the administered dose is metabolized by the intestinal flora).
e) Altered blood flow: NE with local anaesthetic
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B) Altered distribution:
1) Plasma protein (e.g. albumin acidic drugs) & a1-acid glycoprotein, basic drugs) displacement:
Depends on the affinity of the drug to plasma protein. The most likely bound drugs are capable to displace
others. It is clinically important if displaced drug is highly PP binding, with LONG T ½, small Vd, narrow
therapeutic range. The free drug is increased by displacement by another drug with higher affinity.
e.g Aspirin, Phenylbutazone, Clofibrate & Sulfa Displace:
- Oral Anti-coagulants (Dicumarol, Warfarin) Bleeding
- Oral Hypoglycemics (Tolbutamide) Hypoglycemia
-Bilirubin in Neonate Jaundice & Kernictrus
2) Interactions due to disturbances in fluid and electrolyte balance:
Primary drug Interacting drug effect Result of interaction
-Digoxin
-Lignocaine
-Diuretics
-Tubocurarine
-Lithium
-ACEIs
-Diuretic-induced hypokalemia
-Diuretic-induced hypokalemia
-NSAID-induced salt and water retention
-Diuretic-induced hypokalemia
-Thiazide-induced reduction in renal clearance
-Kcl and/or patassium-retaining diuretic-induced
hyperkalemia
-Digoxin toxicity
-Antagonism of antiarrhythmic
effects
-Antagonism of diuretic effects
-Prolonged paralysis
-Raised plasma lithium
-Severe hyperkalemia
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3) Altered Elimination:
A) Altered transporters (which transport drugs to different organs):
P-gp= p-glycoprotein;MDR=multidrug resistance;;OATP=,organic anion transporting polypeptide;OCT[organic cation transporter; OAT,
organic anion transporter
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1-Altered Eflux transporter (Pgp)
B) Altered Uptake transporter
Inhibitor Substrate effect OAT1 Probencide.novobiocin Pencillin,cephalosporones,,cidofover ↓ PCT acidic drug
excretion→↓ renal
excretion &↑systemic
toxicity
OCT1 Cimitidine, desipramine,
phenoxy-benzamine,quinine
amantadine, cimetidine,memantine,
Procainamide ,metformin
OATP Gemfibrazol ,cyclosporine
squinavir ,retoniver ,squinavir
rifampicin
Statins, repaglinide, digoxin ↓ hepatic uptake take
→↑systemic toxicity
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Competitive drug interaction in renal tubules:
Primary drug Competing drug Effect of interaction
*Penicillin
*Methotrexate
*Salicylate
*Indomethacin
*Chlorpropamide
*Digoxin
*Probenecid
*Salicylates
*Sulfonamides
*Probenecid
*Probenecid
*Phenylbutazone Spironolactone
Amiodarone Verapamil
*Increased penicillin blood level
*Bone-marrow suppression
*Salicylate toxicity
*Indomethacin toxicity
*Hypoglycemia
*Increased plasma digoxin
- Alkalinization of urine (NaHCO3) Excretion of weak acid drugs e.g. Aspirin
-acidification by Vit. C Excretion of weak base drugs e.g. quinidine, amphetamine
Drugs that act as weak acids or bases :
Weak acids.:Acetylsalicylic acid ,Furosemide ,Ibuprofen ,Levodopa ,Acetazolamide ,Sulfadiazine,
Ampicillin ,Chlorothiazide ,Paracetamol ,Chloropropamide ,Cromoglicic acid ,Ethacrynic acid ,alpha-
Methyldopamine ,Phenobarbital ,Warfarin ,Theophylline ,Phenytoin.
Weak bases: Reserpine ,Amphetamine ,Procaine ,Ephedrine ,Atropine ,Diazepam ,Hydralazine ,Pindolol
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B) Altered Metabolism: Enzyme inhibitors/inducers
HME Inducers: Phenytoin, Phenobarbitone, Rifampicin, Testosterone & Tobacco smoking Their own
metabolism & Other drugs.
HME Inhibitors: MAO-I, Cimetidine, Estrogen, Na Valproate & Chloramphenicol
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Cytochrome P 450 enzymes:
Common drug substrates Inhibitors
(↑drug level of substrate)
Inducers
(↑drug level of substrate)
CYP1A2
Clozapine, clomipramine,
estrogen, fluvoxamine,
haloperidol , tacrine, theophylline,
Amiodarone, cimetidine,
fluoroquinolones,
ticlopidine, Ciprofloxacin,
enoxacin,fluvoxamine
Polycyclic aromatic
hydrocarbons,Omeprazole
, ritonavir, phenobarbital
CYP2C9
Phenytoin, warfarin, tolbutamide,
glipizide
Amiodarone, fluconazole,
miconazole,phenylbutazone,
sulphinpyrazone
Carbamazepine,
phenobarbital, rifampin,,
St John’s Wort
CYP2D6
Alprenolol, bufuralol, carvedilol,
metoprolol, propranolol, timolol,
amitriptyline,clomipramine,desipr
amine, imipramine, nortriptyline
,flecainide ,mexiletine, fluoxetine,
propafenone, haloperidol , parox-
etine , perphenazine, venlafaxine ,
codeine ,dextromethorphan
Clomipramine, quinidine,
fluoxetine, haloperidol,
paroxetine, Bupropion,
paroxetine, quinidine
Not inducible
CYP2E1
Paracetamol, benzene, ethanol,
isoflurane,theophylline
Disulfiram, diethyl-
dithiocarbamate
Ethanol, isoniazid
CYP3A Diltiazem, felodipine, nifedipine,
verapamil,ciclosporin, tacrolimus,
alprazolam, midazolam,
triazolam, atorvastatin, lovastatin,
clarithromycin,erythromycin,
indinavir, nelfinavir, ritonavir,
saquinavir, losartan, sildenafil
Diltiazem, verapamil,
itraconazole, ketoconazole,
clarithromycin,
erythromycin,troleandomyci
n, Delavirdine , indinavir,
ritonavir,saquinavir,grapefru
it juice,mifepristone,
nefazodone, Amprenavir,
aprepitant,atazanavir,ciprofl
oxacin,darunavir/ritonavir, ,
fluconazole, fosamprenavir,
grapefruit juice,imatinib,
Rifabutin, rifampin,
rifapentine,carbamazepine,
phenobarbital, phenytoin,
topiramate, efavirenz,
nevirapine, St John’s
Wort, Avasimibe,
phenytoin, rifampin,
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II- Pharmacodynamic Drug-Drug interaction:
A) Additive, synergistic or summation interactions
Drugs Result
Anticholinergics + anticholinergics (anti-parkinsonian
agents, butyrophenones, phenothiazines , tricyclic
antidepressants, etc.)
Increased anticholinergic effects; heat stroke in hot and
humid conditions; a dynamic ileus; toxic psychoses
Antihypertensives + drugs causing hypotension (anti-
anginals, vasodilators, phenothiazines)
Increased antihypertensive effects; orthostasis
CNS depressants + CNS depressants (alcohol, anti-
emetics, antihistamines, hypnosedatives, etc.)
Impaired psychomotor skills, reduced alertness,
drowsiness, stupor, respiratory depression, coma, death
QT prolonging drugs + other QT prolonging drugs
(Amiodarone + Disopyramide)
Additive prolongation of QT interval, increased risk of
torsade de pointes
Methotrexate + co-trimoxazole Bone marrow megaloblastosis due to folic acid antagonism
Nephrotoxic drugs + nephrotoxic drugs (gentamicin or
tobramycin with cefalotin (cephalothin)
Increased nephrotoxicity
Neuromuscular blockers + drugs with neuromuscular
blocking effects (e.g. aminoglycoside antibacterials)
Increased neuromuscular blockade; delayed recovery,
prolonged apnoea
Potassium supplements + potassium-sparing diuretics
(triamterene)
Marked hyperkalaemia
Aminoglycoside +B-lactam Synergim
Potentiation: .
- Barbiturates (NOT analgesic) potentiate the analgesic effect of aspirin.
- Change pH:
*alkalinize urine by NaCo3 efficacy of aminoglycoside, sulphonamid
*Acidify urine by vit, C efficacy of B lactam, nitrofurantoin.
- hypokalemia digitalis toxicity
B-Antagonism:
*Chemical e.g. Heparin(Ac.) +Pr.So4(base)
*Physiological e.g. Ad& H on bronchi
*Pharmacological One Agonist + One Blocker + One Receptor.
Iatrogenic Disease: Drug-induced disease.
- Large dose of Reserpine & Chlorpromazine (Iatrogenic Parkinsonism)
-Large dose of Cortisol (Iatrogenic Cushing’s disease)
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Drug-food interaction
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Food Drugs effect
High-carbohydrate meals Iron, levodopa, penicillins (most),
tetracycline, erythromycin
↓ absorption
Acidic foods/juices and sodas (e.g., cola) Ketoconazole ↑ absorption
antacids (Mg , aluminium ) , iron products and
calcium in vitamin-mineral products and liquid
enteral nutritional supplements
Fluoroquinolones (ciprofloxacin,
levofloxacin, ofloxacin,
trovafloxacin), Tetracycline
↓ absorption
vitamin B6 (pyridoxine) found in avocados, beans,
peas, sweet potatoes, bacon, beef liver, pork, tuna &
some nonprescription vitamin-mineral products
levodopa,;
↓blood levels of
dopamine &antipa-
rkinsonism effects
Avocado ;Brassicas (brussel sprouts, broccoli,
cabbage) Oral anticoagulant
Enzymatic inducer
(effect↓)
Grape fruit juice
Amlodipine,nifedipine, Cyclosporine,
tacrolimus Terfenadine, astemizole
,Cisapride , Pimozide Carbamazepine,
Saquinavir, Midazolam, Alprazolam,
Triazolam
Enzymatic
inhibition
(Toxicity)
Soya
Clozapine, Haloperidol, Olanzapine,
caffeine, NSAIAs, Phenytoin,
Zafirlukast, warfarin
Enzymatic
inhibition(Toxicity)
Hypericum perforatum (St John’s wort)
Warfarin, Digoxin, Theophylline,
cyclosporine, phenytoin and
antiretrovirals
Enzymatic inductor
(CYP450)
vitamin K found in green leafy vegetables(spinach,
collard greens),, tomatoes coffee, beef liver, green
tea, , Alfalfa tablets Broccoli ,Brussels sprouts,
Cabbage, Cauliflower (raw), Green tea ,Liver, Soy-
bean, Vegetable oils (canola, soybean) , Watercress
Oral Anti-coagulant Interfere with
efficacy
Consuming foods high in sodium (i.e licorice,
processed meats, canned foods)
Antihypertensives ↓effectiveness of
the drug.
The drug may increase appetite thus increasing
nutrient intake
Cortico-steroid
The drug may decrease appetite thus decreasing
nutrient intake
Diuretic
Foods Containing High Amounts of Tyramine
Ale , Avocados,Bananas,Beans (lima beans, butter
beans, bean pods),Caviar, aged Cheese, Chocolate
Coffee,Figs,Fish ,meat (bologna, fermented meat,
salami, pepperoni, summer sausage),Liver (beef or
chicken), Raspberries, Raisins, Sour cream,Soy
beans or sauce, Tofu, Wines (especially red),Yeast
preparations, Yogurt
MAOIs
acute
exacerbation of
blood pressure.
Effect of Drugs in nutrient body content
Food drug
Taking large amounts of these drugs will cause a loss of Vitamin C in the body. Aspirin
Women who take these drugs often have low levels of folic acid and B6 in the blood. Oral contraceptives
Vitamin D and folic acid levels in the body are ↓by the taking of these types of drugs. Anticonvulsant
Ginseng Warfarin, Heparin, Aspirin and NSAIA
Kava (Piper methysticum) Levodopa
Chamomile Benzodiazepines, barbiturates , opioid
Hawthorn Beta-adrenergic antagonists, Cisapride,
Digoxin, Quinidine
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HERBALS AND DRUG INTERACTIONS
Activity Commonly Used Herbs*
Anti-coagulant chamomile, dong quai (tang-kuei), horse chestnut
Anti-platelet bilberry, bromelain, cayenne, feverfew, flaxseed oil, garlic, ginger, ginkgo, ginseng, green
tea, meadowsweet, motherwort, and turmeric
Pro-coagulant goldenseal, Oregon grape root, shepherd's purse
*other anticoagulant and antiplatelet herbs, white atracytlodes, cnidium (chuanxiong), salvia, garlic,
zedoaria, pueraria, carthamus, lysimachia, cinnamon bark, tien-chi (sanqi), and capillaris (also listed: tang-
kuei and turmeric).
Herb Some Common Uses Possible Side Effects or Drug Interactions
Cayenne
External: used for muscle
spasm and soreness
Internal: GI tract disorders
External: potential for skin ulceration and blistering with
greater than 2 days of use. Internal: overuse may cause severe
hypothermia.
Echinacea
boosts the immune system &
helps fight colds and flu. Aids
wound healing.
Echinacea may cause inflammation of the liver if used with
certain other medications, such as anabolic steroids,
methotrexate or others.
Ephedra (Ma-
Huang)
It is used in many over-the-
counter diet aids as an
appetite suppressant. Or
used for asthma or
bronchitis.
Ephedra may interact with certain antidepressant medications
or anthypertensive medications to cause dangerous elevation in
blood pressure or heart rate. It could cause death in certain
individuals.
MAOI, central nervous system stimulants, alkaloids ergotamines
and xanthines
Feverfew
↓migraine headaches and for
arthritis, rheumatic disease
& allergies.
Feverfew may increase bleeding, especially in patients already
taking certain anti-clotting drugs.
Garlic
↓ Blood cholesterol, TG
levels and blood pressure.
Garlic may increase bleeding, especially in patients already
taking Anticoagulants ,NSAIA, acetylsalicylic acid certain.
Ginger
Ginger is used for reducing
nausea, vomiting and vertigo
Ginger may ↑bleeding, potentiate anticoagulant sulfaguanidine
(enhance absorption)
Ginkgo (ginkgo
biloba)
↑blood circulation & oxyg-
enation and for improving
memory and mental
alertness.
Ginkgo may increase bleeding especially in patients already
taking warfarin, Aspirin and NSAIA
Ginseng increases physical
stamina and mental
concentration.
warfarin (to cause bleeding or to ↓ effectiveness. It may cause
bleeding in women post- menopause . ↑ heart rate or blood
pressure. antidepressants such as phenelzine sulfate (to cause
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Ginseng manic episodes, headaches);); corticosteroids (potentiation);
estrogens (potentiation)
Goldenseal
mild laxative and also
reduces inflammation. Goldenseal may worsen swelling and/or high blood pressure.
Kava-kava
nervousness, anxiety or
restlessness; it is also a
muscle relaxant.
↑the effects of certain anti-seizure, prolong the effects of certain
anesthetics ,↑ the effects of alcohol. It may ↑the risk of suicide
for people with certain types ofdepression.
Licorice
Licorice is used for treating
stomach ulcers.
Certain licorice compounds may cause high blood pressure,
swelling or electrolyte imbalances.corticosteroids and thiazide
diuretics (potentiation); digitalis or other cardiac glycosides
(increased sensitivity)
Saw Palmetto
used for enlarged prostate
and urinary inflammations.
People using saw palmetto may see effects with other hormone
therapies.
St. John's Wort
St. John's Wort is used for
mild to moderate depression
or anxiety and sleep
disorders.
prolong the effect of certain anesthetic agents. warfarin (to
cause bleeding); serotonin-uptake inhibitors (to cause mild
serotonin syndrome); indinavir (decreased bioavailability);
digitoxin, theophylline, cyclosporin, phenprocoumon, and oral
contraceptives (all with reduced bioavailability)
Valerian
Mild sedative or sleep-aid. It
is also a muscle relaxant.
↑the effects of certain anti-seizure or prolong the effects of
certain anesthetic agents.
Herb Interactions Reported or Suspected
Tang-kuei danggui warfarin (to cause bleeding)
Salvia danshen warfarin (to cause bleeding)
Rhubarb dahuang ↑cardiac glycosides and antiarrhythmic (by ↓K via laxative effect)
Aloe luhui ↑cardiac glycosides and antiarrhythmic (by ↓K via laxative effect)
Ma-huang
mahuang
MAO is (to cause hypertension); cardiac glycosides or halothane (to produce cardiac
arrhythmia); caffeine (to ↑cardiovascular side effects)
Astragalus huangqi cyclosporine, azathioprine, methotrexate (to impair intended immuno-suppressive effects).
Bupleurum chaihu sedatives (potentiation)
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Drug Herbal/Food Adverse Effects/Drug Interactions Reported
Alprazolam Kava Synergistic CNS activity of alprazolam
Amantadine Quinine Elevated serum drug levels of amantadine and risk of toxicity
(ataxia, mental confusion)
Amoxicillin and
ampicillin
Khat Delayed or decreased absorption of amoxicillin and ampicillin
Astemizole
Grapefruit (juice) Increased bioavailability of astemizole
Quinine Elevated serum drug levels of astemizole, and increased risk of
cardiotoxicity
Buspirone Grapefruit(juice) Increased serum drug levels of buspirone
Dihydropyridine
Ca. channel
blockers
Grapefruit (juice) Increased serum drug levels: amlodipine 15%, felodipine
>300%, nifedipine 35%, nisoldipine 400%
Carbamazepine
Grapefruit(juice) Increased serum drug levels by about 40%
Quinine Elevated serum drug levels of carbamazepine by about 37%
Cyclosporine Grapefruit (juice) Increased serum drug levels and increased usual ADRs of
cyclosporine
Digoxin
Quinine Elevated serum digoxin levels by about 75%
Licorice Elevates serum digoxin levels 4-fold
Hawthorn Increased cardiac toxicity
Ginseng (Siberian) Elevates serum digoxin levels by about 75%
St. John’s wort Decreases serum digoxin concentration by 25%
Estrogen Grapefruit (juice) Increased serum drug levels by 37%
Herbal tea Increased serum drug levels by 28%
Lithium
diuretic Herbs
(broom, buchu,
dandelion,juniper)
Increased serum drug levels of lithium
Midazolam Grapefruit (juice) Increased serum drug levels of midazolam
Paroxetine and
other SSRIs
St. John’s wort Incoherent, confused, nausea, weakness, and fatigue;
effects occurred 10 days after paroxetine was discontinued and
first dose of St. John’s wort was initiated
Phenelzine Ginseng (Siberian) Insomnia, tremulousness, tension headaches, irritability, and
visual hallucinations
Phenobarbital Quinine Elevated serum phenobarbital levels by about 35%
Quinidine Grapefruit (juice) Reduced and delayed cardiac effects (QTc).
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Spironolactone Licorice Mineralocorticoid of licorice blocked; hypokalemia and muscle
weakness
Theophylline St. John’s wort Increases serum theophylline concentration by about 50%
Triazolam Grapefruit (juice) Increased serum drug levels of triazolam
Warfarin
Dashen Increased anticoagulant activity or increased INR
Ginkgo biloba,
garlic, feverfew,
and cayenne
Platelet aggregation inhibitor effects and increased risk of
bleeding/bruising
Ginseng(Siberian) Decreased anticoagulant activity or decreased INR
Licorice Increased anticoagulant activity or increased INR
Alfalfa Decreased anticoagulant activity or decreased INR
Vitamin E (doses
of 200 IU/day)
Increased anticoagulant activity and increased platelet
aggregation inhibition, increased risk of bleeding
Ginger ↑anticoagulant activity, increased INR, prolonged bleeding
Quinine Increased anticoagulant activity or increased INR
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It may be possible to reduce or prevent ADRs by:
Avoiding unnecessary drug use; if you don't prescribe drugs you will not get ADRs
Consult the BNF and the BNF for Children which are useful sources of information on drug
interactions. Read the Drug Safety Updates from the MHRA http://www.mhra.gov.uk/mhra/drugsafetyupdate
Exercise caution when prescribing at extremes of age. These patients are at higher risk due to altered
pharmacodynamics and pharmacokinetics
Neonates (first 30 days of life) are at risk of toxicity due to inefficient renal filtration, relative enzyme
deficiencies, differing target organ sensitivity, and inadequate detoxifying systems causing delayed
excretion.
Children; drugs are not extensively tested in this group, the drug may not be licensed at all or licensed
but used 'off-label', for which the prescriber is legally responsible.
Elderly; altered response to drugs (pharmacodynamics).
reduced response at receptor level (beta-blockers),
increased central nervous sensitivity (benzodiazepines)
Reduced clotting factors (increased response to warfarin).
Elderly; altered handling of drugs (pharmacokinetics) - see the BNF for specific dose reductions of
individual drugs.
Absorption- may be reduced (reduced levodopa and iron absorption may be clinically significant),
Altered distribution; generally reduced weight in the elderly with decreased body water (need to reduce
loading dose of digoxin) and increased body fat (benzodiazepines can accumulate) and decreased
binding to albumin (phenytoin).
Metabolism- reduced blood flow (propranolol), reduced liver mass (theophylline may become toxic).
Excretion- decreased renal excretion (digoxin, lithium).
Identify patients with co-existing disease which may affect drug elimination
Reduce maintenance dose of digoxin in patients with renal impairment
Reduce dose of oral propranolol in patients with hepatic disease
Identify drugs which pose risk and monitor carefully
Enzyme inducers and inhibitors- flag patient's notes to remind you and others.
Drugs with major effect on a vital process such as warfarin
Drugs with narrow therapeutic range such as digoxin, carbamazepine, theophylline, phenytoin
Drugs where loss of effect may lead to disease breakthrough such as chronic obstructive pulmonary
disease
Patient dependent on prophylactic action such as transplant patients taking ciclosporin
Counsel patients on drug action and possible side-effects, provide written information and encourage
patients to report back progress and /or side-effects
Gender – some ADRs are more prevalent in the female population. Examples of this are the increased
susceptibility of females to the toxic effects of digoxin, heparin and captopril.
The BNF provides cautionary and advisory labels for dispensed medicines. A list of drugs is provided
together with the appropriate code number of the cautionary label and advice on when counselling is
advised. This list is also reproduced within the back cover of the BNF. When prescribing any medicine it
is good practice to check this list for appropriate cautionary and advisory labels so as to reinforce advice,
which will subsequently be given by the pharmacist. For example label 5 states “Do not take indigestion
remedies at the same time of day as this medicine”. Examples of drugs that require this label are enteric
coated aspirin or diclofenac and lansoprazole capsules.
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Information for Practitioners to Relay to Patients about Interactions with Drugs.
Type of Interaction Examples Patient Information
Drug absorption inhibited
by binding, resulting in
low drug levels.
Tetracycline with minerals; alkaloids with
tannins; pectins, resins, and fibers may
bind several drugs.
Take herbs at least one hour apart,
preferably 1.5 hours apart from taking
drugs.
Drug absorption inhibited
by rapid transit time,
resulting in low drug
levels.
Diarrhea or frequent bowel movements
due to colitis or laxative intake speeds
transit of all materials through the
intestinal tract.
Treat diarrhea and avoid excessive use
of laxatives. Induction of diarrhea is
an intended treatment strategy in
Chinese medicine for nephritis.
Drug absorption and/or
elimination modified.
Saponins may improve absorption and
elimination of drugs, altering the blood
levels and rate of change of drug levels;
strongly acid or alkaline herbs may alter
absorption of drugs.
Take herbs at least 1.5 hours apart
from drugs; avoid herbal preparations
that have high saponin content.
Drugs metabolized too
slowly resulting in
elevated drug levels.
Grapefruit juice and herbs that inhibit
CYP enzyme system can result in much
higher levels of drugs in the bloodstream,
and longer persistence of the drugs.
Take herbs at least 1.5 hours apart
from drugs, preferably taking the
drugs first (so that drug metabolism is
already under way by the time the
herbs can inhibit enzyme systems).
Potassium decreased when
using cardiac drugs,
resulting in adverse
cardiac conditions.
Laxative and diuretic herbs may reduce
potassium; these types of herbs are often
given together for weight loss.
Avoid any strong laxative or diuretic
action while using cardiac drugs. To
compensate for mild diuretic or
laxative treatments, consume high-
potassium foods.
Drug action is intensified
by similar effect of herbs.
Blood vitalizing herbs and blood thinning
drugs may prevent adequate clotting;
hypoglycemic herbs and hypoglycemic
drugs may lower blood sugar too far;
caffeine or ephedrine containing herbs and
CNS stimulants disturb nerve functions.
When the drug therapy is already
addressing a particular therapeutic
goal, avoid adding an herbal therapy
with the same goal. Intensify
monitoring of blood conditions
affected by the drugs.
Drugs cause adverse
reaction to occur when
certain substances are
ingested.
MAO inhibitors can cause hypertension
when an ordinary food component,
tyramine, is ingested; some drugs can
cause severe nausea when alcohol is
ingested.
Learn the known reactions and take
reasonable steps to avoid problematic
herbs. It may be unnecessary to have
total abstinence from an herb that
reacts with a drug.
Miscellaneous: reported
drug interactions.
St. John’s wort decreases bioavailability
of indinavir.
Learn the known reactions and avoid
using the combination.
Desired drug effect is
counteracted by herb
effect.
Immune-enhancing herbs may counteract
intended immunosuppressive action of
drugs in autoimmune disorders, including
transplant rejection reactions.
If herbs with known immune-
enhancing actions are to be used, limit
the dosage to avoid counteracting the
drugs.
21
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