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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

21

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