Drug Interactions & effect of

age on drug use

Prof ChM. Dr. Zamri Chik PhD.

Department of Pharmacology

[email protected]
 Drug interactions

• Occur whenever the diagnostic, preventive and therapeutic

action of a drug is modified in the body by other drugs or
substances
• Outcomes
– Loss of therapeutic effect
– Unexpected increase/decrease in pharmacological activity
– Drug toxicity
– Beneficial / harmful effect

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 Risk factors

• High risk patients

– Elderly, Neonates/Infants etc.
– Very sick, multiple disease
– Multiple drugs therapy
– Renal/liver impairment,
– Etc.
• High risk drugs
– Narrow therapeutic index drugs
– Recognized as enzyme inhibitors or inducers
– Recognized as highly bound to plasma protein
– Etc.

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 Risk factors
Type of Drugs List
Narrow therapeutics Index (NTI) Warfarin
Digoxin
Phenytoin
Theophylline
Cyclosporin,
Aminoglycosides antibiotics, etc.
Enzyme inducers Rifampicin
Carbamazepin
Phenobarbitone, etc
Enzyme inhibitors Cimetidine
Quinidine
Erithromycin
Ketoconazole, etc.
Highly plasma protein bound Warfarin
NSAIDs

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 Therapeutic dose

[C]p
Maximum toxic concentration

Minimum Effective concentration

Time

– Drug dose given for the [C]p within the

therapeutic window
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 Mechanisms of drug interactions
Pharmacology

Drug
Body

Blood Tissue Drug receptor

concentration concentration interaction Effect

Pharmacokinetic Pharmacodynamic
drug interactions: drug interactions:
ADME Duplication, antagonism etc.

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 Drug interactions

Drug-drug interactions
Drug-chemical
interactions Drug-food/beverage
interactions

DRUG INTERACTIONS

Drug-herbs interactions

Drug-disease
interactions

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 Drug-drug interactions
• When several drugs are use concurrently, they increase the risk
of drug-drug interactions
– The more drugs a patient takes, the greater the likelihood that an adverse reaction
will occur
– Disproportionate increase, hence indicating drugs interacting together
• Harmful effect;
– Most drug-drug interactions are harmful such as increase in efficacy and increase in
toxicity or reduce in efficacy. E.g. aspirin + warfarin
• Beneficial effect
– Enhance the effect of another drug such as the use of L-Dopa with carbidopa
– Carbidopa inhibits the conversion of L-Dopa to Dopamine in the circulation, hence
increases L-Dopa uptake into the brain
– Neostigmine reverses muscle paralysis induced by vecuronium, etc.

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 Absorption
• One drug may alter the absorption of another drug. E.g.
– Altered GIT absorption; altered pH, bacterial flora, formation of complexes/chelates
etc.

Antacids
Decreases the pH

H2 antagonist

Decrease the tablet

dissolution
of ketoconazole
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 Absorption
• Altered intestinal bacterial flora
– Increase toxicity of certain drugs such as digoxin
In 10% of patients received digoxin,
about 40% of administered dose is
metabolized by intestinal flora

Antibiotics kill the normal flora

INCREASE DIGOXIN TOXICITY

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 Absorption

• Chelation/complexation
– Cholestyramine binds several drugs such as warfarin, Penicilln G,
tetracycline, etc. therefore reduce their absorption
– Calcium chelates with antibiotics such as tetracycline
– Antacids chelate with ciprofloxacin

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 Absorption

• Other examples
– Additional of adrenaline to local anaesthetic injections;
vasoconstriction caused by adrenaline slows the absorption of LA-
prolong its action

Cosmetic dentistry procedures

Deep dental fillings
Root canal treatment
Removal of teeth
Crown and bridge work
Implants
Periodontal gum surgeries

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 Distribution
• Relevant when:
– Drugs involved highly plasma protein bound
– Drugs compete for the same site
– Displacing drug has higher affinity for binding site such as albumin

Protein binding Displacement

Phenytoin 90%
Aspirin (~ 50-80%)
Tolbutamide 96%
Other NSAIDs (95-99%)
Warfarin 99%

Increase free drug conc. Consequently increase the effect

– Other examples: Aspirin & methotrexate

**The dosage regimen of drugs need to be adjusted when they are co-
administered
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 Metabolism
• Some drugs can either inhibit or induce drug-metabolizing
enzyme
• Over 200 drugs cause enzyme induction
• Usually for orally administered drugs

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 Metabolism
• Enzyme inhibition
– Can cause increase in drug effect/adverse effect
➢ Eg. Cimetidine, metronidazole, etc. enhances anticoagulant effect of warfarin
(especially in elderly)
– Can cause beneficial effect
➢ Carbidopa + levodopa

• Enzyme induction
– Can decrease the effect of a drug,
➢ e.g. rifampicin + warfarin & phenobarbital + warfarin
– Can increase the toxicity of a drug,
➢ e.g. phenobarbitone + paracetamol (alkylating metabolite, N-acetyl-p-benzo-
quinone imine)

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 Excretions / Reabsorption
• Some drugs can cause hyperurecaemia and uricosuric effect due to reduce uric acid
secretion and reabsorption

• Also other interactions such as lithium and thiazide diuretics

− Loop and thiazide diuretics indirectly increase the tubular reabsorption of
lithium
• Large doses of vitamin C increases urine’s acidity, thus decreases the excretion of
acidic drugs, e.g. aspirin or increase excretion of basic drugs, e.g. pseudoephedrine

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 Pharmacodynamic
• Alteration of the drug action without changing in its serum
concentration by pharmacokinetic factors. E.g.
– Synergism = 1+1 = 3
– Additive = 1+1 = 2
– Potentiation = 1+0 = 2
– Antagonism = 1+1 = 0 or 0.5

• Duplication
− When the two drugs with similar actions given concurrently (synergistic and
additive effects)
E.g. Warfarin and aspirin

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 Pharmacodynamic
• Potentiation
– Sildenafil inhibits photodiesterase that inactivate cGMP, consequently potentiate
organic nitrate
– Cause severe hypotension
• Opposition (antagonism)
– E.g. NSAIDS + hydrochlorothiazide.
– Propranolol and Salbutamol
– Naloxone & morphine
– Tramadol, buprenorphine and morphine
– Etc.
• Physiological antagonism
– E.g. Doxapram reverses respiratory depression caused by morphine

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 Drug-food interactions
• Foods can interact with drugs in various ways
– Foods can retard drug absorption of many drugs but may
increase absorption of certain drugs, such as griseofulvin
– MAO inhibitors such as phenelzine with tyramine containing
food, such as fermented cheese, beef or chicken liver,
avocados, etc.
• Causes severe hypertension
– Triamterene (K2 sparing diuretic) blocks the excretion of
potasium. Avoids potassium rich foods such as bananas,
oranges and green leafy veg.
• May cause hyperkalaemia
– Avoid taking foods with high vit. K (e.g. spinach) when taking
anticoagulant

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 Drug-beverage interactions
• Milk can reduce absorption of
tetracyclines (chelate to Ca++ in milk)
• Grapefruit juice can cause microsomal
enzyme inhibition (reduced CYP3A).
• Alcohol
– Single may inhibit and chronic may induce
microsomal enzyme
• Caffeine and Xanthine beverages
(Chocolate, coffee, cola, etc.)
– can enhance the effect of theophylline

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 Drug-alcohol interactions
Alcohol-Drug Interactions
Drug Interaction
- increased amount of drug required to induce loss of
Anesthetics
consciousness
(ex: Diprivan, Ethrane, Fluothane)
- increased risk of liver damage
- reduced drug effectiveness
Antibiotics
- nausea/vomiting
- increased sedative effects
Antidepressants
- may decrease effectiveness of anti-depressant
(ex: Elavil)
- potential for dangerous rise in blood pressure
- reduced drug effectiveness
Antidiabetic medications - nausea
- headache
Antihistamines - intensified sedation
(ex: Benadryl) - excessive dizziness
- intensified sedation
Antipsychotic medications
- impaired coordination
(ex: Thorazine)
Antiseizure medications - decreased protection against seizures
(ex: Dilantin) - increased risk of drug-related side effects
Antiulcer medications
- increased presence of drug ⇒ increased risk of side affects
(ex: Tagamet, Zantac)
Cardiovascular medications - extreme dizziness or fainting
(ex: nitroglycerin, Apresoline, Ismelin, - reduced drug effectiveness
Narcotic pain relievers - intensified sedation
(morphine, codeine, Darvon, Demerol) - increased possibility of a fatal overdose
*Adapted from the National Institute on Alcohol Abuse and Alcoholism © Zamri Chik
"Alcohol Alert" January 1995 No. 27 PH 355 publication
 Drug-herbs interactions
• Supplements may intensify or reduce the effectiveness of a
prescription’s drug or cause a serious side effect.
– Patient should consult doctors, so that such interactions can be
avoided.
• Ginkgo biloba which popularly used among elderly to improve
cognitive function can interact with:
– Aspirin, warfarin, vitamin E, to cause bleeding
• Green tea
– decreases calcium absorption
• E.g. garlic, ginger, and ginseng
– Increase the risk of bleeding with anticoagulants, aspirin etc.
• Herbs with unknown interactions
– Recommended to take it 1 hour before or 2 hours after taking
drugs

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 Drug-herbs interactions
Name of Herb Some Common Uses Possible Side Effects or Drug Interactions
Garlic is used for lowering blood
Garlic may increase bleeding, especially in patients
cholesterol, triglyceride levels and
Garlic already taking certain anti-clotting medications.
blood pressure.
Ginger is used for reducing nausea, Ginger may increase bleeding, especially in patients
Ginger vomiting and vertigo already taking certain anti-clotting medications.
Ginkgo, also called ginkgo biloba, is
used for increasing blood circulation Ginkgo may increase bleeding, especially in patients
Ginkgo and oxygenation and for improving already taking certain anti-clotting medications.
memory and mental alertness.
Ginseng may cause decreased effectiveness of certain
Ginseng increases physical stamina anti-clotting medications. Persons using ginseng see
Ginseng and mental concentration. increased heart rate or high blood pressure. It may
cause bleeding in women after menopause.
Goldenseal is used aas a mild
Goldenseal may worsen swelling and/or high blood
laxative and also reduces
Goldenseal pressure.
inflammation.
Kava-kava may increase the effects of certain anti-
Kava-kava is used for nervousness, seizure medications and/or prolong the effects of certain
anxiety or restlessness; it is also a anesthetics. it can enhance the effects of alcohol. It may
Kava-kava
muscle relaxant. increase the risk of suicide for people with certain types
of depression.
Licorice is used for treating stomach Certain licorice compounds may cause high blood
Licorice ulcers. pressure, swelling or electrolyte imbalances.
Saw Palmetto is used for enlarged People using saw palmetto may see effects with other
Saw Palmetto prostate and urinary inflammations. hormone therapies.
St. John's Wort is used for mild to
St. John's Wort may prolong the effect of certain
moderate depression or anxiety and
 Drug-disease interactions

• Disease can affect drug response

• Affect pharmacodynamic and pharmacokinetic of drugs
• Hepatic and renal disease
– Liver Cirrhosis can increase bioavailability for drugs with high first pass
metabolism
– Kidney disease can affect drug excretion, increase toxicity

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 Drug-disease interactions
• GIT disease
– Malabsorption
– Achlohydria decreases aspirin absorption by increasing its ionisation
• Hyperthyroidism - β-adrenoceptors in heart, therefore
reduces β blockers effect
• β blockers taken for heart disease may inhibit
glycogenolysis in diabetic patients
• Aspirin should be used in great caution in patients with
haemorrhagic disorders such as hemophilia

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 Predictability of drug interactions

• List of drug-drug interactions are available:

– British National Formulary (BNF)
– Pharmacology text book, etc.
• The list provide guidance on the possible interactions and
do not always mean the interaction will produce ADR
• ADR depending on:
– The presence or absence of factors that predispose to ADR such as dose,
therapeutic index, disease, organ functionality, etc.

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 Prevention of drug interactions

• Aware of patients’ history on medication/ alternative medicine, current

disease/organs functionality
• Monitoring blood level of some drug with narrow therapeutic index
(TDM) e.g. digoxin, phenytoin etc.
• Monitoring therapy and making adjustments
• Monitoring some parameters that may help to characterise the early
signs of interaction or toxicity. E.g. warfarin → monitor protrombin
time, etc.

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Effect of age on drug use

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 Age classifications
• Most drugs developed and tested in young to middle age adults
• Formulations often are inadequate for administration in children and
older people
• Different in body size, composition and functions

Class Age
Neonates 0-28 days
Infants >28days-12 months
Toddler >12-36 months
Preschool child 3-6 years
School age child 7-12 years
Adolescent 12-18 years
Adult >18 years
Elderly >60 years

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 Neonates/infants
Pharmacokinetics effects
Absorption & distribution

Absorption
Intestinal fluids and the permeability of the Distribution
gut vary during childhood. Vd changes throughout childhood as stores of
Absorption is affected by changes in gastric fat and water change.
pH which < during infancy Infants have a higher percentage of
extracellular water, and stores of body fat
Increase absorption of basic drugs increase throughout childhood.
Infants are at higher risk of toxicity via skin Changes in Vd can alter the drug’s half-life,
absorption (methaemoglobinaemia with etc.
topical anaesthetics)

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 Neonates/infants
Pharmacokinetics effects
Metabolism & Excretion

May have lower GFR

Hepatic / renal Deficient drug- (20% of adults value)
function are not as metabolizing enzymes
E.g.
effective as adults E.g.
Can prolong t1/2 of
E.g. Lack of UDP-glucuronyl renally eliminated drugs
Less efficient to transferase enzyme
system e.g. gentamicin has t1/2 of
eliminate the drugs >18 h in premature
Prolong the effects or - ‘grey baby’ syndrom due newborn babies
increase toxicity to chloramphenicol compared to 1-4h in
adults

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 Paediatric dosing
• Pediatrics dosing normally extrapolated from adults using certain formulas
• Children development during early childhood which can dramatically affect the
pharmacokinetics of different drugs.
• Dosing information for obese children is limited. Obese children should be dosed
using ideal body weight and the dose adjusted based on clinical effect.
– E.g. Higher risk of toxicity from drugs such as paracetamol that do not
distribute into fat, if actual weight is used to calculate the dose.
• Lack of pediatric clinical trials and dosing information has been highlighted by the
USFDA and the EMA as areas of clinical need
– A requirement for more pediatrics data in the evaluation of new drugs.

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 Age - Elderly
• Elderly undergoes many physical changes as part of ageing process
– Less effective absorption, distribution
– Changes in body composition such as body mass, serum albumin, water, fat,
etc.
– Decrease in total body water (due to decrease in muscle mass) and increase in
total body fat affects volume of distribution
– Water soluble drugs (lithium, alcohol, digoxin etc.)
• Serum levels may go up due to decreased volume of distribution
– Fat soluble drugs such as diazepam:
• Half life increased with increase in body fat

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Plasma Half life and Age

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 Effect on Organs-Pharmacokinetics

Stomach & Duodenum Heart- Distribution

- Absorption • Reduced elasticity and
• The main changes in the compliance of the aorta and
secretion of hydrochloric great arteries causes higher
acid and pepsin, which systolic arterial pressure.
are decreased under • A decrease in the rate of
basal conditions myocardial relaxation also
occurs.

Liver- Metabolism Renal-Excretion

• Reduction in liver • Renal mass decreases with
volume and liver age. This reflects the
blood flow reduction in nephrons
• Moderate alteration • Intra-renal vascular changes
of hepatic structure - reduced blood flow in the
and enzymatic afferent arterioles in the
functions cortex
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 Hepatic and Renal Disease

• Less hepatic and renal clearance

– Less hepatic blood flow and metabolism
– Renal clearance declines with ageing (GFR reduced by up to 50%)
– After age 40, GFR decreases an average of 8 mL/min/1.73
m2/decade
• Ageing also reduces the body’s ability to breakdown
alcohol. More susceptible to liver damage by alcohol.
• Hypothermia can reduce the clearance of many drugs

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 Compliance & Polypharmacy
• Extent to which a patient is willing to
take the drug (s) as prescribed
– Does not follow the dose and dosing interval
– E.g. elderly forgot to take the medicine and children
cannot swallow the medicine
– Fear from side effects
– Limited faith in medication effectiveness, etc
– Need to check compliance before changing therapy
• Non compliance/adherence can be a
serious problem in elderly
• Concurrent medications/ multiple
dosing/polypharmacy
– Drug-drug interactions

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 Dose adjustment
• Dose adjustment in elderly
based on creatinine clearance,
etc.
— E.g. Digoxin therapy
CrClest=(140-age)BW/72⋅Scr
— Cl = 1.303(CrCl) +ClNR
• Dose adjustment in elderly
based on body weight, etc.
– E.g. AG antibiotics therapy
– Vd= 0.26 [IBW + 0.4(TBW
−IBW)]
• Paediatric Dosing: Young’s
rule, Clark’s rule, etc.

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 References
1. RANG and DALE’S PHARMACOLOGY (Ritter, Flower, Henderson, Loke, MacEwan & Rang, 9th
edition)
2. BASIC & CLINICAL PHARMACOLOGY (Ed: Katzung &Trevor, 14th edition)
3. Lippincott’s Illustrated Reviews: PHARMACOLOGY (Harvey RA, series editors, 7th edition)
4. British National Formulary (BNF): Appendix I: Interactions

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