Mechanisms of drug interactions Flashcards
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
Effects of drug interaction
Decreased effect: Antagonistic effect
BAD - Decreased therapeutic
effect
GOOD - Decreased toxic effect to detoxify or lower toxic effects, e.g. antidotes of
certain toxic agents
PD drug interaction
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
• 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 drug interaction
The alteration of the PK or disposition (ADME) of one drug by another • Change in Absorption • Change in Distribution • Change in Metabolism • Change in Excretion
PK interactions (1): Absorption a)
a) 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)
- Ex2., H2 antagonists ncrease 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 interactions (1): Absorption b)
b) 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
PK interactions (1): Absorption c)
c) Altered intestinal bacterial flora ;
EX., In 10% of patients receive digoxin…..40% or more of the
administered dose is metabolized by the intestinal flora
-Antibiotics kill a large number of the normal flora of the intestine and Increase digoxin conc. and increase its toxicity
PK interactions (1): Absorption d)
d) Chelation; EX1., Tetracycline interacts with iron preparations -> unabsorpable complex
Changes in absorption
Chelation
Alteration/ action
Chelation - Iron may chelate ciprofloxacin, resulting in decreased absorption
PK interactions (2): Distribution
• Drugs in the bloodstream are often bound to plasma proteins;
• Only unbound drugs can leave the blood and 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)
Drug metabolism
Phase I metabolism:
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, benzodiazepines, hydantoin antiepileptics, glucocortikoids, rifampicin, griseofulvin, St. John´s wort, smoking, grilled meat, chronic alcohol
intake – increase
-Decrease the effect of several drugs, e.g.
cardiotonics, steroid hormones, coumarin
anticoagulants
Enzymatic induction example - Enzyme induction
A drug may induce the enzyme that is responsible for the metabolism of another drug or even itself e.g., Carbamazepine (antiepileptic drug ) increases its own metabolism
-Phenytoin increases hepatic metabolism of theophylline leading to decrease its level -> reduce its action
N.B enzyme induction involves protein synthesis. Therefore, it needs time up to 3 weeks to reach a maximal effect
Enzymatic inhibition
• 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
Enzymatic inhibition example
It is the decrease of the rate of metabolism of a drug by another one. This will lead to the increase of the concentration of the target drug and leading to the increase of its toxicity .
-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.
N.B; When an enzyme inducer (e.g.carbamazepine) is administered with an inhibitor (verapamil) -> the effect of the inhibitor will be predominant
Enzymatic inhibition example 2
Ex.,Erythromycin inhibit metabolism of astemazole and terfenadine -> Increase the serum conc. of the antihistaminic leading to
increasing the life threatening cardiotoxicity
EX., Omeprazole Inhibits oxidative metabolism of diazepam
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
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. cyclosporine • Ginkgo biloba • Kava • Garlic
Drug-Food
interactions
Warfarin (diagram)
Vitamin K-containing foods
Drug-Food interactions EX2.,
Tetracycline interacts with Milk (Ca2+ ) -> Unabsorpable complex
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 (Marathe et al., 2000)
Changes in absorption
Alteration -GI pH
Alteration/ action
GI pH - GI alkalinization by omeprazole may decrease absorption of ketoconazole
Changes in absorption
Alteration -GI flora
Alteration/ action
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
Alteration/ action
Drug metabolism in wall of intestine - Monoamine oxidases (MAO) in the wall of GI tract may be inhibited by MAO inhibitors resulting in increased blood pressure to phenylephrine
Drug metabolism - Phase II
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 1
-Ex1., Sodium bicarbonate. Increases lithium clearance and decreases its action
Passive tubular reabsorption example 2
-Ex2., 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
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.
