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TPTC2 > Mechanisms of drug interactions > Flashcards

Mechanisms of drug interactions Flashcards

1
Q

What is drug interaction?

A

the modifications of effects of one drug by another drug (poly-pharmacy)

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2
Q

What is drug interaction? Pharmacodynamics (PD)

A

(“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

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3
Q

What is drug interaction? Pharmacokinetic (PK)

A 
(“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
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4
Q

Effects of drug interaction
Increased effect: Additive or Synergistic
effect

A 
BAD - Increased toxic effect 
GOOD - Increased therapeutic effect
to produce synergistic therapeutic effects
e.g. several antibiotic combinations
Penicillin-Streptomycin
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5
Q

Effects of drug interaction

Decreased effect: Antagonistic effect

A

BAD - Decreased therapeutic
effect
GOOD - Decreased toxic effect to detoxify or lower toxic effects, e.g. antidotes of
certain toxic agents

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6
Q

PD drug interaction

A

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

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7
Q

PK drug interaction

A 
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
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8
Q

PK interactions (1): Absorption a)

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.

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9
Q

PK interactions (1): Absorption b)

A

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

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10
Q

PK interactions (1): Absorption c)

A

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

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11
Q

PK interactions (1): Absorption d)

A

d) Chelation; EX1., Tetracycline interacts with iron preparations -> unabsorpable complex

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12
Q

Changes in absorption

Chelation

A

Alteration/ action

Chelation - Iron may chelate ciprofloxacin, resulting in decreased absorption

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13
Q

PK interactions (2): Distribution

A

• 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

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14
Q

PK interaction (3):Metabolism

A

the most drug-drug interactions are metabolism based (diagram)

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15
Q

Drug metabolism

Phase I metabolism:

A

Phase I metabolism: involves oxidative metabolism via the Cytochrome P450 (CYP) family of enzymes

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16
Q

Enzymatic induction

A

• 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

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17
Q

Enzymatic induction example - Enzyme induction

A

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

18
Q

Enzymatic inhibition

A

• 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

19
Q

Enzymatic inhibition example

A

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

20
Q

Enzymatic inhibition example 2

A

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

21
Q

PK interaction (4): Excretion

A

• 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

22
Q

Active tubular secretion

A

-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.

23
Q

Passive tubular reabsorption

A
  • 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
24
Q

Pharmacokinetic drug interactions

A 
• Changes in GI absorption
• Displacement from plasma protein binding
• P450 Mediated
– Enzyme inhibition
– Enzyme induction
• Decreased renal elimination
25
Q

Drug-Herb interactions

A 
• St John’s Wort
e.g. cyclosporine
• Ginkgo biloba
• Kava
• Garlic
26
Q

Drug-Food

interactions

A

Warfarin (diagram)

Vitamin K-containing foods

27
Q

Drug-Food interactions EX2.,

A

Tetracycline interacts with Milk (Ca2+ ) -> Unabsorpable complex

28
Q

Drug-Disease interactions

A

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

29
Q

Drug-Disease interactions:

Contraindications of atropine

A

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)

30
Q

Changes in absorption

Alteration -GI motility

A

Alteration/ action

GI motility - Increased GI motility caused by metoclopramide may decrease cefprozil absorption (Marathe et al., 2000)

31
Q

Changes in absorption

Alteration -GI pH

A

Alteration/ action

GI pH - GI alkalinization by omeprazole may decrease absorption of ketoconazole

32
Q

Changes in absorption

Alteration -GI flora

A

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

33
Q

Changes in absorption

Alteration -Drug metabolism in wall of intestine

A

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
34
Q

Drug metabolism - Phase II

A

Phase II metabolism: conjugates the previously oxidized molecule with a water soluble weak acid (glucouronic acid, tauric acid, etc) enhancing overall water solubility

35
Q

How to do drug-drug interactions occur

A

Drug-drug interaction always due to interaction at phase I enzymes (i.e. cytochrome P450)

36
Q

Passive tubular reabsorption example 1

A

-Ex1., Sodium bicarbonate. Increases lithium clearance and decreases its action

37
Q

Passive tubular reabsorption example 2

A

-Ex2., Antacids Increases salicylates clearance and decreases its action

38
Q

What happens when pH increases

A

Ionisation doesn’t occur as it only occurs at acidic pH

39
Q 
PK interactions: Absorption
a)
b)
c)
d)
A

a) altered pH
b) altered motility
c) altered intestinal bacteria flora
d) chelation

40
Q

which drugs have strong affinity

A

Phenytoin (90%)
Tolbutamide (96%)
Warfarin (99%)

41
Q

which drugs have weak affinity

A

Aspirin
Sufonamides
Phenylbutazone

42
Q

Non selective antimuscarinic drugs should never be used to

A

Non selective antimuscarinic drugs should never be used to treat acid-peptic disease.

TPTC2 (8 decks)

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