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Drug interactions

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by

Nick Haddington

on 15 September 2014

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Transcript of Drug interactions

Drug interactions
Pharmacokinetic
Can be classified as...
Pharmacodynamic
Absorption
Distribution
Metabolism
Excretion
1. Effects on gastric pH

2. Adsorption, chelation and complexing

3. GI motility

4. Transporter protein induction/inhibition
(drugs into/out of cells in the intestine)
1. Protein binding

2.Transporter protein induction/inhibition (drugs into/out of tissues)
1. First-pass metabolism
(enzymes and blood flow)

2. Enzyme induction

3. Enzyme inhibition

(Genetic variation)
1. Urinary pH

2. Active tubular renal excretion

3. Renal blood flow

4. Biliary excretion
(and the entero-hepatic shunt)
Generally, these interactions are either mediated via:

1. Different drug acting at the same receptor site

2. Different drugs either having the SAME or OPPOSING pharmacological effects via different mechanistic routes
Gastric pH
Itraconazole:
Antifungal drug, used commonly in haematology for prevention/treatment of fungal infections in the immunocompromised

POORLY SOLUBLE BASE

(PHYSICOCHEMICAL PROPERTIES)


Solubility and absorption REDUCED by other drugs that alkalinise (relatively) the stomach - i.e. PPIs (e.g. omeprazole) and H2 receptor antagonists (e.g. ranitidine)

This is LESS of a problem with itraconazole LIQUID than the capsule, but liquid is sometimes POORLY tolerated
(DRUG FORMULATION)

This interaction can be reduced by giving itraconazole with an acidic CARBONATED DRINK, like cola! (IMPROVING BIOAVAILABILITY)
Adsorption/Chelation
cf MEDICINAL CHEMISTRY

Doxycycline is an antibiotic, the structure of which is a tetracyclic ring

Commonly used to treat a range of infections, including skin and soft tissue infection (SSTI), and lower respiratory tract infections (LRTI)

The ring has a number of CHELATION sites (STRUCTURE ACTIVITY RELATIONSHIPS) adjacent ketone groups means that it can chelate divalent metals (including Fe2+)

Therefore need to avoid giving IRON SALTS and ANTACIDS at the same time


COLESTYRAMINE is a bile acid sequestrant (binds bile acid)

It also binds to a number of drugs in the gut, preventing them from being absorbed

Other drugs should be taken 1 hour before and/or 4-6 hours after colestyramine!
Transporter proteins
(p-glycoprotein) in the gut
Drug transporter proteins in the cells of the wall of the gut usually act by ejecting drugs back into the gut lumen, thereby reducing systemic absorption

If the expression of these transporter proteins is INDUCED, the transporters will eject MORE drug back into the gut, and therefore absorption will be REDUCED

RIFAMPICIN induces expression of p-glycoprotein, which in turn reduces the amount of digoxin that is absorbed - reducing exposure.

(Although the clinical significance of this is probably not great)
These interactions can manifest as...
Beneficial
effects

Adverse
effects

Hypertension
Ever been irritated when an automatic interaction detection system in a dispensing program warns you that using an ACE-inhibitor and a calcium channel blocker together might lower blood pressure together?
Most of the time, we are using these together INTENTIONALLY because we WANT this drug interaction.
Oxycodone and naloxone
Naloxone is a pure opioid competitive antagonist given IV to reverse opioid toxicity

It has also been formulated in a tablet along with oxycodone

The naloxone is NOT (appreciably) absorbed, so does not antagonise the opioid systemically

It does however antagonise the oxycodine at the mu opioid receptors in the GUT, where (otherwise) the oxycodone would be acting, increasing the risk of CONSTIPATION
Parkinsons Disease
Simplistically, PD is a deficit of DOPAMINE in certain areas of the brain, leading to movement disorders.

Metoclopramide is an antiemetic and a dopamine antagonist

Metoclopramide crosses the blood brain barrier, and antagonises dopamine in the brain, counteracting dopamine given therapeutically to releive the symptoms of PD (probably)
(Can also be beneficial or adverse)
Peripheral dopa-decarboxylase inhibitors
These are given WITH LEVODOPA in oral preparations used to treat Parkinson's disease (e.g. co-beneldopa, co-careldopa)

Dopamine cannot cross the blood brain barrier, so it must be given as levodopa, which is then metabolised by dopa-decarboxylase in the brain to the active dopamine.

HOWEVER, dopa-decarboxlase is also present elsewhere in the body, so dopamine would also be produced outside the brain, resulting in systemic side effects of dopamine peripherally (e.g. constipation, nausea).

Giving a PERIPHERALLY ACTIVE DOPA-DECARBOXYLASE INHIBITOR reduces peripheral production of dopamine, and reduces side effects

A BENEFICIAL and INTENIONAL drug interaction
Inhibitors, Inducers and substrates
Remember, when thinking about LIVER ENZYME mediated drug interactions, drugs can be:

A SUBSTRATE for an enzyme
An INHIBITOR of a(n) enzyme(s)
An INDUCER of a(n) enzymes(s)

AND combinations of the above!
Omeprazole and Clopidogrel
Macrolides and Quinolones
Full transcript