Lecture 20 - chemistry of drug drug interactions

Question 1

what are mechanisms of drug drug interactions

Answer 1

Pharmacokinetic interactions are those that can effect the processes by which drugs are absorbed, distributed, metabolised and excreted. Pharmacodynamic interactions occur when the effect of drug A is altered by the presence of drug B without affecting its pharmacokinetics.

Both these types of interactions can lead to enhanced (additivity/synergism) or diminished (infra additive/antagonism) drug responses.

Question 2

what are drug absorption interaction ?

Answer 2

Changes in gastrointestinal pH
Chelation and other complexing mechanisms.
Changes in gastrointestinal motility
Induction or inhibition of drug transporter proteins.
Malabsorption caused by drugs.

Question 3

describe drug distribution interactions

Answer 3

Protein binding interactions
Induction or inhibition of drug transporter proteins

Question 4

describe metabolising interactions

Answer 4

Changes in first pass metabolism
Inhibition or induction of first pass metabolism
Enzyme induction
Enzyme inhibition
Genetic factors

Question 5

describe drug excretion interactions

Answer 5

Changes in urine pH
Changes in active renal tubular excretion
Changes in renal blood flow
Biliary excretion and entero hepatic shunt

Question 6

What are the key elements of pharmacokinetic interactions in drug development and regulation?

Answer 6

These interactions are a major concern within the pharmaceutical industry and can lead to the termination of drug development projects.

Mechanistic evaluation of potential DDI’s is now routinely carried out within drug discovery projects

And a well defined profile of these interactions is required by the FDA and other regulatory bodies for all drugs and drug candidates.

These mechanistic evaluations are focussed around the family of metabolising enzymes called Cytochrome P450’s.

And Drug transporter proteins such as P-glycoprotein and other multidrug resistance proteins (MDR’s).

Question 7

what are cytocrhoem p450

Answer 7

Cytochromes P450 (CYPs) are members of the haemoproteins family.

There are over 50 individual isoforms in humans, each with different substrate specificities.

CYP’s are predominantly membrane bound proteins, and are present in most tissues in the body.

Of particular interest as CYP’s are the major enzymes involved in drug metabolism, primarily involved in phase 1 monooxygenase reactions.

Most drugs undergo deactivation by CYPs, either directly or by facilitated excretion from the body.

Many substances are also bio activated by CYPs to form their active compounds (prodrugs).

Question 8

how are drugs metabolised by cyp450?

Answer 8

Most drugs undergo deactivation by CYPs, either directly or by facilitated excretion from the body.

Many other substances however are bio activated by CYPs to form their active compounds (prodrugs etc.).

Drugs which effect CYP activity, be they inducers or inhibitors, will have an effect on the metabolic rate as well as plasma concentrations and therefore therapeutic effects of any co administered drugs.

Question 9

what are key interaction between drug in cyp450

Answer 9

Drug A and B: When Drug A (a CYP substrate) is used with Drug B (a CYP inhibitor), it can lead to increased levels of Drug A in the body, raising the risk of toxicity.

Drug A and C: When Drug A (a CYP substrate) is used with Drug C (a CYP inducer), it can result in decreased levels of Drug A, potentially reducing its efficacy.

Drug A and D: When Drug A (a CYP substrate) is used with another Drug D (also a CYP substrate), it can lead to variable outcomes. There can be an increase or decrease in the levels of Drug A or Drug D, which could affect the efficacy or toxicity of either drug.

Question 10

describe inducers and inhibitors of cyp450

Answer 10

Inducers have a gradual onset and offset (Involves increased DNA transcription and synthesis of new CYP enzymes)

Onset and offset (Depends on t1/2 of inducer, time to make new CYP proteins, and rate of degradation of CYP proteins).
t
Onset of inhibition can be rapid and long lasting depending on the exact mechanism of inhibition

There are two major mechanisms by which a compound can inhibit the CYP enzymes: oxidative metabolism can lead to a reactive intermediate capable of alkylating either the protein or prosthetic heme group.

Alternatively if the inhibitor contains an amine functional group, N-oxidation can lead to the formation of an irreversible metabolic intermediate (MI) complex between a nitroso group and the heme iron.

examples of inducers include Examples include Rifampicin, Carbamazepine, Phenobarbital, Phenytoin, Nevirapine, Pioglitazone, and St John’s wort.

examples of inhibitors include Sulfamethoxazole, Amiodarone, Cimetidine, Fluoxetine, Fluconazole, and Ritonavir.

Question 11

what are adverse interactions with cyp450 ?

Answer 11

Amiodarone (AMIO) is a class III antiarrhythmic agent, used widely to counter serious arrhythmias, and atrial fibrillations.

amiodarone is known to react with a large number of drugs due to m inhibition of cyp450 mediated metbaolism raising exposure to the vicitim drug

Four specific P450 enzymes are implicated in the majority of these DDIs: CYP1A2, CYP2C9, CYP2D6, and CYP3A4.

AMIO, itself, appears to be a fairly weak inhibitor of these enzymes which raises the possibility that inhibitory metabolites play a more direct role than the parent drug.

AMIO as one of the few pharmaceuticals to cause a metabolism-dependent clinical DDI due entirely to an inhibitory metabolite(s), with little to no contribution from the parent drug.

Question 12

describe ritonavir interactions with cyp450 ?

Answer 12

Ritonavir is an antiretroviral medication used along with other medications to treat HIV/AIDS. This combination treatment is known as highly active antiretroviral therapy (HAART).

Rotonivir has been surpassed in term of its protease activity by subsequent generations of inhibitors such as saquinavir and lopinavir etc. it is now rarely used for its own antiviral activity, but remains widely used as a booster of other protease inhibitors.
These properties arise from ritonavir’s off target inhibitory activity against CYP3A4

Question 13

cdescribe P-glycoprotein

Answer 13

P-glycoprotein 1 (P-gp) also known as multidrug resistance protein 1 (MDR1) is a transmembrane molecular pump which acts to protects our cells from toxic molecules.

It is the most fully characterized member of the ABC-transporter subfamily of proteins.

Responsible for transporting a wide variety of substrates across extra- and intracellular membranes.

Its cone shaped internal cavity allows it to accept a wide range of structurally diverse substrates

Question 14

what is the mchensim of action of P-lycoproetin

Answer 14

It sits in the cell membrane and searches for foreign hydrophobic molecules.

When it finds one, it grabs the molecule in a pocket deep within the protein, and then flips to a new conformation.

The new conformation has an opening towards the outside of the cell, and the molecule is ejected.

The whole process is powered by ATP to ensure that everything happens in a timely manner.

Question 15

explain the interaction between digoxin and amiodarone

Answer 15

Digoxin and amiodarone are medications commonly used in patients with heart failure and/or atrial/ventricular arrhythmias.

The co administration of amiodarone and digoxin can increase the serum concentrations of digoxin, increasing the risk of digoxin toxicity.

Amiodarone increases digoxin concentrations by inhibiting P-glycoprotein (P-gp) which facilitates the elimination of digoxin from the body.

Amiodarone may also influence serum concentrations by changing the tissue distribution of digoxin.

Question 16

what are antacids ?

Answer 16

Antacids are chemically weak bases such as hydroxides trisilicates or carbonates, formulated as salts with one of the polyvalent cations such as calcium (Ca2+), aluminium (Al3+) or magnesium (Mg2+) and used to increase gastric pH.

Question 17

what is the mechanism f action f DDIs?

Answer 17

Alteration of pH-Dependent Dissolution

Dissolution is the rate limiting step of absorption from solid dosage forms and changes can therefore lead to enhanced or reduced absorption.

A classic example are imidazole antifungal agents (such as ketoconazole and itraconazole).

Because these drugs are weak bases with an acid dissociation constant (pKa) of approximately 3.0, they are nearly insoluble at pH >4.0.

If coadministration of an antacid elevates the gastric pH to >4.0 for a period longer than the gastric empting time (for liquid: 10–20 minutes), the drug may reach the small intestine before dissolution takes place and hence absorption is decreased.

Question 18

how does chelation occur in DDI of antacids

Answer 18

Chelation
Chelation reaction may also occurs when polyvalent metallic ions (such as Al3+ andMg2+) and organic molecules can form a ring complex in solution.

Classical examples is concomitant administration of tetracycline antibacterials and a mixture of aluminium hydroxide and magnesium hydroxide (e.g. Maalox).

Coadministration of these drugs reduced the oral bioavailability of tetracycline and its analogues by ‡80%, no effect with PPI etc.

the lower tier of the tetracycline molecule contains two 1,3-diketones with two of the ketones in the enol form. Such monoenols in 1,3-diketons would chelate di- or trivalent metallic ions to form six-membered rings.
Likewise, fluoroquinolone antibacterials are thought to form complexes with polyvalentmetal cations at its 3-carboxyl and 4-oxo functional groups
these complexes are insoluble and thus cannot be absorbed into the mucosa.

Question 19

what re foo drug interactions?

Answer 19

all fruit juice and grape fruit juice (GFJ) in particular contains furanocoumarins
which inhibit intestinal CYP3A and have been shown to increase the oral bioavailability of medications which are CYP3A substrates such as felodipine midazolam and cyclosporine

some drugs which are highly protein bound may be effected by high protein diets.This type of diet can result in increase serum albumin levels as well as increased CYPP450 activity. 4Leading to increased protein binding of the drug (less free drug available to act) and enhanced metabolism by Cyp450 activation.

High dairy diets – milk products are a rich source of divalent cations such as calcium and magnesium.

As we have seen such cations can chelate to a wide range of molecules to form 5 and 6 membered ring structures (see antacids)

This leads to insoluble complexes and therefore reduced absorption.

Other milk proteins such as Casein also have a role in this reduced bioavailability.

Question 20

what are pahramcodynamci interactions?

Answer 20

Pharmacodynamic interactions occur when the effect of drug A is altered by the presence of drug B without affecting its pharmacokinetics.

These are much less studied during drug development.

Pharmacodynamic interactions can occur at the receptor (a), through changes in signalling such as secondary messengers (b), or at the effector level (c)(d).

These interactions can lead to enhanced (additivity/ synergism) or diminished (infra additive/antagonism) drug responses.

Primarily a concerns for drugs which have similar modes of action or have similar and opposing pharmacodynamic effects.

Question 21

what are Interactions at the effector level (positive)

Answer 21

ACE inhibitors with calcium channel blocking agents is a combination medicine often used to treat hypertension.

An ACE inhibitor blocks the angiotensin-converting-enzyme from converting angiotensin I to angiotensin II.

Calcium channel blockers block calcium from entering cells of the heart and smooth muscle in the walls of blood vessels. This results in vasodilation of the arteries, a reduction in heart contraction force, a slowing of heart rate and a reduction in aldosterone production.

These effects cause a decrease in blood pressure in the hypertensive patient and a decrease in symptoms in patients with angina or ischemic heart disease.