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Transcript of drug interactions
theoretical -The more drugs a patient takes the greater the likelihood that an adverse reaction will occur Incidence of drug interactions: -An interaction is said to occur when the effects of one drug are changed by the presence of another drug, herbal medicine, food, drink . What is a drug interaction ? -Many interactions are dose-related so if the effects of the interaction are well monitored they can often be allowed for , often simply by adjusting the dosages. - An easy solution to this practical problem is to choose a non interacting alternative
( if price is not much greater ), but if none is available, it is frequently possible to give interacting drugs together if appropriate precautions are taken. How to solve this problem ? -This kind suggest that patients apparently tolerate adverse interactions
remarkably well. -Many drugs known to interact in some patients, simply fail to do so in others. How seriously should interactions be regarded and handled? -It is therefore clearly important not
to uncritically extrapolate the interactions
seen with one drug to all members of the
same group. -Some interactions can be solved by using another member of the same group of drugs.
1-The serum levels of doxycycline can become subtherapeutic if phenytoin, barbiturates or carbamazepine are given, but other tetracyclines are not affected.
2-Erythromycin causes serum lovastatin levels to rise because it inhibits its metabolism, but does not affect pravastatin levels because these two statins are metabolised in different ways -Some clinicians have become over-anxious about interactions so that their patients are denied useful drugs. -At the other extreme, there are some health professionals who, possibly because they have personally encountered few interactions, fail to consider drug interactions. -A serious reaction in a single patient don’t mean that the drugs in question should never again be given to anyone else. -Don’t depend on charts of interactions , which fail to make a distinction between interactions that are very well documented and well established, and those that have only been encountered in a single patient. Introduction Mechanisms of drug interactions 1-Pharmacokinetic 2-Pharmacodynamic A-absorption B-distribution C-metabolism E-excretion a-Synergistic b-Antagonistic 3-Methotrexate + Co-trimoxazole = Bone marrow megaloblastosis due to increased folic acid antagonism. 2-giving two or nephrotoxic drugs (Aminoglycosides , Ciclosporin , Cisplatin , Vancomycin ) = Increase nephrotoxicity. 1-Potassium sparing drugs (ACEIs , ARBs , potassium sparing diuretics ) + potassium supplements = HyperKalaemia . Examples : -If two drugs that have the same pharmacological effect are given together the effects can be additive. 1-Additive or Synergistic interactions : -they occur when the effects of a drug are changed by the presence of another drug at its
site of action either directly (on the same receptor ) or indirectly (different receptor ) . II-Pharmacodynamic interactions : Lippincott's Pharmacology 5th Edition -The coumarins can prolong the blood clotting time
by competitively inhibiting the effects of dietary
-If the intake of vitamin K is increased, the effects
of the oral anticoagulant are opposed and the prothrombin time can return to normal, thereby cancelling out the therapeutic benefits of
anticoagulant treatment .
-So we either increase the dose of coumarins
or decrease the dose of vitamin K. Example: -Occurs when the drugs effects oppose each other. 2- Antagonistic or opposing interactions: -A clear distinction must be made between those that decrease the rate of absorption and those that alter the total amount absorbed.
-For drugs that are given long-term, in multiple doses (e.g. the oral anticoagulants) the rate of absorption is usually unimportant, provided the total amount of drug absorbed is not markedly altered.
-On the other hand for drugs that are given as single doses, intended to be absorbed rapidly (e.g. hypnotics or analgesics), where a rapidly achieved high concentration is needed, a reduction in the rate of absorption may result in failure to achieve an adequate effect. 1-Drug absorption interactions : Examples :
1-PPIs decrease the absorption of Atazanavir.
2-H2 blockers decrease the absorption
of Fosamprenavir . -Rises in pH due to proton pump inhibitors ,H 2 -receptor antagonists can markedly reduce the absorption of some drugs. -The passage of drugs through mucous membranes by simple passive diffusion depends upon the extent to which they exist in the non-ionised lipid-soluble form. Absorption is therefore governed by the pKa of the drug, its lipid-solubility, the pH of the contents of the gut. Effects of changes in gastrointestinal pH: -Colestyramine binds to a considerable
number of drugs (e.g. digoxin, warfarin,
levothyroxine), thereby reducing
their absorption. -the tetracycline and quinolones can chelate with a number of divalent
and trivalent metallic ions, such as calcium, aluminium, bismuth and iron, to form complexes that are both poorly absorbed and have reduced antibacterial effects. -Activated charcoal is intended to act as an adsorbing agent within the gut
for the treatment of drug overdose or to remove other toxic materials, but
it can also affect the absorption of drugs like acetaminophen , citalopram. Adsorption, chelation and other complexing mechanisms: Color Atlas of Pharmacology 3rd Edition Only the unbound molecules remain free and pharmacologically active,
while those that are bound form a circulating but pharmacologically inactive reservoir Protein-binding interactions: 2-Drug distribution interactions: -Another important factor is clearance , Clinically important protein-binding interactions are present only if a small proportion of the drug is eliminated during a single-passage through the eliminating organ (low-extraction ratio drugs) -Only drugs with a low Vd will be affected. Examples include the sulphonylureas, such as tolbutamide (96% bound, Vd 10 litres), oral anticoagulants, such as warfarin (99% bound, V d 9 litres), and phenytoin (90% bound, V d 35 litres). - A drug that reduces the binding from 99 to 95% would increase the unbound concentration of free and active drug from 1 to 5% (a fivefold increase) . -Depending on the concentrations and their relative affinities for the binding sites, one drug may compete with another and displace it. -In vitro many commonly used drugs are capable of being displaced by others but in the body the effects seem almost always to be buffered so effectively that the outcome is not clinically important. It would therefore seem that the importance of this interaction mechanism has been grossly over-emphasised. -Most drugs that are extensively bound to plasma proteins and subject to displacement
reactions (e.g. warfarin, sulphonylureas, phenytoin, methotrexate and valproate) have low extraction ratios, and drug exposure is therefore independent of protein binding. However, knowledge of altered protein binding is important in therapeutic drug monitoring.
for example a patient taking phenytoin was given a drug that displaced phenytoin from its binding sites. The amount of free phenytoin would rise but this would be quickly eliminated by metabolism and excretion thereby keeping the amount of free active phenytoin the same. However, the total amount of phenytoin would now be reduced. Therefore if phenytoin
was monitored using an assay looking at total phenytoin levels it may appear that the phenytoin is subtherapeutic and that the dose may therefore need increasing. However, as the amount of free active phenytoin is unchanged this would not be necessary and may even be dangerous. Pharmacology An Introduction 6th edition -Some drug metabolism goes on in the serum, the kidneys, the skin and the intestines,
but the greatest proportion is carried out by enzymes of the liver cells. -most drugs are chemically altered within the body to less lipid-soluble compounds, which are more easily excreted by the kidneys. 3-Drug metabolism (biotransformation) interactions: Drugs undergo metabolism by two major types of reactions (phase 1 , phase 2) Lippincott's Pharmacology 5th Edition The majority of phase I oxidation reactions are carried out by the enzyme cytochrome P450. Cytochrome P450 is not a single entity, but is in fact a very large family of related isoenzymes, about 30 of which have been found in human liver tissue. However, in practice, only a few specific subfamilies seem to be responsible for most (about 90%) of the metabolism of the commonly used drugs. The most important isoenzymes are: CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4. Stockley's Drug Interactions, 8th Edition St. John wort induces the metabolism of Ciclosporin by induction of CYP3A4 A-Enzyme induction: A marked effect on the extent of first-pass metabolism by inhibiting or inducing
the cytochrome P450 isoenzymes in the gut wall or in the liver.
Ex: Grape fruit juice and CCBs . Inhibition or induction of first-pass metabolism: Stockley's Drug Interactions, 8th Edition -Rifampicin (rifampin) decrease the serum levels of Ciclosporin, presumably via its effects on CYP3A4. -The raised drug dosage may be an overdose when the drug metabolism has returned to normal. -It may be possible to accommodate the interaction simply by raising the dosage of the drug affected, but this requires good monitoring. -Enzyme induction interactions are delayed in onset and slow to resolve (but it may take days or even 2 to 3 weeks to develop fully, and may persist for a similar length of time when the enzyme inducer is stopped.) Notes on Enzyme induction : 3-Sodium Valproate increase serum levels of Carbamazepine by inhibition of its glucuronidation (phase 2 conjugative metabolism ). 2-Valpromide inhibits epoxide hydrolase (phase 1 hydrolytic metabolism ) resulting in increase of the plasma levels of Carbamazepine. 1-Ritonavir inhibits the metabolism of Sildenafil by CYP3A4 resulting in marked increase of the plasma levels of a single dose of Sildenafil . Examples: -More common than enzyme induction , This results in the reduced metabolism of an affected drug, so that it may begin to accumulate within the body .
-Unlike enzyme induction, which may take several days or even weeks to develop fully, enzyme inhibition can occur within 2 to 3 days, resulting in the rapid development of toxicity. B- Enzyme inhibition: Color Atlas of Pharmacology 3rd Edition - some of the cytochrome P450 isoenzymes are subject to genetic polymorphism which simply means that some of the population have a variant of the isoenzyme with different activity.
Example : CYP2D6 and Codeine -some drugs can be metabolised by more than one cytochrome P450 isoenzyme (meaning that this other isoenzyme may be able to pick up more metabolism to compensate for the inhibited pathway) -If the serum levels remain within the therapeutic range the interaction is not clinically important. Note : Individuals with multiple active copies of CYP2D6, can biotransform up to 50% more codeine into morphine than normal individuals can. In contrast, poor metabolizers individuals who
have no active CYP2D6 genes, convert almost no codeine into morphine and as a result may take multiple doses of codeine without attaining analgesia. This varying ability to metabolize certain drugs may explain why some patients develop toxicity when given an interacting drug while others remain symptom free. The renal tubular cells additionally possess active and passive transport systems for the re-absorption of drugs.
Interference by drugs with :
a-renal tubular fluid pH
b-active transport systems
can alter the excretion of other drugs. most drugs are excreted either in the bile or in the urine 4-Drug excretion interactions: Stockley's Drug Interactions, 8th Edition
-The converse is true for weak bases with pKa 7.5 to 10.5 .
-Acidic drugs will be excreted more in alkaline urine & basic drugs will be excreted more in acidic urine. -At high pH values (alkaline),
weakly acid drugs (pKa 3 to 7.5) largely exist as ionised lipid-insoluble
molecules, which are unable to
diffuse into the tubule cells and will therefore remain in the urine and get excreted -Passive reabsorption of drugs depends upon the extent to which the drug exists in the
non-ionised lipid-soluble form, which depends on its pKa and the pH of the urine. A-change in urinary PH: Stockley's Drug Interactions, 8th Edition -Drugs that use the same active transport systems in the renal tubules can
compete with one another for excretion. B-changes in active renal tubular excertion :
Increase in the clearance of Methotrexate with urinary alkalinisers such as
sodium bicarbonate and acetazolamide. -The clinical significance of this interaction mechanism is small, because almost all drugs are largely metabolised by the liver to inactive compounds and few are excreted in the urine unchanged,thus these interactions are very rare . -A number of drugs are excreted in the bile, either unchanged or conjugated.
-Some of the conjugates are metabolised to the parent compound by the gut flora and are
-This recycling process prolongs the stay of the drug within the body, but if the gut flora are diminished by the presence of an antibacterial, the drug is not recycled and is lost more quickly.
-This may explain the failure of the oral contraceptives that can be brought about by the concurrent use of penicillins or tetracyclines.
-Antimicrobial-induced reductions in gut bacteria may also reduce the activation of sulfasalazine . C-Biliary excretion and the entero-hepatic recirculation : The pumping actions of P-glycoprotein can be induced or inhibited by some drugs. -Thus it will have an impact on the :
1-drug absorption (via the intestine)
2-distribution (to the brain, testis, or placenta)
3-elimination (in the urine and bile). -This is an efflux pump found in the membranes of certain cells, which can
push metabolites and drugs out -The most well known transporter P-glycoprotein interactions: Drug transporter protein interactions : -the induction of the activity of P-glycoprotein by rifampicin (rifampin) within the lining cells of the gut causes digoxin to be ejected into the gut more vigorously which decrease the plasma levels of digoxin .
-In contrast, verapamil appears to inhibit the activity of P-glycoprotein, and is well known to increase digoxin levels . Examples : Herbal & food - Drug interactions -The American Society of Anesthesiologists recommends that all herbal medicines should be stopped two weeks prior to elective surgery. -Monitor for signs of nifedipine adverse effects such as headaches, hot flushes, dizziness and palpitations. If they become apparent, advise the patient to stop taking ginkgo. -Ginkgo may raise the levels of nifedipine
and increase its effects. 1-Ginko Biloba: Drug -Herb interaction: - Patients taking St John ’ s wort with nifedipine or verapamil should have their blood pressure and heart rate monitored to ensure that they are still effective, and the dose should be adjusted if needed. -hence it will decrease the levels of ciclosporin and digoxin .
-St John’s wort also has serotonergic properties and this has resulted in a pharmacodynamic interaction with the SSRIs = Serotonin syndrome -Evidence has shown that the herb
can induce the cytochrome P450 isoenzyme CYP3A4, and can also induce P-glycoprotein. 2- St John’s wort: -The FDA in the US has suggested that concurrent use of St John ’ s wort and protease inhibitors (mainly indinavir )is not recommended. -St John ’ s wort reduces the plasma concentrations of methadone and withdrawal symptoms may occur. -the Faculty of Family Planning and Reproductive Health Care (FFPRHC) in the UK recommend that women taking oral contraceptives (both combined and progestogen-only pills) should either avoid St John ’ s wort or they should use an additional form of contraception. -Large amounts of grapefruit juice markedly increase the plasma levels of lovastatin and simvastatin, In the US the manufacturers suggest that intake of grapefruit juice should be restricted to About 1 litre daily. -Grapefruit juice can increase the bioavailability of ciclosporin. -By chance, grapefruit juice was chosen to mask the taste
of alcohol in a study of the effect of alcohol on felodipine, which led to the discovery that grapefruit juice itself markedly increased felodipine levels.
-In general, grapefruit juice inhibits intestinal CYP3A4, and only slightly affects hepatic CYP3A4.
-This is demonstrated by the fact that intravenous preparations of drugs that are metabolised by CYP3A4
are not much affected. 1- Grapefruit juice: Drug- Food interactions : -This leads to increased cortisol levels in the kidneys and in other selective tissues. Since cortisol, which occurs in much larger amounts than aldosterone, binds with the same affinity as aldosterone to the mineralocorticoid receptor, the result is a hypermineralocorticoid effect of cortisol (fluid retention , hypokalaemia ,hypertension. -Glycyrrhizic acid is hydrolysed in the intestine to the pharmacologically active compound glycyrrhetic acid, which
inhibits the enzyme
11 betahydroxysteroid dehydrogenase -Liquorice contain glycyrrhizin (glycyrrhizic or glycyrrhizinic acid) 2-Liquorice: -There is apparently a great individual variation in the susceptibility to glycyrrhizic acid. In the most sensitive individuals a regular daily intake of no more than about 100 mg glycyrrhizic acid, which corresponds to 50 g liquorice sweets (assuming a content of 0.2% glycyrrhizic acid), seems to be enough to produce adverse effects. -Liquorice may cause fluid retention and therefore reduce the effects of antihypertensives.
-Additive hypokalaemia may also occur with loop and thiazide diuretics. Online resources Textbooks for reference Next lecture: