Friday, February 8, 2019

Pharmacodynamic Drug-drug Interactions

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I Pharmacodynamic interaction:

Pharmacodynamic drug Interactions
PHARMACODYNAMIC INTERACTIONS
In pharmacodynamic DI there is a change in a personal response on the administration of a drug is a significant factor in PDI. These changes are particularly tough to categorize given through several different mechanisms. 

This wide variety also means that in all but the most understandable cases it is important to examine and know these mechanisms. The well-founded feeling exists that there are more unidentified interactions than known ones. At some point the medications straightforwardly vie for specific receptors e.g. beta-2 agonists, for example, salbutamol and beta-blockers, for example, propranolol yet regularly the response is more roundabout and includes the impedance with physiological systems. These communications are a great deal less simple to group about than those which are pharmacokinetic.

Epidemiology:

The purpose of this to focus on hospital admissions which are caused by a specific type of ADR that can be expected to be preventable in almost all cases. The use of multidrug can increase the risk of DD. Aging of the population and the increasing number of available drugs show the importance and awareness of DI in both clinical and forensic works.

The incidence of combinations of the drug having serious ADI was generally low i.e 0.71%  but it was noted for the two individually drugs studies a common anticoagulant warfarin 33% and new-generation antidepressant venlafaxine 46%. The toxicity of serotonin and adverse cardiovascular effects were the most prominent possible adverse outcomes.


Polypharmacy is common in the children's hospital in the United States and has been known as a major risk factor for exposure to potential drug-drug interactions. In hospital admission, the reported incidence of drug-drug interaction ranges from 0% to 2.8% in a review which includes nine studies all of which had some design faults. In Harvard medical practice AE is 8% whereas in US OPD have 10% DI out of 50 patient.

Risk factor:

The risk factor in a patient includes i.e polypharmacy, multiple prescribers, multiple pharmacies, genetic, specific population such as females, malnutrition, critically ill patient, and narrow therapeutic index drugs. One-third of the population was visible to polypharmacy, and 6% were showing to potential DI for 1 year. Patient factors related to improved possibility of potential DI were high age or a high number of concurrent drugs used and a high number of prescribers [16].

The outcome of drug interaction:

  • loss of therapeutic effect.
  • Toxicity.
  • an unexpected increase in pharmacology activity.
  • Beneficial effect.
  • Chemical or physical interaction

Factor contribution to the occurrence of drug-drug interaction:

pharmacokinetic interaction.
multiple pharmacological effects.
Multiple prescribers.
Use of otc medication.
Patient non-compliance.
Drug abuse.

Pharmacokinetic interaction:

Significantly change the PK profile and result in the DI in the situation that interferes with the distribution, absorption, metabolism, or excretion of drugs. Such interaction has the potential to decrease the suitability or rise the danger of toxicities of influenced specialists.

Multiple pharmacological effects:

 Most of the drugs utilized as a part of the current treatment can impact numerous physiological frameworks. There are two medications are direct together that will frequently influence a portion of the same system. The potential medication association between the medications, they're regularly the propensity just to be worried about the essential impact of the medication is included and to ignore the auxiliary exercises they have.

Consolidate treatment with a phenothiazine antipsychotic e.g. chlorpromazine, a tricyclic energizer e.g. amitriptyline, and an antiparkinson operator e.g. trihexyphenidyl is a started in some patient. It has considered the different primary effects of each agent. However, the anticholinergic activity of all three possesses. Any of the medications might be slight in the anticholinergic impact; the added substance impacts of the three specialists might be critical.

Multiple prescribers:

It is exceptionally fundamental for some individuals to check more than one doctor and to be seeing at least one authority notwithstanding a family doctor is very common for a patient e.g. dental specialists, podiatrists who might be recommending the medicine. It is extremely troublesome for one prescriber to know about all the solution that has been recommending by others for a specific patient and such circumstance consummation could emerge.

For instance, one doctor may endorse a pharmaceutical competent for bringing about sluggishness or tiredness e.g. certain antihistamine, opioid analgesic for a patient for whom another physician has prescribed an antianxiety agent of an excessive depressant effect with possible consequences. The patients have seen the different physician he or she frequently will have the remedy apportioned by a similar drug store. In this manner, the drug specialist can assume an imperative part of the identification and counteractive action of medication-related problems.

Use of otc drug:

 Many people hide the use of OTC drugs while possible for numerous drug used in little
era may have the same API but work inversely then incite side
effects. Usually, when using prescribed drugs along with OTC e.g. aspirin, antacids, and
decongestant, etc measured having incompliance to patients. The interaction also may result from the simultaneous utilization of at least two items accessible without a remedy.


Increase the risk of an excessive response to these agents with two nonprescription products promoted for different purposes contain the same active ingredient in the same situation. Acetaminophen is included in many products for its action is antipyretic and analgesic and is included nonprescription sleep-aid formulation. They purchase for the different conditions may contain the same active ingredients that the patient is unaware of the products and therefore with the use of products increased risk of the problem they might assume to be safe because they do not require a prescription.


Patient non-compliance:

For a variety of reasons, many patients do not take the medication in the manner intended by the prescription. Some patient does not receive proper instruction from the prescriber and pharmacist as to how and when taking their medication. In some cases the patient is particularly involving that have taken to the other medication, confusion about the instruction may develop even though the patient may have understood them initially.

It is understandable that the older patient who may have may be taking five or six medication at several time a day at a different time can become confused or forget to take their medication, although these occurrences are by no means unique to the geriatric population, In the situation involving in the noncompliance usually a result in a patient are not taking enough medication, some circumstances could lead to use excessive of the medication that why increasing the drug interaction.
 For example, some patient has forgotten a dose of the medication, then in the next time, double medication can be taken. Some other patients may act on the assumption that if one tablet dose that has been prescribed provides partial but not complete relief of symptoms, a two tablet dose will be even more effective.

Drug abuse or misuse:

Some drugs are individual to manhandle or intentionally abuse medications may likewise prompt to an expanded frequency of medication connection. The antianxiety specialists, opioid pain-relieving, and amphetamines are among the operator frequently manhandled, and the wrong utilization of these medications can bring about various issues, including an expanded potential for medication communication.

Mechanism of drug-drug interaction:

Altered bioavailability:

This alteration may occur when the amount of object drug reaches the systemic circulation which is interfered with by perpetrator drugs. This only occurs when orally drug administered and absorption or first-pass metabolism is changed. The drug which has low oral bioavailability is mostly effected but those who have high bioavailability are less effected e.g. Alendronate has low oral bioavailability. Alendronate co-administration with calcium decrease bioavailability and the result is no absorption of Alendronate. On other hand co-administration of dabigatran with verapamil increase bioavailability and can result in an increased risk of bleeding .


Altered metabolism:

Changes in the metabolism of a drug is very important causes of unexpected drug interaction. These occur when as a result of changing in drug clearance or oral bioavailability. There is some enzyme family that is involved in drug metabolism i.e CYP450 which is the most important for drug metabolism. In this one drug induce these enzyme for other drug so metabolism is affected.
Inhibition of CYP450 increase the conc of some drugs by decreasing its metabolism


e.g. clarithromycin is a strong antagonist of CYP3A catalyst simvastatin metabolism. Thus increasing the risk of myopathy as observed. Drug inhibition of CYP450 is also used as a therapeutic monitoring tool e.g. ritonavir an antiviral agent which is a strong inhibitor of CYP3A which reduces the metabolism of other protease inhibitors and thus increasing their effectiveness in treating HIV.
Induction of a CYP450 decreasing the conc of some drugs by increasing their metabolism e.g. carbamazepine is a strong inducer of CYP3A that increases the metabolism of the combined oral contraceptive, thus increasing the risk of unwanted pregnancy.

Prodrug:

Most of the drugs are depends upon CYP450 for conversion to their active state. As this is usually depending upon a single enzyme pathway. Prodrugs are particularly prone to change in metabolism. Inhibition of such enzyme may lead to prevent the conversion of prodrugs to active drugs which may lead to inappropriate conc of the active drug and therapeutic failure e.g tamoxifen is metabolized by CYP2D6 to its active form endoxifen and concomitant therapy with strong CYP2D6 inhibitor paroxetine has been associated with the increased death rate in breast cancer.

Altered distribution:

This occurs when the conc of the drug at the side of the action is altered without necessarily changing its circulation conc. This is a particular problem with those drugs which target the intracellular or central nervous system. Most drugs cause more alteration in the cell membrane transport of other drugs e.g. verapamil inhibits efflux transporters i.e P-glycoprotein increasing the conc of substrates such as digoxin and cyclosporine. Probenecid block anion transport result in increasing the conc of substrates such as methotrexate and penicillins. DI involved in transport is less understood as compared to DI involving metabolism.

Altered clearance:

This can also occur when excretion or metabolism of the OD is effected by a perpetrator drug. OD with a narrow therapeutic index drug is mainly effected, as modest changes in conc may be clinically imported. Perpetrator drugs known to strongly affect drug metabolism are more likely to cause large conc in alterations and hence clinical consequence as observed.

Altered excretion:

Some of the drugs are eliminated from the body in the unchanged form usually in the urine or with biliary tract in the stool. Changes in the drug clearance may result due to effects on renal tubular function or urine PH e.g. probenecid decrease the renal clearance of anionic drugs such as methotrexate and penicillin.

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