Pharmacodynamic drug interactions, Ruqshan Nazneen, SUCP

Drug interactions is said to occur if affect of one drug is altered by co- administration of another drugs. These can result in either beneficial or harmful effects
CAUSES:
Wrong choice of drug
Multiple Prescribers
Errors in taking drugs
Transmission errors
Wrong route of administration
Wrong dosage
Failing to take account of renal function
Narrow therapeutic index of drugs
Co-morbidities
Polypharmacy
Drug whose activity is affected by such an interaction is called as Object drug and the agent which precipitates such an interaction is referred to as the Precipitant.

1. DONE BY :- Ruqshan Nazneen Pharm D Sultan ul uloom college of Pharmacy, Hyderabad Guided by: Dr. S P Srinivas Nayak Assistant Professor , SUCP, HYD. PHARMACODYNAMIC DRUG INTERACTIONS

2. DRUG INTERACTIONS : Drug interactions is said to occur if affect of one drug is altered by co- administration of another drugs. These can result in either beneficial or harmful effects CAUSES: Wrong choice of drug Multiple Prescribers Errors in taking drugs Transmission errors Wrong route of administration Wrong dosage Failing to take account of renal function Narrow therapeutic index of drugs Co-morbidities Polypharmacy Drug whose activity is affected by such an interaction is called as Object drug and the agent which precipitates such an interaction is referred to as the Precipitant.

3. Types of Drug Action : Stimulation : Certain drugs act by Increasing the activity of specific organ/ system, e.g. Adrenaline stimulates the Heart resulting in an increase heart rate and force of contraction. Depression : Drugs that act by Decreasing the activity of specific organ/system, e.g Alcohol, Barbiturates, General anaesthetics depress the Central Nervous System. Irritation : some agents on Topical application can cause irritation of the skin and adjacent tissues. When an agent is applied on the skin which relieves deep seated pain, it is known as Counterirritant , e.g Eucalyptus Oil . They are useful in myalgia , joint pain and act by Blocking Impulse conduction in the Spinal cord and reflexly increasing local circulation in deeper structures. Replacement : When there is deficiency in endogenous substances , they can be replaced by drugs, like Insulin in Diabetes Mellitus and Thyroxine in Cretinism and Myxedema. Cytotoxic : Drugs that are selectively toxic for the infecting organisms/cancer cells like antibiotics/Anticancer drugs.

4. The three mechanisms by which an interaction can develop are Pharmaceutical Interactions Pharmacokinetic Interactions Pharmacodynamic Interactions PHARMACODYNAMIC INTERACTIONS : These interactions are those in which effect of one drug is altered by other drug at its site of action. These interactions can lead to Toxicity, Loss of therapeutic effect, Unexpected increases in Pharmacological activity. Mechanically these interactions are either DIRECT or INDIRECT Indirect interactions : Both the object and precipitant drugs have unrelated effects These interactions are of major, moderate, or minor status based upon adversity .Example : Salicylates decrease the ability of the platelets to aggregate thus impairing the homeostasis if Warfarin induced bleeding occurs Direct Interactions : Drugs with similar or opposing pharmacological actions are employed These are Categorised as : Additive Effect Potentiation (Supra-additive) Synergism Antagonism MECHANISMS OF DRUG INTERACTIONS

5. ADDITIVE EFFECT : The combined effect of two or more drug is equal to the sum of their individual effect Effect of Drug A+B =Effect of Drug A + Effect of Drug B Example :Combination of Ibuprofen and Paracetamol as an analgesic POTENTIATION (Supra-Additive) : The enhancement of action of one drug by another drug which is inactive is called as Potentiation. Effect of drugs A+B > Effect of Drug A +Effect of Drug B. Example : Levodopa + Carbidopa and Acetylcholine + Physostigmine . Carbidopa and Physostigmine inhibit the breakdown of Levodopa and acetylcholine , respectively thus enhancing their effects SYNERGISM : when two or more drugs are administered simultaneously, their combined effect is greater than elicited by either drug alone. Example : Sulphamethoxazole + trimethoprim and Pyrimethamine + Sulphadoxine ANTAGONISM : when effect of one drug is decreased or abolished in the presence of another drug. Example : Adrenaline and Nor- adrenaline have opposing effects on heart rate. Effect of drug A+B< effect of drug A + effect of drug B.

6. Depending on mechanism involved ,antagonism maybe : Physical Antagonism - based on physical property of drugs. Example : Charcoal adsorbs alkaloids and prevents their adsorption in alkaloidal poisoning. Chemical Antagonism - The two drugs react chemically and form inactive products. Example- Tannins +Alkaloids - insoluble alkaloidal Tannate is formed. Physiological /Functional Antagonism - The two drugs act on different receptors or by different mechanisms but have opposite effects on same physiological function i.e., have pharmacological effects in opposite direction . Example : Histamine and adrenaline on bronchial muscles and B.P. Receptor Antagonism - One drug (antagonist ) blocks the receptor action of the other (agonist ).It may be : COMPETETIVE Antagonism ( equilibrium type) - The antagonist is chemically similar to agonist, competes with it and binds to the same site exclusion to the agonist. Ex : Acetylcholine -Atropine and Morphine- Naloxone. NON- COMPETETIVE Antagonism (Allosteric) - Binds to another site of receptor and does not resemble to the agonist. EX: Diazepam -Bicuculine.

7. Propanolol and Digoxin : propanolol is a non-selective beta receptor antagonist and digoxin belongs to the class of digitalis (cardiac)Glycosides.Propanolol reduces Force of Contraction of heart muscle lowering B.P and heart rate whereas digoxin has positive ionotropic effect by reversibly inhibiting the effect of myocardial Na-K ATPase pump. Both can cause severe Bradycardia. Quinolones and Macrolides ( Antibiotics ) : quinolones causes inhibition of DNA replication by binding to the topoisomerase IV / DNA gyrase whereas macrolides inhibit bacterial protein biosynthesis and bacterial ribosomal translation. Possible effect is QT Prolongation and Torsade de pointes (Ventricular tachycardia with gradual change in amplitude and twisting of the QRS complex. Aminoglycosides and Furosemide (Loop diuretic) : aminoglycosides belongs to antibiotics class which inhibits protein synthesis and Furosemide inhibits Na-K-Cl cotransporter. Aminoglycosides and furosemide both aggravates Ototoxicity and can lead to hearing Impairment. Examples of Typical Additive and Antagonistic Pharmacodynamic Interactions :

8. 4. ACE Inhibitors and K+ Sparing Diuretics : ACEI reduces the activity of Angiotensin Converting Enzyme (ACE) and converts Angiotensin I to Angiotensin II which is thus used in lowering B.P. Spironolactone is a potassium sparing diuretic and both if used in combination can lead to severe Hyperkaelemia which is very lethal. 5. NSAIDS and SSRI ( Selective Serotonin Reuptake inhibitor ): SSRI is a reuptake inhibition of Serotonin by blocking action serotonin transporter. When both are used they can lead to an Increased risk of Gastro- intestinal Bleeding. 6. Verapamil and Beta blocker : Verapamil is a CCB (Calcium channel blocker and their adverse drug action is increased PR interval decreased reduction of systolic B.P which leads to Bradycardia and Asystole. 7. Macrolides , Clindamycin , Chloramphenicol and Azithromycin all of which are antibiotics must not be used in combination as the binding of 50S Ribosomes changes ,leading to mutual antagonism and thus stops Anti- bacterial activity.

9. 8 . Propanolol and Hypoglycemic agents : Propanolol along with insulin or Sulphonylureas masks the Hypoglycemic symptoms leading to Asymptomatic Hypoglycemia which is a very lethal and dangerous condition. 9. Concurrent use of a combination of NSAIDs ( cox-2 ) , Diuretics and ACEI or ARBs can cause severe Nephrotoxicity which leads to Acute Kidney damage and then acute renal failure. Such a condition if developed is called as Triple Whammy. 10. Sildenafil and Nitrates : Sildenafil cause Vasodilation by enhancing NO in the Corpus cavernosum ( given for erectile dysfunction ) and Nitrates are directly Vasodilating in nature which lowers heart rate and B.P and reduces the oxygen demand. Since both show vasodilation , they get contra-indicated and large B.P reduction is seen which leads to severe Hypotension and even death. 11. Clonidine and Chlorpomazine (or imipramine ) : Clonidine is a centrally acting Anti - Hypertensive drug , which if used with any of the above drug will reduce its activity and anti - hypertensive effect is not seen.

10. 12. Benzodiazepines ,Anti - histamines, Opoids and Alcohol must not be used in combination as they cause Sedation and severe Respiratory depression. 13. Incidence of increased Digoxin Toxicity is seen if given with Amiodarone /Clarithromycin/potassium / Quinidine /Hawthorne. 14 . Anti-coagulant (Warfarin ) and Antiplatelet ( clopidogrel , Aspirin ) must not be given in combination specially in normal individuals as they increase the risk of Bleeding. 15. Antagonistic effects are seen when Therapeutic effects of Aspirin , ACEI , Levodopa , Phenprocouman are reduced by addition of Ibuprofen , NSAIDs , Classical Neuroleptics , and Vitamin K respectively .

11. INTERVENTIONS : Identify the patient risk factors Be knowledgeful about the actions of drugs being used Take thorough review of patient history Consider the therapeutic alternatives Avoid complex therapeutic regimens when possible Alter the dose of one interacting drug Allow a gap between administration of interacting drugs Advise the patient to seek guidance if they are going to plan a change in lifestyle or medications Educate the patient Monitor the therapy

12. THANK YOU