Dr. Syamsudin, M.Biomed

Fakultas Farmasi Universitas Pancasila

Pharmacokinetic Vs Pharmacodynamic Drug Interactions

Pharmacodynamic Drug Interaction:

The two possible effects are increase or decrease in drug action. Increased effect may be a result of additive effect or synergistic effect or summation

Pharmacodynamic drug interactions are not caused by a change in plasma concentration of one or both drugs, but by a synergistic or antagonistic effect of the combined drugs.

Interactions

Antagonism

Combined effect < sum of single efects

Reduction/elimination

Competitive antagonism atropine/organophosphate

cholinergic receptor 4 + 6 = 3

Functional antagonism Barbiturate/noradrenalin

Blood pressure 4 + (-4) = 0

Interactions

Additivity

Combined effect = sum of single efects

Inhibition of acetylcholinesterase

(2 organophosphates)

2 + 3 = 5

Synergy

Combined effect > sum of single efects

Liver damage

(ethanol, carbon tetrachloride)

2 + 4 = 15

Potentiation

Combined effect > sum of single efects

Liver damage

(iso-propanol, carbon tetrachloride)

0 + 4 = 10 IRSST - Interactions toxicologiques - Université Montréal

DRUGS HAVING OPPOSING PHARMACOLOGICAL EFFECTS

Interactions resulting from the use of two drugs that have opposing pharmacological effects are easiest to detect. There are factors that could preclude early identification of such an antagonism.

use of CNS stimulant to counteract an excessive sedative effect when phenobarbital is used in the treatment of epilepsy.

use of a sedative to reduce the stimulant action of ephedrine that is being used to treat an asthmatic condition.

DRUGS HAVING SIMILAR PHARMACOLOGICAL EFFECTS

Phenothiazines, tricyclic antidepressants like amitryptyline and benzodiazepine, increase the effect of alcohol in inhibiting motor skills

ALCOHOL - SEDATIVES

ANTIPSYCHOTIC AGENTS - ANTI PARKINSON DRUGS & ANTIDEPRESSANTS

antipsychotic agents such as chlorpromazine are also given an antiparkinson

agent like trihexphenidyl to control the extrapyramidal effects of the former. A

number of patients experience depressive symptoms and tricyclic

antidepressants like amitryptyline is added to therapy. Each of these agents

possesses anticholinergic activity and the additive effect leads to the development

of annoying symptoms like dryness of mouth, blurred vision, urinary retention

and elevation of intraocular pressure.

AMINOGLYCOSIDE ANTIBIOTICS - DIURETICS

The aminoglycoside antibiotics such as gentamycin, streptomycin, neomycin and amikacin have a potential to cause ototoxicity including deafness. Ototoxicity develops rapidly when diuretics like furesemide are administered concurrently by the intravenous route to patients on gentamycin or amikacin therapy. A rapid rise in serum levels of antibiotic also leads to neurotoxicity.

ALTERATION OF ELECTROLYTE LEVELS

DIGITALIS GLYCOSIDES - DIURETICS :

Thiazide diuretics like ethacrynic acid, furesemide and metazolone cause excessive loss of potassium. Potassium depletion or hypokalemia results in arrythmias when digitalis preparations are combined with these diuretics.

The patient is advised to take potassium rich foods like bananas and oranges or fruit juices. Potassium supplements and potassium sparing diuretics, like spironolactone may be prescribed. Diuretic therapy also causes hypomagnesemia, when magnesium is depleted the digitalis toxicity enhances.

DIGITALIS GLYCOSIDES - CALCIUM :

Increase in the level of calcium enhances the sensitivity of the heart to digitalis. Decrease in the response to digoxin is attributed to hypocalcemia.

LITHIUM CARBONATE - DIURETICS :

Sodium depletion is known to enhance lithium toxicity. The sodium depletion caused by diuretics reduces the renal clearance and increases the activity of lithium.

WEIGHT CONTROL PILLS :

The weight control pills available in the market usually contain various combinations of digitalis, thyroid, a diuretic, a laxative, a barbiturate and an amphetamine as anorexic. Combinations is a loss of potassium which increases the sensitivity of the heart to digitalis and leads to digitalis toxicity even at lower dosage. Loss of potassium occurs because the laxative and diuretic increase excretion of this ion, at the same time there is a decreased intake of food and electrolytes because amphetamine reduces the apetite. This example illustrates irrational combination of drugs and raises doubts about their widespread use.

ALTERATION OF RECEPTOR SITE INTERACTIONS

WARFARIN - DEXTROTHYROXINE :

Alteration of the receptor site interaction is the mechanism that explains the enhanced activity of warfarin in patients receiving dextrothyroxine. It is reported that dextrothyroxine enhances the effect of warfarin by increasing the affinity of the drug for the receptor site.

WARFARIN - ANABOLIC STEROIDS :

Several anabolic steroids such as methandrostenolone and oxymethodone increase the activity of coumarin anticoagulant warfarin by increasing affinity of anticoagulant for the receptor site. Therefore warfarin should be used carefully for patients on therapy with anabolic steroids containing 17-alkyl group in their molecular structure.

ANTICOAGULANTS - ANTIBIOTICS :

A number of anti-infective agents enhance the activity of simultaneously administered anticoagulants. This effect is the result of interference of anti-infective agent with production of vitamin K by microorganisms in the gastrointestinal tract. Broad spectrum antibiotics like tetracyclines and chloramphenicol that reduce intestinal bacterial flora are most likely to cause problems of this type, where there is reduction of vitamin K synthesis, a cofactor essential for coagulation. Decreased coagulant effect results in increased anticoagulant response

ALTERATION OF GASTROINTESTINAL FLORA :

ANTIBIOTIC COMBINATIONS :

ENHANCEMENT OF ANTIBACTERIAL ACTION (SYNERGISM) :

Use of ampicillin and pencillin along with aminoglycoside antibiotics such as streptomycin or kanamycin for treatment of enterococcal endocarditis.

FOR TREATMENT OF MIXED INFECTIONS :

When infective micro-organisms do not response to the same antibiotic, a combination of antibiotics is administered.

Verapamil + Propranolol Verapamil increased the AUC and Cmax and shortened the

tmax of propranolol and Propranolol decreased the AUC and Cmax of verapamil.

The greater reduction of heart rate with the combination of verapamil and propranolol was only partially explained by higher plasma concentrations of propranolol.

The combination of propranolol and verapamil produced clinically important synergistic adverse effects during exercise.

Negative dromotropic effects occurred primarily by direct AV node inhibition and were more important than previously recognized.

Salbutamol + β-adrenoceptor blocking agents β-adrenoceptor blocking agents inhibit the

bronchodilator activity of salbutamol. Consequently β-blockers should not be used in asthmatic patients as they may increase airways resistance.

Antidepressants Sympathomimetics Monoamine Oxidase Inhibitors (MAOI’s) Inhibit breakdown of Noradrenaline Dopamine Decongestants (pseudoephidrine) Asthma (salbutamol) Foods rich in tyramine Beer, Hot Dogs, Wine, Beans MAOI’s enhance effects of these drugs and enhance the action of tyramine

Blockade of Neuronal Uptake:

Important mechanism by which action of noradrenaline is terminated is its active reuptake into noradrenergic neurones. Blockade of this reuptake potentiates pressor action of noradrenaline, adrenaline and other substances such as phenylepherine, which depend on the same uptake process. Example: - tricyclic antidepressant – imipramine, adrenergic neurone blockers – guanethidine, bethanidine.

Transmitter Depletion:

When any normally available neuron transmitter concentration if affected, drug depending on them to give effect will no give expected responses. Example: - Pressor responses to tyramine reduced in reserpinised subjects.

MAO-Inhibitor Drug interactions

Sympathomimetics (e.g. pseudoephedrine in cold remedies)

Risk of hypertensive crisis

Reserpine, guanethidine, tricyclic antidepressants

Excitement

Increase in blood pressure and body temperature

Levodopa (L-DOPA)

Excitement

Hypertension

Anticholinergics (Henbane, Datura)

Risk of hallucination

Antihistamines, barbiturates, ethanol, opioids

Action of these drugs prolonged - risk of respiratory depression

Pethidine (Demerol)

Risk of high fever, sweating, excitement, delirium, convulsions, respiratory depression (MAOIs retard metabolism of pethidine, but not its demethylation, therefore excess norpethidine is formed).

Methylenedioxymethamphetamine (MDMA, "Ecstasy")

Risk of hypertensive crisis

Serotonin syndrome

Dextromethorphan (DXM, cough-syrup)

Serotonin syndrome

Imitrex/Sumatriptan, Migraine Medicine

Dimethyltryptamine (DMT, ayahuasca)

Allows oral consumption without metabolisation[4

Pharmacodynamic Interactions NSAID’s Antihypertensives For inflammation/ headache.

Most block Prostaglandin synthesis. PGE2 and PGI2 cause renal arteriolar dilation Antagonist 1 Antagonist

Angiotensin Converting Enzyme (ACE) Inhibitors Diuretics Loss of ability to dilate renal arterioles (via PGE2 and PG2) can lead to hypertensive crisis in people taking antihypertensives

ACE leads to formation of angiotensin II, but also inactivates BK because it also is kininase II, which degrades BK.

BK has potent vasodilatory effects that can be attributed to two endothelium-related mechanisms: a direct effect and an indirect one due to the release of additional mediators, such as PG and nitric oxide.

BK induces PG liberation by means of phospholipase A activation. Thus, arachidonic acid released from membrane phospholipids is converted, by

cyclo-oxygenase, into PG (PGD2, PGE2, PGF), PGI2 and thromboxane A2. PGI2, specifically, is also a potent vasodilator (7) and may thus contribute to the vasodilatory effect of ACE inhibitors.

Consequently, ACE inhibitors decrease vasoconstriction due to reduced angiotensin II synthesis, and indirectly produce vasodilatation through the increase of BK, nitric oxide and PG (7). On the other hand, the negative interaction of ASA/ACE inhibitors can be explained by the blockade of cyclo-oxygenase by ASA (4). It is therefore suggested that ASA inhibits PGI2 synthesis to an extent sufficient to compromise the hemodynamic effects of captopril.

Pharmacodynamic Interactions Benzodiazepines (and antihistamines, anticonvulsants, barbiturates) Alcohol CNS depressant CNS depressant ‘Additive’ CNS depression Respiratory depression, hypotension, coma

Barbiturate Site

Digoxin + Klaritromisin Clarithromycin increases the serum concentration and toxicity of

digoxin possibly due to inhibition of P-glycoprotein transport.

Inhibition of the growth of Eubacterium lentum (responsible for intestinal metabolism of digoxin in some patients).

Clarithromycin use in digoxin-stable patients has been reported to cause increased digoxin serum concentration and toxicity in some patients.

A study of patients hospitalised for drug toxicity found that those admitted for digoxin toxicity were 12 times more likely to have been treated with clarithromycin in the previous week.

Monitor digoxin levels and for signs of digoxin toxicity during concurrent use.

Clinical effects of drug-drug interactions with benzodiazepines

Respiratory depression with alcohol, barbiturates, tricyclic and tetracyclic drugs, dopamine receptor antagonists, opioids, antihistamines

With mirtazapine ↑ sedation

With lithium, antipsychotics, and clonazepam → ataxia and dysarthria

With clozapine → delirium

Indirect Pharmacodynamic Interactions Indirect pharmacodynamic interactions occur when the pharmacologic effect of one drug affects another drug’s therapeutic effect. An example of this type of interaction would be the coadministration of a diuretic and digoxin. Although this combination is commonly used in many patients, we must to monitor for diuretic-induced hypokalemia and hypomagnesemia. Hypokalemia and hypomagnesemia may place a patient receiving digoxin at risk of dysrhythmias.

Receptor Blockade:

(i) Alpha-adrenergic receptor blockade prevents pressor effects of sympathomimetic amines.

(ii) Commonly observed additive effect –alcohol with CNS depressants leads to increased drowsiness, reduced alertness, and impaired psychomotor skills.

(iii) Antihypertensives with drugs causing hypotension (antianginals, vasodilators) leads to increased hypotensive effects.

(iv) Antagonistic effect: - Hypnotic taken with caffeine shows no effect due to nullification.

(v) Hypoglycemic taken along with glucocorticoids – hypoglycemic effects are opposed.

Specific Patient Populations at Risk for Drug Interactions

The elderly are at increased risk for drug interactions due to expected age-related changes in renal and hepatic function.

HIV/AIDS and the opportunistic infections associated with this disease;

connective tissue disorders; GI disorders (ie, peptic ulcer disease and GI motility

disorders); cardiovascular disorders (ie, hyperlipidemia); disorders requiring anticoagulation in the short and long

term; chronic respiratory disorders (ie, asthma and chronic

obstructive pulmonary disease); seizure disorders.

Thank You