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Central Nervous System Drugs

Central Nervous System Drugs. Faculty of Pharmacy Department of Pharmacology. 5 th year Pharmacy Students. Drug-Drug Interaction. Benzodiazepines.

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Central Nervous System Drugs

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  1. Central Nervous System Drugs Faculty of Pharmacy Department of Pharmacology 5th year Pharmacy Students Drug-Drug Interaction

  2. Benzodiazepines

  3. Mechanism:It act through benzodiazepine receptor and potentiate GABA action by more frequent opening of chloride ion channel which lead to hyperpolarization and depression Note:shown to bind and modulate the major GABA receptor in the brain, GABA awhile GABAb receptors are not altered by benzodiazepines.Pharmacological action:it make dose dependant CNS depretionThese CNS depressive effects result in anxiolytic, muscle relaxant, hypnotic, anti- grade amnesia, anticonvulsant, and sedative effects that define thetherapeutic uses of benzodiazepines.

  4. * Benzodiazepines used as anticonvulsants are long-acting and have rapid entry into the brain. * Short- to intermediate-acting benzodiazepines are favored for treatment of insomnia.Adverse effects :Drowsiness, sedation, and ataxia are the most frequent adverse effects .Notes:The benzodiazepines are generally lipophilic drugsSo the benzodiazepines have relatively high plasma protein binding.Diazepam is regarded as a long-acting benzodiazepine. Metabolism.In summary, P450 3A4 (and 3A5) are extensively involved in many pathways of oxidative metabolism of benzodiazepines.P450 2C19 is involved in many of the N- demethylation reactionsand may play a role in some other oxidative pathways. P450

  5. BENZODIAZEPINE DRUG INTERACTIONSMost pharmacokinetic drug interac-tionsinvolve either the inhibition or induction of specific P450s involved in the metab- olism of benzodiazepines.Pharmacodynamic drug interactions with other CNS depressants are more likely to have lethal as well as clinical and forensic, consequences. These drugs, which include : ethanol, opioids, and barbiturates, also cause respiratory depression1.midazolam or diazepam is combined with the opioidspapaveretum, pethi dine, or morphine during anesthesia, potentiation of the sedativeor subjective effects. 2.acute use of ethanol is associated with the inhibition of drug metabolism; chronic use induces metabolism.

  6. 3.chronic disulfiram treatment was found to diminsh the elimination of chlordiazepoxide and diazepam.(Both disulfiram and certain benzodiazepines are used to treat alcoholism.)4.Interactions with Grapefruit Juice inhibition of P450 3A4.5.Among the antibiotics, the antitubucular agent rifampin (rifampicin) is well known for its ability to induce drug metabolism.6.macrolide antibiotics are well-known inhibitors of P450 3A4 erythromycin, clarithro- mycin.7.carbamazepine and/or phenytoin enhances the elimination of diazepam8.Benzodiazepines have an acidic pKa, and changes in the pH of the gastrointestinal tract may influence their rate of absorption.

  7. 9*Propranolol has mixed effects on benzodiazepinesIt enhanced the elimination of alprazolam it inhibited the elimination of diazepamit had no effect on the elimination of lorazepam (274) or oxazepam 10.cimetidine : Enzyme inhibitors.

  8. Epilepsy is a chronic neurologic disorder characterized by recurrent seizures. Epilepsy is recognized as a syndrome of disturbed electrical activity in the brain . Precipitating factors: Hyperventilation, sleep, sleep deprivation, and sensory and emotional stimuli consider as precipitating factor. MEDICATIONS UTILIZED IN THE TREATMENT OF EPILEPSY EX: 1.Phenytoin and Fosphenytoin 2. Carbamazepine and Oxcarbazepine 3. Valproate 4.Ethosuximide

  9. Phenytoin and FosphenytoinAction; Indicated for treatment of generalized seizure phenytoin weaker organic acid than the barbituratesThis results in very poor aqueous solubility of phenytoin.Parenteral phenytoin must be formulated as a highly alkaline aqueous solution to maintain adequate solubility.Fosphenytoin is a phenytoin prodrug. to improve the solubility of phenytoin for parenteral use.**are effective at reducing seizure frequency and severity without causing generalized central nervous system depression.M.O.A : Act by Blooking Na Channel.

  10. Adverse Reactionslethargy, fatigue, incoordination, blurred vision, and drowsinessgingival hyperplasia.Drug Interactions :1.As phenytoin is displaced from plasma proteins, the free fraction of phenytoin increases. This is followed by an increase in the clearance of phenytoin, a decrease in total phenytoin concentration.2.Long-term use of phenytoin decreases folic acid absorption.(Supplementation of folic acid, alone or as a vitamin, has the poten tial to decrease plasma phenytoin concentrations and subsequently decrease seizure control )

  11. EthosuximideEthosuximide is indicated for the treatment of absence seizures.M.O.A: Ethosuximide exhibits antiseizure activity by reducing low-threshold Ca cur rents in the thalamic region.Note: absorption of oral syrup may be faster than that of oral tabletsProtein binding of ethosuximide is very low.Contraindications and PrecautionsPatients with active hepatic or renal disease may be at increased risk of side effectsbecause of altered pharmacokinetics of ethosuximideDrug InteractionsCBZ may induce the metabolism of ethosuximide resulting in loss of seizure control

  12. Carbamazepine and Oxcarbazepine CBZ enhances the inactivation voltage-activated Na channels Notes :*The pharmacologic effect of oxcarbazepine is due to a principal metabolite, 10 hydroxy-oxcarbazepine * use of CBZ is not contraindicated among pregnant womenDrug Interactions1.CBZs metabolic fate and its influence on the cytochrome p450 system make CBZ the subject of many significant drug interactions2.Cimitidine, Erythromycin inhibits the metabolism of CBZ resulting in clinically significant increases in plasma CBZ concentration.3.valproic acid can effectively increase the plasma concentration of the 10,11-epoxide metabolite without changing the concentration of CBZ.

  13. include fluoxetine, paroxetine, sertraline, fluvoxamine, and citalopram. SSRIs act by inhibiting neuronal uptake of serotonin (5HT). Actions: treatment of depression. SSRIs are also used in treating other psychiatric disorders such as panic disorder. Fluoxetine, paroxetine, and sertraline are highly protein bound, especially to -1 acid glycoproteins

  14. Selective serotonin Reuptake Inhibitors ADVERSE REACTIONS The most commonly reported adverse reactions to SSRIs are nausea anorexia, diarrhea, insomnia, nervousness, headache, anxiety, dry mouth, constipation, hypotension, and fatigue.

  15. Selective serotonin Reuptake Inhibitors Drug Interactions: 1.Drugs such as sulfonylureas, barbiturates, phenytoin, carbamazepine, rifampin are CYP enzyme inducers that cause an increase in metabolism of the drugs including SSRIs. 2.Enzyme inhib itors such as cimetidine, erythromycin, isoniazid ,verapamil, and propoxyphene can lead to an increase in plasma levels of affected drugs.

  16. Selective serotonin Reuptake Inhibitors 3.fluvoxamine significantly increases melatonin (sleep aid) levels by reducing its metabolism due to inhibition of CYP1A2 and CYP2C9 4.Any drug or drug combinations that increase serotonin neurotransmission can cause serotonin syndrome. Serotonin syndrome is an acute condition that is characterized by changes in mental status, restlessness, dyskinesia, clonus and myoclonus, autonomic dysfunction such as mydriasis, hyperthermia, shivering, diaphoresis, and diarrhea

  17. Antipsychotics include two general classes of drugs. (1)Traditional antipsychoticsare thought to act by exerting effects principally on the dopamine neurotransmitter system. The traditional antipsychotics became known to many as neuroleptics based on their frequent effects of substantially slowing movement (2). Atypical antipsychotics,designed in laboratories to provide psychotic symptom relief without movement problems, affect other neurotransmitter systems and present other potential concerns.

  18. M.O.A :These medicines block dopamine transmission at D2 receptors in the mesolimbic nerve.(Dopamine activity in the brain substantianigra is necessary for unrestricted movement.)Potent blockade of dopamine transmission from the substantianigra at D2 receptors is therefore associated with severely slowed move ments, a resting tremor, loss of the ability to instinctively maintain upright posture.( Parkinsonism.) Anti cholinergics such as benztropine and trihexyphenidyl reduce the dopamine-blocking effects on the substantianigra without affecting dopamine blocking that treats psychosis

  19. Adverse effects:1. akathisia is its treatmentbeta-blockers and benzodiazepines.2. Complicating tardive dyskinesia was its sometimes irreversible stop traditional antipsychotics hoping the tardive dyskinesia would somehow improve Or take clozapine.NOTE :Lithium added to traditional antipsychotics also increases the risk for tardive dyskinesia and of akathisia.3.Cognitive Side Effects due to :Dopamine Blockade4.Sexual dysfunction occurs in a number of individuals taking dopamine-blocking Mech: By increase prolactin.5.anticholinergic effects also include dry mouth, blurred vision, constipation, and urinary retention.6.Antihistaminic effects are responsible for sedation and weight gain.atypical antipsychotics block a far lower percentage of D2 receptors than traditional antipsychotics.

  20. Interactions and Drug Metabolism1*Medicines that slow the metabolism of traditional antipsychotics do so by inhibiting those enzymes in the liver that would otherwise break down the antipsychotics.This causes the antipsychotics to accumulate, and for side effects, including cognitive effects, to be more pronounced.2*medicines that stimulate CYP enzymes in the liver to break down antipsychotics faster gain forensic significance when a subsequent drop in medication levelsleads to a relapse of symptoms.

  21. 3*The antidepressant nefazodone has been shown to decrease the clearance of haloperidol from the body by about 33%.Given haloperidols association with parkinsonism, and that effects increase in risk associated with falls4*Cigarette smoking activates the metabolism of CYP1A2. Therefore, aperson who stops smoking may have a corresponding increase in blood levels of anantipsychotic metabolized through this pathwayalong with serious side effects asso ciated with that change, especially if dramatic5* It increase hypo tension If taken with Antihypertensive agent. Mech: Antipsychotic block α Receptor.6.*Anti-cholinergic &Antipsychotic cause additive CNS dysfunction.

  22. Opioids and Opiates Def : Naturally or synthetic or semi-synthetic substance which have analgesic action and tendency to abuse. (consider as narcotic analgesics) *The main groups of drugs in clude morphine analogs *such as oxymorphone, codeine, oxycodone, hydrocodone, heroin - diamorphine), and nalorphine; and the synthetic derivatives such as meperidine, fentanyl, methadone, propoxyphene, butorphanol, pentazocine, and loperamide

  23. Opioids and Opiates Opioid Receptors They are mu (µ), delta (), and kappa (). Natural occuring morphine like substance: Endorphine – Enkephaline. Mechanism of Action 1.inhibition of adenylcyclase activity, leading to a reduction in intracellular cAMP conc. 2.They either close a voltage-gated Ca channel on presynaptic nerve terminals and thereby reduce trans mitter release. 3.they hyperpolarize and thus inhibit postsynaptic neurons by opening k

  24. Note :direct application of opioid agonists to the spinal cord, which provides a regional analgesic effect while minimizing the unwanted respiratory depression , nausea and vomiting, and sedation that may occur from the supraspinal actions of systematically.Clinical use of opioid analgesics consists primarily in balancing the analgesia against adverse side effects. 1.Central Nervous SystemThe CNS effects include analgesia, via altered pain tolerance, sedation, euphoriastimulating the chemoreceptor trigger zone in the medulla. As the doseis increased, the subjective analgesic and toxic effects, including respiratory depression

  25. Respiratory SystemRespiratory depression occurs by direct effect on the medullary/respiratory center**the combination of opiates with other medications such as general anesthetics, alcohol, or sedative-hypnotics may present a greater risk of respiratory depression resultingfrom the synergic effects of these drugs on the respiratory center.**opioidsalso depress the cough reflex at least in part by a directeffect on a cough center in the medulla**dextrometorphando not depress respirationCardiovascular SystemHistamine release may con tribute to the haemodynamic changes as well as dermal pruritus. Transient bradycardiaand hypotension

  26. Gastrointestinal Systemdelayed gastric emptying. This may also contribute to the observed nausea and vomitingNotes :*Tolerance and Physical Dependence & abuse.**Naloxoneremains the drug of choice as the initial reversal agent in suspected opioid overdose

  27. DRUG INTERACTIONS1.Metoclopramide increases the rate of absorption of oral morphine and exacerbates its sedative effects. MECH:Metoclopramide increases the rate of gastric emptying so that the rate of morphine absorption from the small intestine is increased .2.The bioavailability and the degree of analgesia of oral morphine are increased by the concurrent use of clomipramine, desipramine, and possibly amitriptyline. (The reasons are not understood)3.The respiratory depressant effect of morphine is significantly increased by alcohol.

  28. 5.Rifampin significantly reduced the peak plasma morphine concentration and AUC 6.cimetidine with morphine or opium and methadone Decreased metabolism of morphine is the probable mechanism7.Clearance of morphine is approximately doubled by the concurrent use of oral contraceptives. 8. The plasma clearance rate of 5-fluoro uracil (5FU) in mice is significantly reduced by concomitant use of morphineThe effects of morphine are due to reduced hepatic elimination of 5FU rather than to a decrease in its renal excretion. 9.methadoneelevates Zidovudines serum concentration, increasing the risk of side effects.

  29. 10.Dexamphetamine and methylphenidate increase the analgesic effects of morphineand reduce some of its side effects such as respiratory depression and sedation.

  30. Depression is a disorder consisting, in varying degrees, of low mood lethargy, and loss of interest in former pleasures.MONOAMINE OXIDASE INHIBITORSMAOIs such as tranylcypromine (2-phenylcyclopropylamine, Parnate) and phenelzine (2-phenylethylhydrazine, Nardil)and more recently moclobemideare not hepatotoxic and have been widely applied in the treatment of depressive illness.Mechthe MAOIs reduce the activity of monoamine oxidase enzymes A and B, which degrade monoamine substrates such as dopamine, noradrenalin, and serotonin. MAO-A is more prevalent in the central nervous system (CNS)and inhibition of this enzyme has been associated with the antidepressant response

  31. Note:Moclobemidenot cause hypertension when taken with tyramine containing compound.Drug Interacyions:1.The depressive form of the MAOI/narcotic analgesic interaction is characterizedby respiratory depression, hypotension, and coma, and reflects accumulation of free narcotic due to inhibition of liver enzymes by the MAOI.2.Meperidine has been demonstrated to inhibit the neuronal reuptake of serotonin and, like the SSRIs, can provoke an excitatory serotonin syndrome response when coadministered with an MAOI.3. food & nonselective MAOIs Is life threatening.Ex: fermented cheese., chocolate.

  32. TRICYCLIC ANTIDEPRESSANTSamitriptyline, imipramine, doxepin, dothiepin, and clomipramine.The TCAs exhibit two main pharmacological properties: they alter the reuptake and deactivation of neurotransmitters released during neurotransmission and they are competitive antagonists at muscarinic acetylcholine receptor.Symptoms such as sedation, blurred vision, dry mouth, and urinary retention appear to be related to the antimuscarinic actions. Notes :TCA metabolite also active against depression.his cytochrome P450 enzyme has since come to be known as CYP2D6 and has been confirmed as acommon mediator of TCA hydroxylation .

  33. DRUg INTERACTIONs.1.amounts of the TCAs in blood were decreased by carbamazepine, due to enzyme induction, and increased by dextropropoxypheneand neuroleptics, particularly thioridazine.2. because the N-desmethylated metabolite of fluoxetine is more persistentin blood and tissues and is a potent inhibitor, of CYP2D6 in its own right inhibition of TCA hydroxylation in clinical settings maybe more significant after fluoxetine than after any of the other SSRIs3.Ticlopidine is employed clinically as an inhibitor ofplatelet aggregation and is also a potent inhibitor of CYP2D6 and CYP2C19 the enzymes critically involved in the hydroxylation and N-demethylation of theTCA.

  34. 4.Ethanolmay also have a clinically important interaction with the TCA. ethanol ingested together with amitriptyline, increasedthe amount of the TCA which reached the systemic circulation, possibly because ofreduced hepatic clearance during absorption.

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