24 - neuropharmacology of centeral nervous system

neuropharmacology of centeral nervous system made by haramaya university

1. Opioid and Non-opioid analgesics

2. Nonsteroidal anti-inflammatory drugs

3. Chemistry & Pharmacokinetics Most of are well absorbed , and food does not substantially change their bioavailability . Metabolism …Most by phase I followed by phase II Some direct glucuronidation phase II alone. Excretion….. renal excretion is the most important route for final elimination , Nearly all undergo varying degrees of biliary excretion and reabsorption ( enterohepatic circulation). highly protein-bound (~ 98%), usually to albumin. Most of the NSAIDs ( eg , ibuprofen, ketoprofen ) are racemic mixtures,

4. Chemistry & Pharmacokinetics All NSAIDs can be found in synovial fluid after repeated dosing Pharmacodynamics Main mechanism: Inhibition of prostaglandin biosynthesis Aspirin irreversibly acetylates and blocks platelet COX , while the non-COX-selective NSAIDs are reversible inhibitors. Other mechanisms: Inhibition of chemotaxis , down-regulation of IL-1 production, decreased production of free radicals and superoxide, and interference with calcium-mediated intracellular events.

5. Pharmacodynamics… selective COX-2 inhibitors do not affect platelet function Compared to older NSAIDs, COX-2-selective Inhibitors Improved Efficacy Less GI side effects Can increase the incidence of edema, hypertension, and possibly, myocardial infarction NSAIDs decrease the sensitivity of vessels to bradykinin and histamine , affect lymphokine production from T lymphocytes, and reverse the vasodilation of inflammation .

6. Pharmacodynamics… All newer NSAIDs have analgesic, anti-inflammatory, and antipyretic, and all (except the COX-2–selective agents and the non acetylated salicylates ) inhibit platelet aggregation All NSAIDs have Nephrotoxicity, Due to autoregulation of renal blood flow, which is modulated by prostaglandins Hepatotoxicity also can occur with any NSAID. Several NSAIDs (including aspirin) Chronic use…reduce incidence of colon cancer The mechanism for this protective effect is unclear.

7. Aspirin Aspirin’s long use and availability without prescription Diminishes its use compared to the newer NSAIDs. Widely used for antiplatelet effects ( i.e , doses of 81–325 mg once daily). Pharmacokinetics Aspirin (acetylsalicylic acid; ASA) has a pKa of 3.5 Aspirin is rapidly hydrolyzed (serum half-life 15 minutes) to acetic acid and salicylate by esterases in tissue and blood. Salicylate bound to albumin. Alkalinization of the urine increases the rate of excretion

8. Pharmacokinetics Mechanisms of Action : Aspirin irreversibly inhibits platelet COX so that aspirin’s antiplatelet effect lasts 8–10 days (the life of the platelet). In other tissues, synthesis of new COX replaces the inactivated enzyme so that ordinary doses have a duration of action of 6–12 hours . Clinical Uses : (-)the incidence of transient ischemic attacks, unstable angina , coronary artery thrombosis with MI , and thrombosis

9. Adverse effects side effects of aspirin with antithrombotic dose gastric upset (intolerance )….Common Hepatotoxicity asthma, rashes, GI bleeding less common C/I…. The antiplatelet action of aspirin is C/Is with hemophilia. Although previously not recommended during pregnancy, aspirin may be valuable in treating preeclampsia - eclampsia .

10. Nonacetylated salicylates Drugs In this class ….. magnesium choline salicylate, sodium salicylate, and salicyl salicylate. They have A nti-inflammatory effect but D o not inhibit platelet aggregation. They may be preferable when COX inhibition is undesirable such as in patients with asthma , those with bleeding tendencies, and even (under close supervision) those with renal dysfunction . The nonacetylated salicylates are administered in doses up to 3–4 g of salicylate a day and can be monitored using serum salicylate measurements .

11. Cox-2 selective Inhibitors COX-2 selective inhibitors, or coxibs inhibit only COX-2 isozyme induced at sites of inflammation COX-2 inhibitors do not have impact on platelet aggregation, Platelet aggregation is mediated by thromboxane produced by the COX-1 isozyme. In contrast, they do inhibit COX-2-mediated prostacyclin synthesis in the vascular endothelium. D o not offer the cardioprotective Recommended doses of COX-2 inhibitors c ause renal toxicities similar to traditional NSAIDs.

12. Celecoxib Celecoxib is a selective ( 10–20 times more for COX-2 ) Dose = 100–200 mg bid T1/2=11 S/E…. cause rashes. It interacts occasionally with warfarin—as would be expected of a drug metabolized via CYP2C9. Meloxicam Meloxicam is related to piroxicam preferentially inhibits COX-2 (but less than Celecoxib) Therapeutic dose of 7.5 mg/d. It is associated with fewer clinical GI symptoms and complications than piroxicam , diclofenac, and naproxen. Similarly Inhibit TXA2, even at supratherapeutic doses, does not reach result in (-) platelet function

13. Nonselective cox inhibitors Drugs in this class : Diclofenac, Diflunisal , Etodolac, Flurbiprofen, Ibuprofen, Indomethacin, Ketoprofen , Nabumetone, Naproxen, Oxaprozin , Piroxicam, Sulindac, Tolmetin Diclofenac Dose: 50–75 mg qid T1/2 = 1.1 S/E….. GI ulceration may occur less frequently than with some other NSAIDs . Diclofenac/misoprostol decreases upper GI ulceration but may result in diarrhea Diclofenac/omeprazole ….prevent of recurrent bleeding, but renal adverse effects were common in high-risk patients. Diclofenac , 150 mg/d,…. impair renal blood flow and GFR.. A 0.1% ophthalmic preparation is promoted for prevention of postoperative ophthalmic inflammation

14. Diflunisal D iflunisal is derived from salicylic acid but not metabolized to salicylic acid or salicylate . Active after It undergoes cleavage of the glucuronide moiety . Diflunisal is subject to capacity-limited metabolism, In RA the recommended dose is 250-500 mg BID. T1/2….13 hr Etodolac Etodolac is a racemic with 6.5 (t1/2) Dose…200–400 mg TID/QID times daily. The recommended dose in OA and RA 300 mg BID/TID--- 500 mg twice

15. Flurbiprofen Flurbiprofen is a propionic acid derivative MOA…Its (S)(–) enantiomer inhibits COX non selectively, in addition Flurbiprofen is affect tumor necrosis factor α (TNF-α) and nitric oxide synthesis. a topical ophthalmic formulation used for inhibition of intraoperative miosis . flurbiprofen is also rarely associated with cogwheel rigidity, ataxia, tremor, and myoclonus .

16. Ibuprofen It is a simple derivative of phenylpropionic acid Dose = (<1600 mg/d) T ½……2hr Compared to indomethacin , ibuprofen Less decreasing Urine output effect causes less fluid retention When given with aspirin antagonizes the irreversible platelet inhibition induced by aspirin. Limit aspirin's cardioprotective effects

17. Indomethacin It is an indole derivative with a potent inhibitor activity Other mechanism may also inhibit phospholipase reduce neutrophil migration, and decrease T-cell and B-cell proliferation Dose: 50–70 mg tid T ½….4–5

18. Ketoprofen Ketoprofen is a propionic acid derivative that inhibits both COX ( nonselectively ) and lipoxygenase . Concurrent administration of probenecid elevates ketoprofen levels and prolongs its plasma half-life . Dosagr …..100–300 mg/d is equivalent to that of other NSAIDs. T ½….. 1.8 hr

19. Nabumetone Nabumetone is the only nonacid NSAID in it is given as a ketone prodrug . Its half-life > 24 hours Compared to other NSAIDs…..Less damaging GI effect higher dosages ( eg , 1500–2000 mg/d) It is a very expensive NSAID.

20. Oxaprozin Oxaprozin is a propionic acid derivative NSAID. difference from the other members of this subgroup is a very long half-life (50–60 hours), It is mildly uricosuric the drug has the same benefits and risks that are associated with other NSAIDs.

21. Piroxicam It is an oxicam with Effects at high concentrations inhibits polymorphonuclear leukocyte migration, decreases oxygen radical production, and inhibits lymphocyte function. T1/2 = 57 hr Analgesic dose: 20 mg QD

22. Sulindac Sulindac is a sulfoxide prodrug. metabolized to the active sulfide metabolite and has enterohepatic cycling prolongs the duration of action to 12–16 hours. Uses RA, suppresses familial intestinal polyposis and it may inhibit the development of colon , breast , and prostate cancer

23. Sulindac.. Among the more severe adverse reactions Stevens-Johnson epidermal necrolysis syndrome, thrombocytopenia , agranulocytosis , and nephrotic syndrome cholesteric liver damage (some times)

24. Opioid analgesics Introduction Source Opium, the source of morphine, is obtained from the poppy, Papaver somniferum and P album. After incision, the poppy seed pod exudes a white substance that turns into a brown gum that is crude opium. Opium contains many alkaloids , the principal one being morphine, which is present in a concentration of about 10%. Codeine can also be found in opium and is synthesized commercially from morphine.

25. Classification & Chemistry Opioid drugs include full agonists, partial agonists, and antagonists– Morphine is a full agonist at the µ (mu)-opioid receptor, the major analgesic opioid receptor Opioids may also differ in receptor binding affinity. For example, morphine exhibits a greater binding affinity at the µ-opioid receptor than does codeine Other opioid receptor subtypes include δ ( delta) and κ ( kappa) nociception/opioid-receptor-like subtype 1 (ORL-1) receptors Some opioids, eg , nalbuphine , a mixed agonist-antagonist, are capable of producing an agonist (or partial agonist) effect at one opioid receptor subtype and an antagonist effect at another

26. Opioid receptor subtypes, their functions, and their endogenous peptide affinities

27. Classifications of opioids

28. Common opioid analgesics

29. Endogenous Opioid Peptides Opioid alkaloids produce analgesia through actions at central nervous system (CNS) receptors the receptors also respond to certain endogenous peptides with opioid-like pharmacologic properties these endogenous substances are known as endogenous opioid peptides . Three families of endogenous opioid peptides have been described: the endorphins, endorphins, the pentapeptide enkephalins (methionine- enkephalin [met- enkephalin ] and leucine- enkephalin [ leu-enkephalin ]), and the dynorphins . These three families of endogenous opioid peptides have overlapping affinities for opioid receptors

30. endogenous opioid peptides The endogenous opioid peptides are derived from three precursor proteins: prepro-opiomelanocortin (POMC), preproenkephalin ( proenkephalin A), and preprodynorphin ( proenkephalin B ). POMC contains the met- enkephalin sequence, β- endorphin, and several nonopioid peptides, including adrenocorticotropic hormone (ACTH), β- lipotropin , and melanocyte-stimulating hormone Preproenkephalin …. contains six copies of met- enkephalin and one copy of leu -encephalin Leu - and met- enkephalin have slightly higher affinity for the δ (delta) than for the µ-opioid receptor Preprodynorphin yields several active opioid peptides that contain the leu-enkephalin sequence dynorphin A, dynorphin B, and α and β neoendorphins

31. endogenous opioid peptides In contrast to the analgesic role of leu - and met- enkephalin , an analgesic action of dynorphin A—through its binding to κ-opioid receptors—remains controversial Pharmacokinetics of Exogenous Opioids Most opioid analgesics are well absorbed when given by S C, IM, and PO. Certain analgesics such as codeine and oxycodone are effective orally ……have reduced first-pass metabolism nasal insufflation of certain opioids can rapidly result in therapeutic blood levels. Other routes of opioid administration include oral mucosa via lozenges, and the transdermal route via patches. transdermal can provide delivery of potent analgesics over days.

32. Distribution Although all opioids bind to plasma proteins with varying affinity, the drugs rapidly leave the blood and distributed to brain , lungs, liver, kidneys, and spleen. Drug concentrations in skeletal muscle may be much lower, but this tissue serves as the main reservoir because of its greater bulk . fatty tissue …accumulation can be very important, particularly after frequent high-dose for drugs that are slowly metabolized, eg , fentanyl .

33. Metabolism The opioids are converted in large part to polar metabolites (mostly glucuronides For example, morphine, which contains free hydroxyl groups, is primarily conjugated to morphine-3-glucuronide (M3G ), M3G has neuroexcitatory properties ( not mediated by µ receptors) approximately 10% of morphine …….> morphine-6-glucuronide (M6G ), analgesic potency four to six times that of its parent compound. These metabolities have limited ability to cross the blood-brain barrier and probably do not contribute significantly to the usual CNS A ccumulation of these metabolites may produce unexpected adverse Especialy with larger dose and renal failure This can result in M3G-induced CNS excitation (seizures) or enhanced and prolonged opioid action produced by M6G ..

34. Hepatic p450 metabolism Hepatic oxidative metabolism is the primary route of the phenylpiperidine opioids (fentanyl, meperidine, alfentanil , sufentanil ) accumulation of a demethylated metabolite of m eperidine , normeperidine , occur in patients with decreased renal function and in those receiving multiple high doses of the drug. normeperidine may cause seizures. In contrast, no active metabolites of fentanyl have been reported.

35. Hepatic p450 metabolism Codeine, oxycodone, and hydrocodone undergo metabolism by P450 isozyme CYP2D6, resulting in the production of metabolites of greater potency . For example, Codeine demethylated morphine Slow metabolizer experience no significant analgesic effect ultra-rapid metabolizers experience respiratory depression and death Hydrocodone hydromorphone H3G (excitatory) Oxycodone oxymorphone ( O3G).

36. Metabolism Genetic polymorphism of CYP2D6 linked to the variation in analgesic and adverse responses seen among patients. metabolites of oxycodone and hydrocodone (minor consequence) the parent compounds are currently believed to be directly responsible for the majority of their analgesic actions. Accumulation of oxycodone and its metabolites associated with prolonged action and sedation. Methadone is metabolized by mainly CYP2B6

37. Plasma esterase metabolism Esters ( eg , heroin, remifentanil) are rapidly hydrolyzed by common plasma and tissue esterases . Heroin (diacetylmorphine) is hydrolyzed to monoacetylmorphine and finally to morphine, which is then conjugated with glucuronic acid . Excretion Polar metabolites, are excreted mainly in the urine. Small amounts of unchanged drug may also be found in the urine . Enterohepatic circulation…. glucuronide conjugates (but small portion) In patients with renal impairment active polar metabolites effect should be considered before the administration of potent opioids such as morphine

38. Cellular actions At the molecular level, opioid receptors form a family of proteins that physically couple to G proteins this interaction affect ion channel gating , modulate intracellular Ca2+ disposition , and alter protein phosphorylation The opioids have two well-established direct Gi /0 protein-coupled actions they close voltage-gated Ca2+ channels on presynaptic nerve terminals and thereby reduce transmitter release, and they open K+ channels and hyperpolarize and thus inhibit postsynaptic neurons

39. Relation of physiologic effects to receptor type.. The majority of currently available opioid analgesics act primarily at the µ-opioid receptor Analgesia and the euphoriant , respiratory depressant , and physical dependence properties of morphine result principally from actions at µ receptors . opioid analgesic effects are complex and include interaction with δ and κ receptors.

40. Relation of physiologic effects to receptor type... µ-receptor–selective agonists could be clinically useful if their side-effect profiles were more favorable than those found with current µ-receptor agonists, such as morphine. Although morphine does act at κ and δ receptor sites, it is unclear to what extent this contributes to its analgesic action. The endogenous opioid peptides differ from most of the alkaloids in their affinity for the δ and κ receptors

41. Relation of physiologic effects to receptor type... T o develop opioid analgesics with a reduced incidence of respiratory depression or propensity for addiction and dependence compounds that show preference for κ-opioid receptors have been developed. Butorphanol and nalbuphine have shown some clinical success as analgesics, but they can cause dysphoric reactions and have limited potency. B utorphanol has also been shown to cause significantly greater analgesia in women than in men.

42. Relation of physiologic effects to receptor type... Another approach to improve the therapeutic window of drugs that target opioid receptors is to develop opioid-like molecules that are analgesic but have significantly reduced adverse side effects (respiratory depression, constipation, and dependence).

43. Tolerance and dependence Tolerance ….is a gradual loss in effectiveness Attempts to reproduce the original analgesic response require a larger dose to be administered (with variable success). Along with tolerance, physical dependence develops. Physical dependence is a characteristic withdrawal or abstinence syndrome when a drug is stopped or an antagonist is administered

44. Mechanisms of opioid tolerance The mechanism of development of opioid tolerance and physical dependence is poorly understood , Hypothesis persistent activation of µ receptors during severe chronic pain appears to play a primary role A second hypothesis for the development of opioid tolerance and dependence is based on the concept of receptor recycling. activation of µ receptors by endogenous ligands results in receptor endocytosis followed by resensitization and recycling of the receptor to the plasma membrane methadone , a µ-receptor agonist used for the treatment of opioid tolerance and dependence, induces receptor endocytosis

45. Opioid-induced hyperalgesia (OIH) Hyperalgesia opioid can increase the sensation of pain, resulting in a state of hyperalgesia in persistent administration can be produced from morphine , fentanyl, and remifentanil. Emerging targets for OIH Spinal dynorphin and activation of the bradykinin and Antagonizing NMDA receptors have emerged as important candidates for the mediation of opioid-induced hyperalgesia.

46.  Organ System Effects of Morphine and Its Surrogates Central nervous system effects The principal effects of opioid analgesics with affinity for µ receptors are on the CNS; the more important ones include analgesia , euphoria , sedation , and respiratory depression …high degree of tolerance occurs to all of these effects Table: degrees of tolerance that may develop to some of the effects of the opioids. High Moderate Minimal or None Analgesia Euphoria, dysphoria Bradycardia Miosis Mental clouding Sedation Constipation Respiratory depression Antidiuresis Convulsions Cough suppression

47. Analgesia Pain consists of both sensory and affective (emotional) components. Opioid analgesics are unique in that they can reduce both aspects of the pain experience NSAID….do not affect emotional aspect Euphoria IV drug users who receive morphine experience a pleasant floating sensation with lessened anxiety and distress. dysphoria, an unpleasant state characterized by restlessness and malaise, also may occur. Sedation Drowsiness and Sleep induction is induced More common in elderly the patient can be easily aroused from this sleep (but morphine with other central depressant drugs such as the sedative-hypnotics may result in very deep sleep)

48. Respiratory depression All of the opioid analgesics can produce significant respiratory depression by inhibiting brainstem respiratory mechanisms. Dose dependent Cough suppression Suppression of the cough reflex is a well-recognized action of opioids. Therapeutic use Codeine used for pathologic cough. However , cough suppression by opioids may allow accumulation of secretions and thus lead to airway obstruction and atelectasis .

49. Miosis Miosis is a pharmacologic action to which little or no tolerance develops, even in highly tolerant addicts it is valuable in the diagnosis of opioid overdose. blocked by opioid antagonists and be blocked by atropine. Truncal rigidity Several opioids can intensify tone in the large trunk muscles. Likely mediated by supraspinal action is likely. The effect is most apparent when high doses of the highly lipid-soluble opioids ( eg , fentanyl, sufentanil , alfentanil , remifentanil) are rapidly administered intravenously . overcome by administration of an opioid antagonist, which of course will also antagonize the analgesic action of the opioid. Preventing truncal rigidity while preserving analgesia requires the concomitant use of neuromuscular blocking agents.

50. Nausea and vomiting opioid analgesics can activate the brainstem chemoreceptor trigger zone to produce nausea and vomiting. Temperature Homeostatic regulation of body temperature is mediated in part by the action of endogenous opioid peptides in the brain. Agonist produce hyperthermia .

51. Peripheral effects Cardiovascular system Most opioids have no significant direct effects on the heart and, other than bradycardia , no major effects on cardiac rhythm. Exception…… Meperidine ( antimuscarinic action can result in tachycardia) BP…..Hypotension due to peripheral arterial and venous dilation central depression of vasomotor-stabilizing mechanisms and release of histamine. No consistent effect on cardiac output is seen, and the electrocardiogram is not significantly affected ..

52. Gastrointestinal tract Opioid receptors exist in high density in GIT, Effect……Constipation In the large intestine, propulsive peristaltic waves are diminished and tone is increased ; this delays passage of the fecal mass and allows increased absorption of water, which leads to constipation……the basis for the use of opioids in the management of diarrhea, mediated gastric secretion of hydrochloric acid is decreased.

53. Biliary tract The opioids contract biliary smooth muscle, which can result in biliary colic Renal Renal function is depressed by opioids. It is believed that in humans this is chiefly due to decreased renal plasma flow. In addition, µ receptor opioids have an antidiuretic effect in humans. enhance renal tubular sodium reabsorption. Uterus The opioid analgesics may prolong labor. Fentanyl and meperidine (pethidine) inhibit uterine contractility morphine had no reported effects

54. Endocrine Opioids stimulate the release of ADH, prolactin, and somatotropin but inhibit the release of luteinizing hormone chronic opioid therapy can have low testosterone resulting in decreased libido, energy, and mood. Women can experience dysmenorrhea or amenorrhea. Pruritus The opiates, such as morphine and codeine, produce flushing and warming of the skin accompanied sometimes by sweating , urticaria , and itching

55. Clinical Use of Opioid Analgesics Analgesia Acute Pulmonary Edema Cough Diarrhea Shivering Applications in Anesthesia

56. Dependence versus addiction

57. Introduction… There is a conceptual and mechanistic separation of “dependence” and “addiction .” The older term “physical dependence” ……..dependence “ psychological dependence” ….. addiction. Every addictive drugs produce acute effects, but they all induce strong feelings of euphoria and reward. With repetitive exposure…..induce adaptive changes such as tolerance ( ie , escalation of dose to maintain effect ) If the drug is no longer available ………”withdrawal syndrome” Dependence is not always a correlate of drug abuse — it can also occur with many classes of non-psychoactive drugs, eg , sympathomimetic VC & VD Addiction, on the other hand, consists of compulsive, relapsing drug use despite negative consequences Non-substance-dependent disorders

58. Introduction… Although dependence invariably occurs with chronic exposure, only a small percentage of subjects develop a compulsion, lose control, and become addicted. For example, very few patients who receive opioids as analgesics desire the drug after withdrawal. And only (1 out of 6 ) become addicted within 10 years of first use of cocaine. Conversely , relapse is very common in addicts after a successful withdrawal when, by definition, they are no longer dependent.

59. Addictive drugs increase the level of dopamine (da): reinforcement mesolimbic dopamine system as the prime target of addictive drugs. This system originates in the ventral tegmental area (VTA), VTA…….projects to the nucleus accumbens ( NAc ), the amygdala, the hippocampus, and the prefrontal cortex Most projection neurons of the VTA are dopamine-producing neurons. As dopamine neurons of the VTA fires…… dopamines are released in the nucleus accumbens and the prefrontal cortex. Direct application of drugs into the VTA also acts as a strong reinforcer , and systemic administration of drugs of abuse causes release of dopamine. Even selective activation of dopamine neurons is sufficient to drive reinforcement and elicit adaptive behavioral changes typically observed with addictive drugs.

60. Figure: Major connections of the mesolimbic  dopamine  system in the brain

61. As a general rule, all addictive drugs activate the mesolimbic dopamine system each addictive drug has a specific molecular target to activate the mesolimbic system, three classes can be distinguished: Drugs that binds to Gio protein-coupled receptors, Drugs that interacts with ionotropic receptors or ion channels, and Drugs that targets the dopamine transporter MOA… The first is a direct stimulation of the dopamine neurons ( eg , nicotine). The second mechanism is the interference with the reuptake of dopamine or the promotion of nonvesicular release ( eg , amphetamines).

62. CNS Stimulants

63. Introduction Molecular Basis of CNS Stimulants Imbalance between inhibitory and excitatory processes as in the brain. This hyper-excitability of neurons results from: potentiation or enhancement of excitatory neurotransmission (e.g. amphetamine) depression or antagonism of inhibitory transmission (e.g. Strychnine) presynaptic control of neurotransmitter release (e.g. picrotoxin)

64. Introduction Central nervous system (CNS) stimulants are common in clinical practice, and have a high potential for abuse but still have legitimate uses in clinical practice The CNS stimulants can be classified as analeptic stimulants psychomotor stimulants Methylthantines Analeptic stimulants analeptic stimulants ’ historically describes a group of drugs used to lighten narcosis , stimulate respiratory centers and restore depressed central nervous system function

65. Analeptics Analeptics can be subcategorized as convulsants (strychnine, picrotoxin and bicuculline ) or respiratory stimulants ( doxapram , nikethamide and pentylenetetrazole ) convulsants Strychnine ……… Although highly toxic , the plant alkaloid strychnine was used in medicinal tonics until the early 20th century MOA …. causes CNS excitation by competitively antagonizing glycine it is used as an adulterant in illicit drugs such as heroin No longer used in clinical practice , strychnine is available as a rodenticide

66. Strychnine… Low dose heightened awareness, restlessness and tachypnea High dose exaggerated motor responses to visual , auditory and tactile stimulation , tonic extension, Generalized convulsions , and respiratory arrest

67. Convulsants … Picrotoxin MOA….nonspecific in that it is a potent antagonist at GABAA and GABAC, moderate at glycine, and weak at 5HT3 receptors. it has been used a a CNS stimulant and an antidote in poisoning by CNS depressants, especially the barbiturates. In medical laboratory ……to induce convulsion in animal model

68. Convulsants Bicuculline is also a competitive antagonist of GABAA respiratory stimulants Doxapram and Nikethamide - used to counteract postanesthetic respiratory depression and for acute hypercapnia in chronic pulmonary disease. Pentylenetetrazole - used clinically as a tool for screening to screen compounds for anti-epileptic activity

69. Psychomotor stimulants This group includes sympathomimetic amides, such as amphetamines, cocaine , and ephedrine. Sympathomimetic effects are produced…. chronotropy , inotropy , vasoconstriction, bronchodilation, respiratory stimulation, increase in wakefulness and psychomotor activity, muscle tremor, and appetite suppression.

70. Psychomotor stimulants Sympathomimetics can be subclassified based on their site of the action: direct acting (acting at the post-synaptic adrenoreceptors ), indirect acting, or dual acting (working through both direct and indirect mechanisms ). MOAs of indirect acting agents Indirect acting sympathomimetics can work through several mechanisms by preventing re-uptake of monoamines Uptake-1 (cocaine ) and Uptake-2 inhibitors corticosteroids and bhaloalkylamines (e.g. phenoxybenzamine ). By inhibiting transport into intracellular storage vesicles (-) VMAT-2, so increasing cytosolic concentrations of monoamines . VMAT inhibitors include amphetamines, methamphetamines by preventing metabolic degradation of catecholamines Not considered as CNS stimulants

71. A mphetamines Amphetamines are a group of synthetic phenyl ethylamine derivatives, structurally similar to noradrenaline and dopamine Substitutions to the basic chemical structure of the parent compound amphetamine can produce multiple amphetamine analogues (Figure )

72. Amphetamines (Not substrate for COMT & MAO) Amphetamines are potent psychomotor stimulants which readily cross the BBB resulting in I ncrease wakefulness , alertness, excitement euphoria Reduce fatigue , insomnia , appetite

73. Medical uses of Amphetamines Despite widespread illicit use, amphetamines have legitimate medical indications such as management (ADHD) and narcolepsy. Previously amphetamines such as sibutramine Used as anorexiants to aid weight loss. S/E Repeated doses of amphetamines have been reported to cause psychotic behavior with accompanying paranoia, Aggressive behavior and hallucinations Chronic use is associated tolerance and physical dependence Amphetamine use with other agents ( e.g cocaine)… sympathetic overstimulation

74. Amphetamines S/E… Enhanced sympathetic activity in the perioperative period may result in haemodynamic instability, severe hypertension, cardiac dysrhythmias, myocardial ischaemia , altered pain perception. Table: Selected agents for acute management of hypertensive crises in adults due to amphetamines

75. MDMA (‘ecstasy’) D emonstrates both CNS stimulatory and hallucinogenic effects. It remains a popular recreational drug which is widely abused . MOA acts as a potent indirect serotonergic agonist , Blocking serotonin re-uptake at the serotonin transporter, and stimulating an efflux of serotonin from storage vesicles. Noradrenaline and dopamine release are also enhanced.

76. MDMA (‘ecstasy ’)….. MDMA consumption is associated with increase in serotonin causes excessive production of antidiuretic hormone ( ADH) fatal hyponatremia. hyperthermia leading to rhabdomyolysis secondary to serotonergic effects at the hypothalamic thermoregulatory center. Fulminant hepatic failure

77. Methylphenidate MOA…..Block dopamine and noradrenaline re-uptake transporters abused intranasally and intravenously Methylphenidate acts to improve attention, alertness , reduce fatigue and can induce a feeling of euphoria

78. Cocaine Cocaine is a natural alkaloid extracted from Erythroxylon coca leaves . At low concentrations, cocaine acts by blocking the reuptake of noradrenaline , dopamine and serotonin at the blocking membrane transporters. At higher concentrations, cocaine blocks voltage-gated Na + and K+ channels In clinical practice, cocaine is still used to provide topical anaesthesia and vasoconstriction for nasal procedures ; . Cocaine is well recognized as a drug of misuse, and is associated with morbidity and mortality. Associated with…..Myocardial ischaemia , coronary artery vasospasm, tachyarrhythmias & uncontrolled hypertension,

79. Cocaine Associated with ….. Myocardial ischaemia , coronary artery vasospasm , tachyarrhythmias & uncontrolled hypertension , intracerebral haemorrhage

80. Modafinil MOA …. The exact mechanism of action is unclear, In vitro studies it to inhibit the reuptake of dopamine (+ It activates glutamatergic circuits while inhibiting GABA Medical Uses licenced for treatment of excessive daytime somnolence associated with narcolepsy. It improves cognition mood & Decreases fatigue Recovery from anesthesia ( single dose 200 mg dose of )

81. Methylxanthines Drugs in this class : theophylline , caffeine MOA …. act as non-specific adenosine antagonists and competitive inhibitors of cAMP -phosphodiesterase Allow cAMP to build in the cells

82. Pharmacodynamics effect cAMP produces CNS stimulation , increase in myocardial contractility, smooth muscle relaxation (including bronchodilation) and diuresis . Theophylline is used for both the acute and chronic management of asthma and ( COPD) Theophylline has a narrow therapeutic index at lower concentrations, theophylline causes bronchodilatory , antiinflammatory and immunomodulatory effects; at higher concentrations, agitation, tachycardia, dysrhythmias, and seizures may occur.

83. Caffeine has a more favourable safety profile

84. Nonaddictive drugs of abuse