NEUROSCIENCE REVIEW DRUGS FOR HEADACHES, ANTICHOLINESTERASES, OPIOID ANALGESICS. Harvey Berman, PhD, MPH

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1 NEUROSCIENCE REVIEW DRUGS FOR HEADACHES, ANTICHOLINESTERASES, OPIOID ANALGESICS Harvey Berman, PhD, MPH

2 ERGOT ALKALOIDS

3 Claviceps purpurea fungal sclerotia growing on barley Ergot in barley

4 WHAT IS THIS? Seizures, headache, muscle spasms, diarrhea, nausea, vomiting Gangrene of the fingers and toes Ergotism

5 The following signs are indicative of ergot poisoning? Ischemia secondary to constriction of peripheral arteries and arterioles. Extremities become cold, pale, and numb. Muscle pain develops. Gangrene may result.

6 PATHOLOGY OF MIGRAINE HEADACHE A neurovascular disorder Vasodilation Inflammation Neural events à vasodilation à pain Key components Neurons of the trigeminal vascular system, which innervate the intracranial blood vessels Important roles CGRP: promotes migraine Serotonin: suppresses migraine

7 IMPLICATION OF CGRP IN MIGRAINE HEADACHE Plasma levels of CGRP rise during a migraine attack Stimulation of neurons of the trigeminal vascular system promotes release of CGRP CGRP promotes vasodilation and release of inflammatory neuropeptides Sumatriptan relieves migraine, lowers elevated levels of CGRP Sumatriptan suppresses release of CGRP from cultured trigeminal neurons

8 IMPLICATION OF SEROTONIN IN MIGRAINE HEADACHE Plasma levels of 5-HT drop by 50% during a migraine attack Depletion of 5-HT with reserpine can precipitate an attack in migraine-prone individuals Administration of 5-HT or sumatriptan, both of which can activate 5-HT receptors, can abort an ongoing attack.

9 DURING A MIGRAINE ATTACK CGRP Serotonin

10 OVERVIEW OF DRUG TREATMENT OF MIGRAINES Drugs used to abort an attack Nonspecific analgesics Aspirin-like agents Opioid analgesics Migraine-specific drugs Ergot alkaloids Drugs used to prevent an attack β-blockers (e.g., propranolol) TCA (e.g., amitriptyline [ELAVIL]) AED (e.g., divalproex [DEPAKOTE]) Serotonin 1B/1D agonists (Triptans)

11 DRUGS FOR TREATMENT OF MIGRAINES ABORTIVE THERAPY Principles Drug selection depends on the intensity of the attack Mild à aspiring, acetaminophen, ibuprofen Moderate-to-severe à migraine-specific drug Ergot alkaloid Ergotamine Dihydroergotmine Serotonin 1B/1D agonist Opioid analgesic may be necessary Butorphanol

12 Which of the following is a serotonin agonist useful for aborting an acute migraine headache and is not derived from a fungus? A. Bromocritpine B. Cimetidine C. Ergotamine D. LSD E. Nitroprusside F. Phenoxybenzamine G. Sumatriptan

13 Which of the following is the most useful for reversing severe ergot-induced vasospasm? A. Bromocritpine B. Cimetidine C. Ergotamine D. LSD E. Nitroprusside F. Phenoxybenzamine G. Sumatriptan

14 The use of sumatritpan is contra-indicated in which of the following conditions? A. Post-partum women B. Uncontrolled hypertension C. Moderate to unresponsive severe migraines D. Hepatic insufficiency E. Renal dysfunction

15 The therapeutic effect of the triptan class of drugs is caused by which mechanism of action? Antagonism of serotonin 5-HT 2 receptors Stimulation of serotonin 5-HT 1D receptors Antagonism of dopamine receptors Antagonism of α-adrenergic receptors

16 A 35-year-old woman with a history of migraine reports to her physician that the last time she used her medicine to stop an acute attack of migraine, she felt numbness and tingling in her extremities and blanching and cyanosis of her fingers. Which one of the following medicines did she take? A. Sumatriptan B. Dihydroergotamine C. Morphine D. Naproxen

17 DRUGS FOR TREATMENT OF MIGRAINES ABORTIVE THERAPY Use of abortive medications (nonspecific and migraine-specific) should be limited to 1 or 2 days a week. Why? More frequent use can lead to medication overuse headache (drug-rebound headache)

18 ANALGESICS ABORTIVE MIGRAINE THERAPY Aspirin-like drugs Aspirin Acetaminophen (used in combination with other drugs) Ibuprofen Opioid analgesics Butorphanol nasal spray (STADOL-NS) Meperidine (DEMEROL)

19 ERGOT ALKALOIDS: ERGOTAMINE ABORTIVE MIGRAINE THERAPY Mechanism of action Precise mechanism unknown Alters neurotransmission at: Serotonergic junctions à 5-HT 1B and 5-HT 1D receptor subtypes Dopaminergic junctions α-adrenergic junctions Appears to suppress inflammation Associated with trigeminal vascular system By suppressing release of CGRP

20 ERGOT ALKALOIDS: ERGOTAMINE ABORTIVE MIGRAINE THERAPY Mechanism of action Cranial arteries Ergotamine acts directly to cause vasoconstriction Reduces amplitude of pulsations Can effect blood flow by depressing the vasomotor center.

21 ERGOT ALKALOIDS: ERGOTAMINE ABORTIVE MIGRAINE THERAPY Therapeutic uses Pharmacokinetics Oral / sublingual bioavailability = low Rectal / inhalation bioavailability = high Overdose Ergotism Ischemia secondary to constriction of peripheral arteries and arterioles. Extremities become cold, pale, and numb. Muscle pain develops. Gangrene may result.

22 ERGOT ALKALOIDS: ERGOTAMINE ABORTIVE MIGRAINE THERAPY Drug interactions Should not be combined with Triptans (e.g., sumatriptan, etc) Could lead to prolonged vasospastic reaction. How to avoid vasospastic reaction? Dosing of ergot alkaloid and serotonin agonists should be separated by at least 24 hours Physical dependence Withdrawal syndrome è headache, nausea, vomiting, restlessness (i.e., it resembles a migraine attach) These symptoms are likely to cause patient to resume dosing the drug, perpetuating a cycle of dependence.

23 ERGOT ALKALOIDS: ERGOTAMINE ABORTIVE MIGRAINE THERAPY Contraindications Hepatic or renal impairment Sepsis à gangrene Coronary artery disease Peripheral vascular disease Should not be taken during pregnancy. Why? Promotes uterine contractions à fetal harm or abortion FDA Pregnancy Risk category X à Risk outweighs any benefits

24 ERGOT ALKALOIDS: DIHYDROERGOTAMINE ABORTIVE MIGRAINE THERAPY Similar to ergotamine But, less nausea and vomiting No physical dependence Minimal peripheral vasoconstriction (when used alone) Diarrhea is prominent

25 ERGOT ALKALOIDS: DIHYDROERGOTAMINE ABORTIVE MIGRAINE THERAPY Pharmacokinetics Administered parenterally or by nasal spray Not orally à extensive first-metabolism CYP3A4 Pharmacologically active metabolite à 8 -hydroxydihydroergotamine Combined half-life = 21 hours

26 ERGOT ALKALOIDS: DIHYDROERGOTAMINE ABORTIVE MIGRAINE THERAPY Drug interactions Potent inhibitors of CYP3A4 can raise dihydroergotamine to dangerous levels à risk of intense vasospasm Thus, concurrent use of CYP3A4 inhibitors is contra-indicated. HIV protease inhibitors (ritonavir, nelfinavir) Azole antifungal agents (ketoconazole, itraconazole) Macrolide antibiotics (azithromycin, clarithromycin) Less potent inhibitors should be used with caution Saquinavir, fluconazole, grapefruit juice Should not be administered within 24 hours of a serotonin agonist (e.g., sumatriptan)

27 ERGOT ALKALOIDS: DIHYDROERGOTAMINE ABORTIVE MIGRAINE THERAPY Contra-indications Patients with CAD Peripheral vascular disease Sepsis Pregnancy Hepatic or renal impairment Must not be combined with potent CYP3A4 inhibitors

28 TRIPTANS Sumatriptan

29 SEROTONIN 1B/1D -RECEPTOR AGONISTS TRIPTANS Relieve migraine pain by Constricting intracranial blood vessels Suppressing release of inflammatory neuropeptides

30 SUMATRIPTAN [IMITREX] Mechanism of action Analog of serotonin Selective stimulation of 5-HT 1B and 5-HT 1D receptors No affinity for 5HT 2 or 5-HT 3 Does not bind to adrenergic, dopaminergic, muscarinic, histaminergic receptors. Binding to 5-HT 1B and 5-HT 1D receptors On intracranial blood vessels à vasoconstriction On sensory nerves of the trigeminal vascular system à suppresses release of CGRP à reduces release of inflammatory neuropeptides à diminishes perivascular inflammation

31 SUMATRIPTAN [IMITREX] Mechanism of action (a slide of its own) Binding to 5-HT 1B and 5-HT 1D receptors On intracranial blood vessels à vasoconstriction On sensory nerves of the trigeminal vascular system à suppresses release of CGRP à reduces release of inflammatory neuropeptides à diminishes perivascular inflammation

32 SUMATRIPTAN [IMITREX] Therapeutic use To abort an ongoing migraine attack Pharmacokinetics Oral / intranasal administration à low bioavailability ( 15%) Sub-Q à high bioavailability ( 97%) Metabolism Hepatic with elimination in urine Half-life = short ( 2.5 hrs)

33 SUMATRIPTAN [IMITREX] Adverse effects Chest symptoms (heavy arms, chest pressure, but no pain) Not related to ischemic heart disease Coronary vasospasm (rare) Teratogenesis Sumatriptan should be avoided during pregnancy Should be avoided if pregnant or planning to become pregant FDA Pregnancy Risk category C

34 SUMATRIPTAN [IMITREX] Drug interactions Ergot alkaloids + Triptans ALL cause vasoconstriction Excessive prolonged vasospasm can occur Thus, sumatriptan should not be used within 24 hours of an ergot drug or another triptan. Monoamine oxidase inhibitors Can inhibit or depress degradation of sumatriptan à plasma levels to rise. Sumatriptan and MAO-Is should not be used together. Sumatriptan should not be used within 2 weeks of stopping an MAO-I.

35 OTHER SEROTONIN 1B/1D -RECEPTOR AGONISTS All are administered orally; one zolmitriptan is also given by intranasal spray. All are equal to sumatriptan in efficacy and safety. All have the same mechanism of action: Activation of 5-HT1B/1D receptors à intracranial vasoconstriction + decreased perivascular inflammation All have FDA Pregnancy Risk category C Selection of one or another is based on: pharmacokinetics, side effects, and drug interactions

36 ANTI-CHOLINESTERASES

37 WHAT ARE ANTI-CHOLINESTERASES? They are drugs that inhibit (block or reduce) the enzyme activity of AchE. They exert effects on Skeletal muscle Structures innervated by the parasympathetic nervous system Thus, their actions are physiologically widespread

38 ACTION OF ANTI-ACHES They inhibit AchE. Prolong action of Ach in synapse at Muscarinic sites Nicotinic sites Ganglia Skeletal muscle

39 ACTIONS OF ANTICHOLINESTERASE AGENTS Inhibition of AchE Prolongs the action of Ach + Excessive stimulation at muscarinic and nicotinic sites

40 STEPS IN CHEMICAL NEUROTRANSMISSION

41 CHOLINERGIC NEUROTRANSMISSION

PARASYMPATHETIC NERVOUS SYSTEM Constricts pupil, stimulates lacrimation, alters shape of lens Stimulates salivation Constricts bronchi ß HR, impulse conduction; ß

43 PARASYMPATHETIC NERVOUS SYSTEM Constricts pupil, stimulates lacrimation, alters shape of lens Stimulates salivation Constricts bronchi ß HR, impulse conduction; ß automaticity Stimulates gallbladder contraction Stimulates gastric acid secretion; increases gastric, intestinal motility Contracts bladder detrusor, relaxes sphincter Causes erection

45 PsNS SNS Pre-ganglionic fibers Long Short Post-ganglionic fibers Short Long Ganglia Closer to target organs Closer to spinal cord

47 CHOLINERGIC SYNAPSES AchE is the enzyme that inactivates the neurotransmitter Ach. AchR is located on surface of smooth muscle and skeletal muscle.

48 ANTI-ACHES EXERT ACTIVITY AT NICOTINIC AND MUSCARINIC ACHR machr: anti-aches produce excessive muscarinic stimulation Lacrimation Salivation Miosis ß HR nachr: anti-aches produce muscle fasciculation (initial) and then paralysis

49 TWO FAMILIES OF ANTI-ACHES Irreversible (long-acting) DFP (Isofluorophosphate) Echothiophate Reversible Neostigmine (Prostigmin) Physostigmine Edrophonium (Tensilon) Tacrine (Cognex)

50 EFFECTS OF ANTI-ACHES ON SKELETAL MUSCLE Prototype: Neostigmine Increases the actions of Ach released from motor nerves that innervate skeletal muscle. Increases activity of SKM by stimulating nicotinic receptors on the muscle cells. High doses cause excessive and prolonged skeletal muscle stimulation Þ muscle fatigue or paralysis.

51 EFFECTS OF ANTI-ACHES ON ANS Neostigmine inhibits breakdown of Ach at: Muscarinic sites Autonomic ganglia

52 MUSCARINIC SIGNS OF ANTI-ACHES - 1 Eye Constriction of pupil (miosis) Heart ß HR ß Automaticity; ß Electrical impulse conduction

53 MUSCARINIC SIGNS OF ANTI-ACHES - 2 GI tract Ý Tone Ý Motility Relaxation of sphincters Ý Gastric acid secretion

54 MUSCARINIC SIGNS OF ANTI-ACHES - 3 Urinary tract Stimulation of bladder detrusor muscle Relaxation of urinary sphincter muscle.

55 MUSCARINIC SIGNS OF ANTI-ACHES - 4 Lung Bronchoconstriction Ý Mucous secretion in respiratory tract

56 MUSCARINIC SIGNS OF ANTI-ACHES - 5 Other Ý Sweat-lachrymal gland activity Autonomic Ganglia Effects on autonomic ganglia are possible with high doses Outcome is unpredictable

57 THERAPEUTIC USES Myasthenia gravis Glaucoma Alzheimer's Disease Atropine overdose

58 REPRESENTATIVE ANTI-CHOLINESTERASE AGENTS Neostigmine Physostigmine Pyridostigmine Why is physostigmine least useful in treatment of myasthenia gravis?

59 ORGANOPHOSPHATE ANTI-CHOLINESTERASE AGENTS Irma Pelicano is hard at work in her garden, spraying her roses and irises when she slips and breathes in a large amount of a plant pesticide. Which of the following signs would not be expected if the pesticide was an organophosphate agent? A. Pinpoint pupils B. Dry mouth C. Lachrymation D. Browache

60 What signs are expected if an individual is exposed to an organophosphate nerve gas? DFP Sarin Soman

61 What signs are expected if an individual is exposed to an organophosphate nerve gas? DFP Sarin Soman Bronchi Heart GI tract GU tract Eyes Sweat glands

62 MYASTHENIA GRAVIS A disease characterized by: Weakness and fatigue of skeletal muscle The defect is in neurotransmission at the neuromuscular junction It is an autoimmune disease that results in a reduced number of nicotinic receptors

63 MYASTHENIA GRAVIS Diagnosis Edrophonium (Tensilon, 2 mg), an anti-ache of rapid onset and very short duration is given i.v. Myasthenic patients show a brief improvement. Normal patients do not.

64 MYASTHENIA GRAVIS Treatment Anti-AchE agents are mainstay of therapy e.g., Pyridostigmine, Neostigmine. They improve efficiency of neuromuscular cholinergic transmission Dose needs to be carefully controlled. Why?

65 OCULAR Treatment of wide-angle glaucoma Anti-AchE agents inhibit AchE Causing a build-up of Ach in the iris muscle Leads to contraction of the iris (miosis) Increasing the flow of aqueous humor through the Canal of Schlemm Lowering of intraocular pressure How do the actions of this drug compare with those of pilocarpine?

66 ALZHEIMER S DISEASE A neurodegenerative disorder Loss of cholinergic neurons Therapy is palliative Aim is to increase cholinergic neurotransmission by increasing the amount of Ach in the CNS

67 ALZHEIMER S DISEASE Useful agents are reversible anti-aches Tacrine, among others Main requirement? That the drugs penetrate into the CNS

68 ANTI-ACHE POISONING Inadvertent overdose Therapeutic agents Insecticides Intentional Chemical agents of warfare Nerve gases: DFP, sarin, soman

69 THERAPY OF ANTI-ACHE POISONING Administration of 2 agents Atropine Protects machr from excessive stimulation by Ach 2-PAM Restores activity of AchE

70 ANTICHOLINESTERASES Therapeutic utility Glaucoma Myasthenia gravis Alzheimer s Disease Atropine overdose

71 WHERE IS ACETYLCHOLINE RELEASED? Muscarinic sites Eye Tear ducts Salivary glands Heart Sweat glands GI tract Urinary tract Brain Nicotinic sites Skeletal muscle Autonomic ganglia

72 OPIOID ANALGESICS

73 OPIOID ANALGESICS Morphine (9-17 % by weight opium) Chiefly responsible for pharmacological actions of opium Codeine (0.3-4 %) Methylmorphine, has similar but weaker actions Thebaine (0.2 %) Practically devoid of analgesic activity No medicinal use, but it provides a synthetic route of hydroxylated opioids

74 TRUE OR FALSE Opioids are not effective in relieving sharp intermittent pain. False Continuous dull pain is relieved more effectively than sharp intermittent pain. However, even sharp pain can be relieved with sufficiently large doses.

75 TRUE OR FALSE In pain-free individuals, the response to morphine is generally pleasant, relieving feelings of anxiety and fear. False In patients suffering from pain, morphine induces a feeling of well being and tranquility (euphoria). In pain-free individuals, the response to morphine is not always pleasant: General malaise Sensations of anxiety or fear (dysphoria)

76 TO WHICH OF THE FOLLOWING DOES TOLERANCE NOT DEVELOP? Miosis Depressed respiration Constipation Analgesia Euphoria

77 WHAT ARE THE SIGNS OF OPIOID POISONING? Coma Pinpoint pupils Depressed respiration

78 What is the opioid receptor principally responsible for the analgesic, euphoric, and respiratory depressant actions of morphine? μ κ δ σ

79 OPIOID CASE 1 As a consequence of an ether explosion while working in his organic chemistry lab, a 25-year-old graduate student suffers extensive 3 rd degree burns over his right arm, face and neck. He rates his pain as excruciating, 10 out of 10. The opioid that is least advisable for controlling the student s pain over the course of several weeks is which one of the following? A. Fentanyl B. Morphine C. Meperidine D. Buprenorphine

80 OPIOID CASE 3 A woman is admitted to Kenmore Mercy hospital and is diagnosed with aseptic encephalitis. After a suitable workup, the ER nurse administers an IV dose of morphine to treat the woman s pain. Within 30 seconds the patient feels heavy, unable to move her arms and legs, experiences difficulty breathing, intense fear, and anxiety. How do you explain these reactions?

81 OPIOID CASE 2 An 82 year-old woman with end-stage hepatic cancer is provided with morphine to reduce her pain and suffering. While she has been on morphine over the past month, she has experienced breakthrough pain requiring increased doses of morphine. Although her pain relief improves with the higher drug dose, over a period of several days the patient s pain returns. This outcome: A. is a consequence of acute dysphoria precipitated by chronic morphine treatment B. is to be expected because she is experiencing tolerance to the analgesic effects of morphine C. is to be expected because she has become dependent on morphine and is experiencing an abstinence syndrome D. is to be expected because her pain is neuropathic in origin, and opioid analgesics control such pain less effectively than they control nociceptive pain E. is related to morphine-induced contraction of the sphincter of Oddi

82 OPIOID CASE 4 A former heroin addict is maintained on methadone, but succumbs to temptation and buys an opioid on the street. He takes it and rapidly experiences signs of withdrawal. Which opioid did he buy? A. Meperidine B. Heroin C. Pentazocine D. Codeine

83 USE OF OPIOID ANALGESICS IN PALLIATIVE CARE Elderly patient in pain. How to alleviate pain if higher doses of morphine are required, thus increasing risk of death? Is the physician or should the physician be culpable if the patient dies after administration of a pain-relieving dose of morphine? Consider your response in the context of the Thomistic Doctrine of Double Effect: Foresight vs Intention

84 DOCTRINE OF DOUBLE EFFECT A person may legally perform an action that he foresees will produce a good and a bad effect provided that four conditions are verified at one and the same time: 1. that the action in itself be good or at least indifferent 2. that the good effect and not the evil effect be intended 3. that the good effect not be produced by the evil effect 4. that there be a proportionately grave reason for permitting the evil effect.

85 SOME MAIN POINTS 1. All opioids depress respiration, some more than others. 2. Some increase HR an BP > increased heart work. 3. Of the strong agonists: they are equi-efficacious as analgesics, and differ mainly in potency. 4. Naloxone may not be able in all cases to equally surmount i.e., antagonize the effects of the very potent fentanyl-like agents and the agonist-antagonist agents (e.g., pentazocine).

Cholinergic receptors( cholinoceptors ) are two families muscarinic and nicotinic depending on their affinities to cholinomimetic agents(agents that

Cholinergic receptors( cholinoceptors ) are two families muscarinic and nicotinic depending on their affinities to cholinomimetic agents(agents that Cholinergic drugs Cholinergic drugs Are drugs act on receptors that are activated by acetylcholine(ach) which is the neurotransmitter of the parasympathetic nervous system. ACH is synthesized in the cholinergic