Neuro Pharm Review

1. Neuro Pharm Review John Reed

2. How does a local anasthetic work? • At normal usage [] Na+ channels are blocked on pain fiber neurons

3. What are the properties of an ideal local anesthetic? • 1. Action must be reversible • 2. Non-irritating to the tissues and no secondary local action • 3. Low degree of systemic toxicity (since LA will eventually distribute from site of administration to other tissues) • 4. Rapid onset and sufficient duration of action for the procedure

4. Are local anesthetics (LAs) mainly acids or bases? • Bases (pKa 7.6 to 9.0) with 56 to 98% ionization • Do the free bases or cations cross membranes? • Unionized free bases preferentially cross cell membranes, while cations get stuck in the channels

5. Which LAs have ester (COOC) linkages? • Cocaine, benzocaine, procaine, tetracaine • Which LAs have amide (CNCO) linkages? • Lidocaine, etidocaine, mepivocaine, bupivocaine • Where is the base binding site? • It is just exterior to the activation gate in Na+ ion channels • How do the bases get to this area? • They either flow through the membrane and up through an open inactivation gate or directly through the membrane and protein channel as free base that then links with available H+

6. Which nerve fibers are most sensitive to LAs? • The narrowest diameter (unmyelinated) fibers (C (pain)>B>Aδ (pain and temp)>Aα(proprioception motor)) are the most sensitive • What is the order of recovery from LA nerve block? • The reverse, thickest fibers recover first • What is the most important factor in determining potency of a LA? • Lipid solubility – procaine<lidocaine,mepivacaine<tetracaine, bupivocaine, etidocaine

7. What is the effect of tissue inflammation on LA action? • Inflamed tissue has a lower pH, leading to less free base formation and migration into nerve endings and thus, slower action • Do amides or esters have the longer half lives? • Amides have much longer half lives since they have to be transported to the liver for metabolism whereas esters are broken down in the plasma

8. Epidural – somewhat wide area Subarachnoid space – very wide area Nerve trunk – regional block Local – infiltration, subcut at area to be numbed Surface or topical – apply directly to mucous membranes Where should LAs be injected to acquire certain areas of blockage?

9. Why are vasoconstrictors often coadministered with LAs? • They restrict the site and prolong the duration of action of the LA • Which LAs are broken down rapidly in blood and therefor remain local? • Esters • How are amides distributed? • They remain intact in the blood and are rapidly distributed to highly perfused tissue (like brain and heart) and then redistributed into fat • Where are the LAs metabolised? • Esters in the plasma by pseudoChE and amides in the liver by microsomal esterase

10. What are the first side effects from LAs? • CNS effects, then cardiovascular • What are the CNS side effects of LAs? • First drowsiness, lightheadedness, visual disturbances and restlessness • Then nystagmus and shivering • Finally convulsions, paralysis of ventilatory muscles and death

11. Which general anesthetic (GA) has minimal cardiac effects? • N2O (nitrous oxide) • What GAs cause some cardiac depression? • Enflurane, isoflurane, desflurane (don’t use in patients with COPD, is a lung irritant), sevoflurane (used in peds due to less pungent odor) • What GA causes significant cardiac depression? • Halothane (bradycardia, ↓ CTY, ↓ SVR)

12. How do GAs work? • They seem to bind directly to GABA Cl- channels and do NOT work by sticking in membranes and disrupting ion channels (Meyer-Overton principle)

13. What is the relationship between blood solubility and induction rate in an inhaled GA? • Inverse, lower solubility → higher induction rate (= faster rise in arterial tension) • How are ventilation rate and depth related to induction rate for an inhaled GA? • Direct relationship so ↑ RR and depth or respiration → ↑ induction rate • What is the relationship between pulmonary blood flow and induction rate? • Inverse, ↑ blood flow = ↓ induction rate (more blood flow means more anesthesia going away from the brain)

14. What are the major and minor routes of metabolism and elimination in GAs? • Exhalation is the major route and liver/kidney metabolism are minor routes (except in mthoxyflurane and halothane) • Which GA causes hepatotoxicity? • Halothane, 1 in 30000 get severe hepatitis • Which GA leads to nephrotoxicity? • Methoxyflurane metabolism releases harmful fluoride ions

15. Which GA can lead to vitamin B-12 deficiency with attendant megaloblastic anemia and peripheral neuropathies? • N2O oxidizes B-12 and decreases methionine synthase activity • What is malignant hyperthermia and what agents can cause it? • Rare, autosomal dominant genetic disorder of skeletal musculature → tachycardia, hypertension, severe muscle rigidity, hyperthermia, hyperkalemia, & acid-base imbalance with acidosis after anesthesia w inhalants (especially halothane) & muscle relaxants • How is this treated? • Treat with dantrolene (block muscle calcium release), restore electrolyte and acid-base balance, & reduce body temperature

16. What is 1.0 MAC? • Minimum alveolar concentration or Conc’n of GA agent @ 1 atm. of inhaled gas mix preventing response to skin incision in 50% of patients • Note that the effects of surpassing 1 MAC by much can be rapidly fatal • Also note that 0.5 MAC of N2O + 0.5 MAC of isoflurane does equal 1 MAC of anesthesia • Most inhalable agents are given at 0.8 – 1.2 MAC along with some injectable agent

17. Do injectable anesthetics act more or less rapidly than inhaled ones? • They act much more quickly • What are commonly used injectable anesthetics? • Barbiturates (thiopental, methohexital, thiamylal, propotol,etomidate), benzodiazapenes (BZDs), ketamine (NMDA receptor blockers), opioids (morphine, meperidine, fentanyl, sufentanil, alfentanil, remifentanil) • How do barbiturates and BZDs work? • They bind to the GABA Cl- channel and keep it open resulting in cell hyperpolarization

18. How does the extrapyramidal system work? Parkinson’s results from damage to The nigrostriatal dopaminergic neurons Dopamine hyperpolarizes the cholinergic neuron, leading to shut down of GABAergic inhibition

19. How do we treat Parkinson’s? • Dopamine does not cross the BBB so levadopa (L-Dopa) is used instead • What is the problem with administering only L-dopa to treat PD? • >95% is metabolized by peripheral decarboxylases in the GI tract leading to anorexia, nausea, vomiting and a build up of dopamine with attendant tachycardia, atrial fib, postural hypotension and hypertension

20. What can be coadministered with levadopa to inhibit GI break down? • Carbidopa inhibits the decarboxylases but does not cross the BBB so L-Dopa is still broken down to dopamine in the brain • What are long term dopamine side effects? • chorea, ballismus, & other dyskinesias and mental effects can include depression, anxiety, agitation, insomnia, confusion, delusions, euphoria • To whom should you never give L-dopa? • Psychotics • How can you treat the behavioral complications? • Give atypical antipsychotics (never typicals) • Typical antipsychotics (chlorpromazine, haloperidol) are D2 receptor antagonists and cause PD

21. What is another way to treat PD? • Use MAO-B inhibitors (selegiline) alone or with L-dopa/carbidopa to decrease dopamine breakdown • Use COMT inhibtors (entacapone and tolcapone) with L-dopa/carbidopa to prevent peripheral breakdown of L-dopa • Use direct D2 receptor agonists to stimulate the cholinergic interneurons • Ergot alkyloids bromocriptine and pergolide • Pramipexole and ropinerole do not cause vasoconstriction like bromocriptine • Better in advanced disease and don’t require decarboxylase activity • Never use in psychotic patients • Have similar side effect profile to L-dopa

22. How can PD induced by antipsychotics be treated? Trihexyphenidyl, benztropine, procyclidine, biperiden - inhibit muscarinic receptors on GABAergic neurons, improve tremor and rigidity but not bradykinesia, and are preferred for treating parkinsonism induced by antipsychotics since L-Dopa may aggravate psychosis

23. What causes Huntington’s chorea (HC)? Dominantly-inherited genetic disorder leading to dysfunction and degeneration of striatal cholinergic and GABAergic neurons (outcome opposite of parkinsonism)

24. What are teatments for HC? • Typical antipsychotics haloperidol, fluphenazine, perphenazine block inhibitory control over remaining striatal circuitry and relieve psychosis that can accompany Huntington’s chorea • Newer “atypical” antipsychotic olanzapine; Reserpine & tetrabenazine deplete cerebral dopamine stores • Benzodiazepines like diazepam to potentiate GABA signaling

25. How do we treat essential tremor? • β-blockers propranolol, or primidone if β-blockers can’t be tolerated • What is the most common treatment for Tourette’s syndrome? • Haloperidol • How do we treat restless leg syndrome (RLS or akathisia)? • With a D2 receptor agonist ropinirole (no one knows why this works; it IS counterintuitive)

26. What are the major differences between typical and atypical antipsychotic drugs (APDs)? • Typical APDs lead to PD, tardive dyskinesia and do not treat negative psychotic symptoms at all • Typicals generally inhibit D2 dopamine receptors while atypicals inhibit different NT receptors • Atypicals show less extrapyramidal motor disorders as side effects

27. What are typical APDs? • Chlorpromazine • Haloperidol • What are atypical APDs? • Clozapine • risperidone, olanzapine, ziprasadone

28. What are the effects of APDs? • Antipsychotic effects: Reduce delusions, hallucinations; improve perception & thought organization • What diseases do APDs treat? • Schizophrenia, psychotic episodes in affective illnesses, mania in bipolar disease, Tourette’s syndrome,and disturbed behavior in senile dementia/Alzheimer’s disease

29. What other interesting side effect do most APDs have? • They are antiemetics • They block D2 receptors in the CTZ • What is prochlorperazine? • It is also a D2 receptor blocker (similar to typical APDs) but it doesn’t cross the BBB so it only has entiemetic properties

30. What do you do if you start to see extrapyramidal side effects after administration of antipsychotics? • Switch to atypical APD with lower D2-R antagonism; Co-administer anti-muscarinics (a.k.a.anti-cholinergics) to directly inhibit receptors on GABAergic neurons • What is tardive dyskinesia? • It is a late onset and sometimes irreversible side effect of APDs (usually typicals) defined by Abnormal involuntary persistent movements of hands, tongue, lips, face. Choreoathetoid (writhing, dance-like) movements while seated are common

31. What causes tardive dyskinesia (TD)? • Thought caused by supersensitive D2 receptors on striatal cholinergic interneurons in response to APD blockade…too little GABAergic output leads to OPPOSITE outcome toparkinsonism

32. How do we treat TD? Discontinue or reduce APD or switch to atypical APD with lower D2-R antagonism; Discontinue all drugs wanti-cholinergic effects in CNS (esp. antiparkinsonism drugs, tricyclic antidepressants) Give benzodiazepines like diazepam to potentiate GABA

33. What is the Neuroleptic Malignant Syndrome (NMS)? • Rare (0.5~1%), life-threatening condition that can occur on 1st dose or APD overdose, associated with EPS sensitivity. Haloperidol & phenothiazines >> atypicals (but latter can NMS) • Symtoms include marked muscle rigidity, severe EPS, autonomic motor dysfunction, hyperthermia, elevated creatine phosphokinase, altered consciousness, leukocytosis How do we treat this condition? • Withdraw APD; give D2-R agonist eg., bromocriptine; give muscle relaxants diazepam / dantrolene

34. What are other typical side effects of APDs? • Sedation, weight gain, confusion, blurred vision, dry mouth, constipation, urinary retention,postural hypotension,dizziness • These stem from antihistaminic, anticholinergic,antiadrenergic effects

35. What was clozapine and what is one major side effect? • Clozapine is an atypical APD • It can cause agranulocytosis and requires intensive blood monitoring What about olanzopine? • It is also an atypical but w/o the agranulocytosis side effect • Weight gain with ↑ risk of diabetes and hyperlipidemia

36. What do prostoglandins and prostocyclins do? • They cause vasodilation, edema, airway relaxation, ↑ kidney perfusion and mucous and bicarb production in the GI tract, and temperature regulation via the hypothalmus What do leukotrienes do? • They cause monocyte and granulocyte chemotaxis and airway constriction What do thromboxanes do? • They activate platelets while prostocyclins oppose this.

37. Where do NSAIDs, corticosteroids and other drugs work in the eicosanoid pathway?

38. NSAIDs What do NSAIDs help with? • Antipyresis (control body temp) • Analgesia (control pain), especially headaches and muscle pain • Anti-inflammation (high doses for RhA) • They can also be used to treat gout What are some side effects of NSAIDs? • GI Irritation • Hypersensitivity • Renal toxicity

39. Summary of common NSAIDs DRUG ANALG ANTIPYR ANTI INFLAM TOXICITIES & SPECIAL FEATURES Acetylsalicylic Acid + + + GI/Salicylism/ Reyes Synd./ Resp. Suppress./ Prophylactic uses Acetaminophen + + - Little GI tox. Hepatotox. Chronic kidney tox. CNS Action Ibuprofen (advil) + + + Modest GI tox. Chronic kidney tox. • Who should you never give aspirin to and why? • Never give aspirin to babies • It can cause a demyelinating disease

40. What is the cox 2 inhibitor (NSAID) recently pulled off the market? • rofecoxib (Vioxx) Why are they better in some ways than other NSAIDs? • They are effective anti inflammatories with reduced GI adverse side effects Why was it pulled off the market? • Adverse cardiovascular effects

41. What are some leukotriene receptor antagonists and what are they used for? • Zileuton, Zafirlukast and montelukast • They are used in asthma therapy to open airways What are their advantages? • possible monotherapy in mild persistent asthma • reduce corticosteroid use in moderate to severe disease • well tolerated

42. What are disease modifying anti rheumatic drugs (DMARDs)? • They are TNF and IL-1 inhibitors that help retard the inflammatory process • Both lead to an increased risk of TB and other opportunistic pathogens What do anti-histamines do? • Binds H1 receptors on endothelial cells to block vasodilatation and edema, and on sensory neurons to block pain, itching What are their side effects? • Sedation (1st Gen cross the BBB), Hypersensitivity, GI upset

43. What are the CNS effects of opioids? • Decreased sensitivity to painful stimuli • Sense of well-being • Drowsiness without amnesia • Depression of cough reflex (brainstem) What are opioid side effects? • Hypotension, bradycardia, decreased GI motility, increased tone, constipation, Urinary retention, depressed renal function, decreased uterine contractions, may prolong labor, release of mast cell histamine, altered hormone release, pinpoint pupils (miosis)

44. What risk is there for patients on (or recently on) MAO-Is who take opioids? • Seratonin syndrome What are the 3 types of opiod receptors? •  (mu),  (delta),  (kappa) What do they do and what are the endogenous ligands?

45. Positive reinforcement is dopamine release via opioid modulation

46. How do opioid receptors work? • In the presynaptic nerve terminal they inhibit the release of pain NTs (glutamate and substance P) via G-protein coupled Ca2+ channel inhibition • They cause hyperpolarization in postsynpatic nerve terminals via opening K+ channels • All 3 opioid receptor types are on presynaptic terminals and only μ receptors are on postsynaptic terminals

47. Which opioids are full agonists? • Fentanyl, morphine (heroine), codeine Which opioids are partial agonists? • Buprenorphine What are the opioid antagonists? • Naloxene (for treating ODs), naltrexone (more for long term withdrawal treatment) How does pentazocene act? • pentazocine is a κ-agonist, μ-weak partial antagonist (good for moderate to severe pain) • It and others can precipitate withdrawal

48. What is severe pain treated with? • Short acting, high affinity for μ receptor opioids like fentanyl (100 times more powerful than morphine due to higher lipophilicity), heroine (a morphine prodrug), morphine (reduces coughing) or meperidine (reduces shivering) What is more moderate pain treated with? • Codeine (lower abuse liability than those above), oxycodone (more potent than codeine) or tramodol (also an MAO-I with possible seratonin syndrome side effect but less respiratory and other side effects)

49. What is buprenophine good for? • Helps with cocaine and opiate withdrawal or moderate to severe pain What do you use to reverse an opioid overdose? • Naloxene, an opioid receptor antagonist • Remember that it is shorter acting than most opioids so will need to be readministered • Non selective antagonist with μ>δ>κ

50. What are symptoms of opiate withdrawal? • Often is the opposite of direct effects of opiates • Lacrimating, yawning, dilated pupils, sweating, rhinorrhea, abdominal pain, nausea, diarrhea, goose-flesh, irritability, cramps • Almost never results in death