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Flashcards in Exam 3 Deck (214):
1

Difference between sedative anxiolytics and hypnotics

- Sedative anxiolytics: Induce calmness w/relief of anxiety (chronic overwhelming and continuous worrying about life events)

- Hypnotic: produce drowsiness, sleep

2

Do we need to know what are sedative-hypnotics vs anxiolytics in benzo categories?

Do we need to know what are sedative-hypnotics vs anxiolytics in benzo categories?

3

Describe graded dose-dependency of CNS function with sedative-hypnotic agents.

1. Sedation or sleep

2. Anesthesia and coma

3. Respiratory depression and death

4

What drugs belong to the categories shown on the following graph:
see image

- Drug A: barbiturates and alcohols

- Drug B: benzodiazepines and newer hypnotics – safer to use

5

Benzodiazepines. What are the drugs belonging to this category?
a. Clinical use; b. MOA; c. Adverse effects/toxicity; d. Drug interactions; e. Metabolism

- -zolam and –zepam drugs, also clorazepate

a. Use: Anxiolytic, sedative/hypnotic, many others

b. MOA: binds benzo receptor on GABA-A receptors (Cl channels) potentiating GABA effects: increase frequency of opening and conductance of the Cl- = hyperpol = inhibition of neuron

c. Adverse effects: Tolerance, respiratory depression, dependence, anterograde amnesia (flunitrazepam: date rape drug), withdrawal. Relative contra: pregnancy, elderly, substance abuse, sleep disorders, occupation.

d. Interactions: additive CNS depression when combined w/ethanol, opioids, anticonvulsants, phenothiazine (anti-psychotic), antihistamine, TCA

e. Metabolism: liver CYP3A4+glucuronidation. Short-duration/life = lorazepam, oxazepam, alprazolam and triazolam. Rest = long-lived active metabolites. Hepatic processing slows with older age d/t increased Vd (more fat) and decreased rate of elimination (Ke). This is concern with drugs of 3- hydroxyl benzos: lorazepam and oxazepam.

6

Date rape drugs

- Flunitrazepam

- GHB

7

What is antagonist drug to benzodiazepine overdose?

- Flumazenil. Competitive inhibitor. Can reverse effects.

8

Benzodiazepine-related new drugs. What are the drugs belonging to this category?
a. Clinical use; b. MOA; c. Adverse effects/toxicity; d. Drug interactions

- Z drugs: eszopiclone, zolpidem

a. Use: Hypnotic (says sedative) for insomnia

b. MOA: binds to benzo receptors GABA-A, only alpha-1 isoform = increase frequency and opening for Cl = hyperpolarization = inhibition of neuron

c. See benzos

d. See benzos

9

Barbiturates. What are the drugs belonging to this category?
a. Clinical use; b. MOA; c. Adverse effects/toxicity; d. Drug interactions

a. Clinical use; b. MOA; c. Adverse effects/toxicity; d. Drug interactions
- Drugs: Pentobarbital, phenobarbital, thiopental

a. Use: anesthesia, sedative/hypnotic (replaced by benzos), anticonvulsant (phenobarb: status epilepticus in pregnancy), medically-induced coma (pentobarb)

b. MOA: increase duration of GABA-gated Cl channel opening = hyperpolarization = inhibition of neuron

c. TI is low

d. None mentioned

10

Ramelteon. a. Class; b. Clinical use; c. MOA; d. Adverse effects/toxicity

a. Class: melatonin receptor agonist

b. Use: hypnotic (says sedative) for insomnia

c. MOA: MT1 (sleep onset) and MT2 (circadian pattern) receptor agonist. Effective at inducing sleep onset, little influence on sleep architecture.

d. Adverse effects: minimal, no dependence with regular use

11

Buspirone. a. Class; b. Clinical use; c. MOA; d. Adverse effects/toxicity

a. Class: partial 5-HT(1a) receptor agonist

b. Use: non-sedating anxiolytic for anxiety w/o amnesia or muscle relaxant properties as benzo

c. MOA: activation of 5-HT(1a) = reduced neuronal excitability = less firing and 5-HT release. Note, no GABA effects therefore no sedation properties.

d. Adverse effects: non-specific CP, tachy, palps, dizzy, nervousness, tinnitus, GI distress. Minimal abuse liability.

12

What beta-blocker can be used for anxiety?

- Propanolol. Not an anxiolytic, but tx manifestations of anxiety (stage fright, performance anxiety, tachy)

13

What antihistamines are used as mild sedative/anxiolytic?

- hydroxyzine and diphenhydramine

14

Is ethanol an anxiolytic?

- Yes, via sedative action

15

Compare and contrast major depressive disorder with bipolar disorder

- MDD (aka unipolar depression): depressed mood, anhedonia (loss of pleasure), loss of interest in life, appetite changes, sleep abnormalities, altered cognition, suicidal thoughts/attempts. Tx with antidepressants.

- Bipolar disorder (aka manic depression): alternating periods of depression (see above) and mania: excitement, hyperactivity, impulsivity, disinhibition, aggression, psychosis, diminished need for sleep, cognitive impairment. High risk for suicide in these patients. Tx with mood stabilizers.

16

What are some major downfalls of use chemical antidepressants?

- Delay of therapeutic response: can take weeks (2-4) to months (problematic for suicidal patients)

- Side effects can limit usage (fatal, esp. when combing classes)

17

Hypotheses of depression

1. Monoamine/biogenic amine hypothesis: deficiency in level of 5-HT, NE and DA

2. Neurotrophic hypothesis: loss of BDNF (brain-derived neurotrophic factor) – neuronal atrophy and death. BDNF acts on TRK-B receptors to increase survival and growth of neurons

18

Classes and names of antidepressant medications

1. Monoamine oxidase inhibitors (MAOIs): phenelzine, tranylcypromine, selegiline

2. Tricyclic antidepressants (TCAs): imipramine, desipramine, amitriptyline

3. Selective serotonin reuptake inhibitors (SSRIs): fluoxetine, sertraline, paroxetine, citalopram, escitalopram, fluvoxamine

4. Atypical antidepressants

a. Selective serotonin-NE reuptake inhibitors (SNRIs): venflaxafine, duloxetine

b. 5-HT(2) antagonists: trazadone

c. Other: buproprion, mirtazapine

19

MAOIs. What are the drug names in this category?
a. Clinical use; b. MOA; c. Adverse effects/toxicity; d. Drug interactions

- Drugs: phenelzine (MAO-A and B inh), tranylcypromine (MAO-A and B inh), selegiline (MAO-B inh at low dose used for PD, high dose antidepressant)

a. Use: tx resistant MDD, atypical depressions, anxiety (social, panic disorder)

b. MOA: increase synaptic availability of NE and 5-HT by blocking their catabolism via inhibitor of MAO enzymes (MAO-A and B)

c. Adverse effects: dirty drugs. Most common = orthostatic HoTN and weight gain. Tyramine (wine and cheese) food interaction = HTN crisis. Others. Overdose = hyperthermia, seizures, shock, delirium, comatose state.

d. Interactions: any drug that increases 5-HT and NE (SSRIs, TCAs)

20

Differences between MAO-A and B

- MAO-A targets tyramine, NE, 5-HT and DA

- MAO-B targets mainly DA

21

What anti-depressant drug can be used for PD?

- Selegiline at low dose as MAO-B inh, targeting mainly DA.

22

TCAs. What are the drug names in this category?
a. Clinical use; b. MOA; c. Adverse effects/toxicity; d. Drug interactions

- Drugs: imipramine, desipramine, amitriptyline

a. Use: Chronic pain conditions (know this one). Also major depression (if SSRIs not effective), phobic and panic anxiety states, OCD.

o Imipramine: treat enuresis (bedwetting)

o Desipramine: neuropathic pain

o Amitriptyline: sedative

b. MOA: block re-uptake of 5-HT and NE by inhibition of SERT and NET respectively. Also anticholinergic, histaminergic and alpha-adrenergic antagonist.

c. Adverse effects: dirty drug. Most serious = lethal cardiac arrhythmias (Na/Ca channel blocker). Also orthostatic intolerance/HoTN = hip breaker in elderly. Delirium (more pronounced in elderly). Overdose = 3 Cs = convulsions, coma, cardiac arrhythmias.

d. Interactions: MAOIs, SSRIs. Don’t combine anti-depressants.

23

Drug used to treat enuresis

- Imipramine

24

SSRIs. What are the drug names in this category?
a. Clinical use; b. MOA; c. Adverse effects/toxicity; d. Drug interactions

- Drugs: fluoxetine, sertraline, paroxetine, citalopram, escitalopram, fluvoxamine

a. Use: major depression, other psych conditions (GAD, PTSD, OCD, panic disorder, PMDD (premenstrual dysphoric disorder – severe PMS), bulimia)

b. MOA: selectively inhibits SERT blocking re-uptake of 5-HT into pre-synaptic terminal = increased synaptic 5-HT

c. Adverse effects: safest of all antidepressants, clean drug. Short term: nausea, GI upset, diarrhea. Long term: sexual dysfunction, others. Also discontinuation syndrome.

- Discontinuation syndrome: sudden discontinuation of short half-life SSRIs (paroxetine, sertraline) causes adverse side effects in some patients 1-7 days after stopping. Why? Clearance faster than re-adaptation to receptor regulation and sensitization. Symptoms = dizziness, paresthesias and anxiety.

d. Interactions: serotonin syndrome

- Serotonin syndrome (rare): switching SSRIs, usually in combo with another SSRI, MAOIs or TCAs. D/t long half-life, must go through taper off, period when no longer taking drug and clears out of system. Then start a new anti-d. Symptoms = lethargy, restlessness, mental confusion, flushing, diaphoresis, tremor. Fluoxetine has longest half-life in class and must be discontinued for 4-5 weeks prior to use of other anti-d. Others discontinued for 2 weeks.

- Paroxetine, fluoxetine and fluvoxamine = inhibitors of CYP2D6. Codeine, beta-blockers, 1c anti-arrhythmics, benzos, CCBs and TCAs are CYP substrates. Therefore if co-administered, accumulation of drugs occur. Underlines: TCAs and SSRIs should never be combined.

25

Venlafaxine. a. Class; b. Clinical use; c. MOA; d. Adverse effects/toxicity; e. Drug interactions

a. Class: selective serotonin-NE reuptake inhibitors (SNRIs)

b. Use: severe depression

c. MOA: inhibition of SERT (weaker) and NET (stronger) transporters.

d. Adverse effects: similar to TCAs, not as severe. Serotonergic effects: GI issues, sexual dysfunction, weight gain. Also discontinuation syndrome. NA effects.

e. Interactions: none specifically mentioned.

26

Duloxetine. a. Class; b. Clinical use; c. MOA; d. Adverse effects/toxicity; e. Drug interactions

a. Class: selective serotonin-NE reuptake inhibitors (SNRIs)

b. Use: chronic pain (more so than TCAs): fibromyalgia, DM neuropathy, back pain, arthritis

c. MOA: inhibition of SERT and NET transporters equally.

d. Adverse effects: similar to TCAs, not as severe. Serotonergic effects: GI issues, sexual dysfunction, weight gain. Also discontinuation syndrome. NA effects.

e. Interactions: none specifically mentioned.

27

Trazadone. a. Class; b. Clinical use; c. MOA; d. Adverse effects/toxicity; e. Drug interactions

a. Class: 5-HT(2) antagonist

b. Use: sedative effects w/o tolerance/dependence; unlabeled hypnotic (for insomnia)

c. MOA: blockage of 5-HT(2), weak SERT, NET inhibition. Also blocks H1 (causing sedative effects)

d. Adverse effects: priapism (peripheral alpha-1 blocking), GI disturbances, sedation

e. Interactions: none specifically mentioned.

28

Bupropion. a. Class; b. Clinical use; c. MOA; d. Adverse effects/toxicity; e. Drug interactions

a. Class: atypical antidepressant

b. Use: smoking cessation, MDD

c. MOA: blocks NE and DA reuptake and increases pre-synaptic release of catecholamines

d. Adverse effects: lowers seizure threshold, agitation, insomnia

e. Interactions: none specifically mentioned.

29

Mirtazapine. a. Class; b. Clinical use; c. MOA; d. Adverse effects/toxicity; e. Drug interactions

a. Class: atypical antidepressant

b. Use: anti-depressant, anti-emetic, anxiolytic/hypnotic, sedation, appetite stimulant

c. MOA: blocks pre-synaptic alpha-2, increase release of 5-HT and NE; blocks 5-HT(2) and 5-HT(3) = anti-emetic effect; blocks H1 = sedation, appetite stimulant

d. Adverse effects: sedation, weight gain, few sexual side effects

e. Interactions: none specifically mentioned.

30

Which anti-depressant drugs are inhibitors of CYP2D6? Why is this a concern?

- Paroxetine, fluoxetine and fluvoxamine = inhibitors of CYP2D6. Codeine, beta-blockers, 1c anti-arrhythmics, benzos, CCBs and TCAs are CYP substrates. Therefore if co-administered, accumulation of drugs occur. Underlines: TCAs and SSRIs should never be combined.

31

What is the treatment for bipolar disorder? MOA? Side effects? Drug interactions?

- Lithium = drug of choice for controlling the manic and depressive phases. It is maintenance treatment d/t slow onset of action. Use anticonvulsants (valproic acid and carbamazepine) to tx the acute mania.

- MOA (lithium): Elusive per Duric. Stabilizes activity at post-synaptic terminal is all that we kneed to know. Following is for completeness

o Prevents recycling of IP (back to PIP2) = mood dampening effect. Also inhibits release of NE (to prevent mania). May also inhibit 5-HT(1a/b) autoreceptors) reducing synaptic glut.

- Side effects: tremor, hypothyroidism, NDI, skin reactions

- Thiazide and loop diuretics diminish Li clearance = toxicity.

32

What class of antidepressants would be considered the last line for tx of depression?

- SSRIs = safest of all antidepressants

- MAOIs for tx resistant, atypical depression

- TCAs have bad side effects and for major depression

33

What class of antidepressants is considered to be the safest?

- SSRIs

34

Why is buproprion used to tx smoking cessation?

- MOA unknown for use in smoking cessation. May involved antagonism of nicotinic receptors.

35

Why do factors that promote Na loss (low Na diet, excessive sweating, dilutional hyponatremia) induce lithium toxicity?

- Li uses the same transporter as Na. When Na is low, body must hang on to as much as it can, therefore also holding onto Li, which can result in a toxicity.

36

Define seizures. What is epilepsy?

- Sudden, transient episodes of brain dysfunction and altered behavior d/t abnormally excessive synchronous and rhythmic firing of certain populations of hyper-excitable neurons

- Chronic neuro disorder characterized by recurrent seizures.

37

Causes of seizures

- Altered excitation thresholds of cerebral neurons d/t injury

- Congenital abnormalities

- Genetic factors

- Infections, hypoglycemia, hypoxia etc.

38

Classification of seizures. Describe symptoms of each.

1. Partial (focal) seizures: starts in a specific location in brain, remains in that location usually

a. Simple partial: minimal spread of abnormal neuronal discharge

- Limited motor or sensory manifestation, no LOC, person remains alert and remembers what happens

b. Complex partial: starts in small area, quickly spreads to other areas affecting alertness and awareness

- Altered consciousness +/- automatisms (lip smacking, fumbling, swallow)

c. Partial becoming generalized: partial seizure that spreads throughout brain becoming generalized (usually tonic-clonic)

2. Generalized seizures: involve the entire brain with global EEG changes and bilateral manifestations

a. Absence (petit mal): sudden onset and abrupt cessation – LOC brief w/no motor signs to symmetrical jerking of eyelids, extremities or body. Typically observed in children.

b. Tonic-clonic (grand mal): tonic spasms and major convulsions of entire body (bilaterally), LOC. 4 phases (see another flashcard)

c. Others = tonic, atonic, clonic/myoclonic, infantile spasms, status epilepticus (continuous / very rapid recurring seizures usually T-C type – medial emergency)

39

4 phases of tonic-clonic (grand mal) seizure

1. Aura: sense of impeding seizure

2. Tonic: muscle tensing, rigidity followed by tremor

3. Clonic: convulsions

4. Stuporous state and sleep

40

3 stages in mechanism generating epileptic seizures

1. Initiation

2. Synchronization of surrounding

3. Propagation (recruitment of nml neurons)

* ultimately: balance between IPSP and EPSP. Too much EPSP input = seizure

41

Treatment options for epilepsy

1. Antiepileptic meds

2. Surgery

3. Vagus nerve stimulation

42

What meds are used to treat partial seizures?

- Carbamazepine, phenytoin, valproate

43

What meds are used to treat TC (grand mal), tonic and atonic seizures?

- Carbamazepine, phenytoin, valproate

44

What meds are used to treat absence (petit mal) seizures?

- Ethosuximide (ETH), valproate

45

What meds are used to tx myoclonic seizures?

- Clonazepam, valproate

46

What meds are used to tx status epilepticus?

- Diazepam, lorazepam, phenytoin, fosphenytoin

- Diazepam is preferred initial agent for status epilepticus. This can be followed by phenytoin. Lorazepam has a longer duration of action and can be used as stand-alone.

47

Phenytoin. a. Class; b. Clinical use; c. MOA; d. Adverse effects/toxicity; e. Drug interactions

a. Class: hydantoin. Note: newer more soluble prodrug of phenytoin used IV and IM now = fosphenytoin

b. Use: generalized TC (grand mal) seizure, partial seizure, status epilepticus

c. MOA:

- blocks and prolongs inactivated state of VG Na channels = decrease release of glut = block high-frequency firing of neurons

- enhances release of GABA

- prevents seizure propagation

d. Adverse effects: gingival hyperplasia, sedation, ataxia, nystagmus, diplopia, cardiac dysrhythmias, hirsutism, osteomalacia, megaloblastic anemia, fetal hydantoin syndrome (teratogen)

e. Interactions: barbiturates and warfarin decrease phenytoin metabolism, barbs and carbamazepine increase metabolism, salicylates and valproic acid displace protein binding increasing free fraction

48

Carbamazepine. a. Class; b. Clinical use; c. MOA; d. Adverse effects/toxicity; e. Drug interactions

a. Class: tricyclic similar to TCA. Note: newer drug Oxacarbazepine similar to this is available with shorter half-life, active metabolite has longer duration and fewer interactions

b. Use: generalized TC (grand-mal) seizures, partial seizures, trigeminal neuralgia

c. MOA: inhibition of VG Na channels = decrease release of glut = block high-frequency firing of neurons

d. Adverse effects: SIADH (increased ADH secretion = fluid retention = hyponatremia), CNS depression, osteomalacia, aplastic anemia, megaloblastic anemia

e. Interactions: phenytoin, valproate, phenobarbital and others

49

What is the drug of choice for trigeminal neuralgia?

- Carbamazepine

50

What drug can be used for status epilepticus in pregnant women? Also for neonatal seizures?

- Phenobarbital, a barbiturate. Primidone is metabolized to phenobarbital.

51

Ethosuximide. a. Class; b. Clinical use; c. MOA; d. Adverse effects/toxicity; e. Drug interactions

a. Class: Cyclic ureide

b. Use: absence seizures (petit mal), other

c. MOA: blocks pre-synaptic T-type Ca channels = blocking of high-frequency firing of neurons

d. Adverse effects: GI distress, sedation, anorexia, HA and may exacerbate TC seizures

e. Interactions: none mentioned.

52

Valproic acid. a. Class; b. Clinical use; c. MOA; d. Adverse effects/toxicity; e. Drug interactions

a. Class: ?

b. Use: absence seizures (petit mal), other

c. MOA:

- inhibition of T-type Ca channels = blocks neuronal firing

- inhibition of GABA transaminase = increased GABA activity = inhibition of hyperexcitable cerebral neurons

d. Adverse effects: hepatotoxic syndrome (uncommon), teratogenic risk, GI upset, others

e. Interactions: none mentioned.

53

Diazepam and lorazepam. a. Class; b. Clinical use; c. MOA; d. Adverse effects/toxicity; e. Drug interactions

a. Class: benzodiazepines

b. Use: status epilepticus (diazepam is initial agent, followed by phenytoin or another; lorazepam is stand-alone and has longer duration of action). Diazepam also for treatment of spasms associated with excess exertion, MS, CP, injury.

c. MOA:

- potentiates GABA-A responses by increased frequency of Cl channel opening (for seizures)

- increases central inhibitory actions of GABA on alpha motor neurons in spinal cord (for spasms)

d. Adverse effects: sedative effects and development of tolerance, respiratory depression, CNS depression

e. Interactions: additive CNS depression when combined w/ethanol, opioids, anticonvulsants, phenothiazine (anti-psychotic), antihistamine, TCA

54

Gabapentin. a. Class; b. Clinical use; c. MOA; d. Adverse effects/toxicity; e. Drug interactions

a. Class: amino acid agent, analog of GABA. Note: pregabalin is similar, also GABA analog

b. Use: generalized TC (grand-mal) seizures, partial seizures, neuropathic pain (eg. post-herpetic neuralgia and fibromyalgia)

c. MOA: block pre-synaptic VG Ca channels = decreases excitatory transmission

d. Adverse effects: somnolence, dizziness, ataxia, GI issues

e. Interactions: none mentioned.

55

Lamotrigine. a. Class; b. Clinical use; c. MOA; d. Adverse effects/toxicity; e. Drug interactions

a. Class: ?

b. Use: partial seizures, generalized seizures, absence seizures

c. MOA: blocks pre-synaptic VG Na and Ca channels = inhibition of neuronal firing

d. Adverse effects: Stevens-Johnson syndrome (uncommon): especially if used with valproate/switched from valproate. This is a rash where epidermis separates from dermis

e. Interactions: valproate, carbamazepine, phenytoin

56

Felbamate. a. Class; b. Clinical use; c. MOA; d. Adverse effects/toxicity; e. Drug interactions

a. Class: ?

b. Use: adjunct in seizure states

c. MOA: block Na channels and glut receptors

d. Adverse effects: aplastic anemia, hepatic failure

e. Interactions: ?

57

Topiramate. a. Class; b. Clinical use; c. MOA; d. Adverse effects/toxicity; e. Drug interactions

a. Class: ?

b. Use: anticonvulsant

c. MOA: ?

d. Adverse effects: sedation, confusion, paresthesias, anorexia

e. Interactions: acidosis w/zonisamide

58

Tiagabine. a. Class; b. Clinical use; c. MOA; d. Adverse effects/toxicity; e. Drug interactions

a. Class: ?

b. Use: partial seizures

c. MOA: inhibitor of GABA uptake

d. Adverse effects: sedation, dizziness, headache, tremor

e. Interactions: ?

59

Baclofen. a. Class; b. Clinical use; c. MOA; d. Adverse effects/toxicity

a. Class: centrally acting muscle relaxant

b. Use: spasticity with MS, spinal and brain injury

c. MOA: GABA-B receptor agonist: increase K conductance = hyperpolarization = reduction in Ca influx = reduction in excitatory transmitter release

d. Adverse effects: less sedation

60

What are the types of anesthesia? What are the pros and cons to each?

- General: + = body wide anesthesia; - = disturbance of all organ systems

- Local: + = limit anesthesia to small area w/minimal system disturbance; - = may not be adequate

61

Triad of anesthesia

- Asleep, pain-free, still

62

Define characteristics of an ideal anesthetic agent

- Unconsciousness, amnesia, analgesia, skeletal muscle relaxation, areflexia, good minute-to-minute control

63

Why are pre-anesthetic medications given? What medications?

1. Relieve anxiety: benzos (midazolam)

2. Prevent allergic reactions: antihistamines (diphenhydramine, ranitidine)

3. Prevent nausea/vomiting: antiemetics (dexamethasone, scopolamine)

4. Provide analgesia: opioids (fentanyl, morphine, hydromorphone)

5. Prevent bradycardia and secretion: atropine, glycopyrrolate

This is to achieve balanced anesthesia. Includes NM blocking agents / paralytics such as succinylcholine or rocuronium

64

What history is important to know about before patient is to undergo anesthesia?

- Family hx of malignant hyperthermia

- CV problems

- Respiratory disease

- Allergies to medicine and food

65

Describe the phases of general anesthesia

1. Induction (initial administration until desired level reached): analgesia, amnesia, euphoria

2. Maintenance (desired level maintained): excitement, delirium, combative

3. Emergence (from sub-optimal concentration until zero – waking up):

4. Recovery (from discontinuation until full restoration of consciousness and normal function)

66

Describe stages of anesthesia in terms of effects on brain

1: analgesia

- analgesia, amnesia, euphoria

2: excitement

- excitement, delirium, combative behavior

3: surgical anesthesia

- unconscious, regular respiration, decreasing eye movement

4: medullary depression

- respiratory arrest, cardiac depression/arrest, no eye movement

Note: ideally want to get through stage 2 quickly.

67

Two types of general anesthetics. What are each typically used for?

1. Inhalable: usually for maintenance, can be used for induction in peds

2. IV/fixed: induction use and short procedures, more common to be used now for maintenance

68

General mechanisms of action of anesthetic

1. Increase GABA-A receptor Cl channel activity

2. Activation of VG K channels = hyperpolarization

3. Inhibit glut NMDA receptors

69

Advantages and disadvantages of inhalable anesthesia

+: easy to control depth, readily reversible w/minute-to-minute control

-: induction not as fast or smooth as with fixed agents

70

What factors determine the rate of anesthetic onset and recovery?

1. Anesthetic concentration in inspired air: [ ] of anesthesia gas increases as partial pressure increase. Use of vaporizer increases partial pressure of anesthesia = faster achievement of anesthesia in blood

2. Pulmonary ventilation rate: increase in alveolar ventilation = more gas molecules/time = faster anesthesia onset

3. Solubility in blood and lipidL lower coefficient = less soluble = higher rise in partial pressure in blood = faster equilibration with brain

a. Blood gas partition coefficient (Otswald coefficient)

b. Brain blood partition coefficient:

4. Pulmonary blood flow: low blood flow = faster partial pressure rise in blood and brain = faster onset

5. AV concentration gradient: insoluble agents = slow uptake = alveolar concentration rises fast = fast induction??

6. Elimination: less soluble = faster elimination

71

What is meant by the MAC in terms of inhalable anesthetics? What is clinical relevance? How does MAC value change with solubility of agent?

- Minimum alveolar concentration: refers to concentration of anesthetic in inspired air at equilibrium when there is no response to noxious stimulus in 50% of patients. Similar to ED50.

- Lower MAC = more potent anesthetic. Note: MAC values of inhaled anesthetics are additive.

- Higher lipid solubility = lower MAC = more potent anesthetic

72

Nitrous oxide. a. Class; b. Clinical use; c. MOA; d. Adverse effects/toxicity

a. Class: inhalable anesthetic

b. Use: general anesthesia as complimentary agent (2nd gas effect) to other more potent agents. Never used as sole agent. Used for minor procedures (dentistry) or EMS.

c. MOA: ? low potency w/ MAC = 110%

d. Adverse effects: diffuse hypoxia (with abrupt discontinuation it diffuses out and dilutes o2), increase risk of spontaneous abortion and decreased probability of conception

73

What are the advantages and disadvantages of nitrous oxide?

- Advantages: 2nd gas effect (carrier agent) = reduces induction time for primary agent = decrease in required concentration of primary agent = decreased toxicity of primary agent

- Disadvantages: lack of potency, minimal muscle relaxation, side effects (see card)

74

General use of halogenated agents

- Maintenance of anesthesia

75

Halothane. a. Class; b. Clinical use; c. MOA; d. Adverse effects/toxicity

a. Class: inhalable anesthetic, halogenated agent

b. Use: maintenance anesthetic agent (MAC = 0.76%)

c. MOA: ?

d. Adverse effects: respiratory depression, decrease cardiac contractility and HR = decrease CO and HoTN. Post-op hepatitis. Also poor analgesia and muscle relaxation. Hyperthermia.

76

Enflurane. a. Class; b. Clinical use; c. MOA; d. Adverse effects/toxicity

a. Class: inhalable anesthetic, halogenated agent

b. Use: maintenance anesthetic agent (MAC = 1.68%)

c. MOA: ?

d. Adverse effects: respiratory depression, reduced cardiac contractility and HR. Less hepatoxicity compared to halothane. CNS stimulation effects: EEG convulsion pattern, jerking, twitching. Avoid in patients with seizures. Hyperthermia.

77

Isoflurane. a. Class; b. Clinical use; c. MOA; d. Adverse effects/toxicity

a. Class: inhalable anesthetic, halogenated agent

b. Use: primary maintenance anesthetic

c. MOA: ?

d. Adverse effects: pungency limits mask induction, very long duration (slow release from fat hours post-op), lower myocardial sensitivity compared to other halogenated agents. Lower toxicity: can be used in liver/kidney impaired patients.

78

Desflurane. a. Class; b. Clinical use; c. MOA; d. Adverse effects/toxicity

a. Class: inhalable anesthetic, halogenated agent

b. Use: maintenance anesthetic (fastest onset and recovery) – 2nd most common

c. MOA: ?

d. Adverse effects: irritating to respiratory passages = cough and laryngeal spasm. Also myocardial and respiratory depression. Tachycardia. Negligible organ toxicity compared to others.

79

Sevoflurane. a. Class; b. Clinical use; c. MOA; d. Adverse effects/toxicity

a. Class: inhalable anesthetic, halogenated agent

b. Use: maintenance anesthetic, most commonly used (rapid onset and recovery, very potent, low solubility and high potency), excellent for mask induction (low airway irritation)

c. MOA: ?

d. Adverse effects: mild respiratory and cardiac depression, may cause renal and hepatic toxicity

80

What are the general adverse effects of inhalable anesthetics?

- Depression of CV function

- Depression of respiration and response to CO2

- Decreased BF to liver and kidneys

- Organ toxicity

- Malignant hyperthermia

81

Which halogenating agent should be avoided d/t respiratory irritation?

- Desflurane.

82

Which halogenating agents have pungent smell leading to problems with mask induction?

- Enflurane and isoflurane

83

Which halogenating agent is the most ideal in terms of potency?

- Sevoflurane.

84

Advantages and disadvantages for IV anesthetic agents?

- Advantages: quick, easy and smooth induction w/rapid and complete recovery

- Disadvantages: can’t reverse the effect except via metabolism

85

Thiopental. a. Class; b. Clinical use; c. MOA; d. Adverse effects/toxicity

a. Class: barbiturate, IV anesthesia

b. Use: commonly used induction agent, not for maintenance or sole anesthetic; no analgesia (hyperalgesia)

c. MOA: ?

d. Adverse effects: accumulates in adipose leading to toxicity, short duration = difficult to control level of anesthesia, decrease in respiration, myocardial depressant

86

Propofol. a. Class; b. Clinical use; c. MOA; d. Adverse effects/toxicity

a. Class: IV anesthesia

b. Use: used for majority of anesthesia inductions (continuous IV drip) w/excellent quality of recovery

c. MOA: ?

d. Adverse effects: significant decrease in BP, dose-dependent CV depression, venous irritant (often given with lidocaine at site)

87

Ketamine. a. Class; b. Clinical use; c. MOA; d. Adverse effects/toxicity

a. Class: IV anesthesia

b. Use: dissociative anesthesia (intense analgesia, catalepsy and amnesia: pt immobilized, appears awake, may move eyes, but has no awareness of event nor recollection after recovery). Excellent for patients with compromised cardiac status (tamponade, GSW, GI bleed)

c. MOA: Non-competitive glut NMDA R antagonist

d. Adverse effects: Emergence phenomenon: unpleasant dreams, hallucinations and disorientation during emergence. Contraindicated in psych hx patients.

88

Midazolam. a. Class; b. Clinical use; c. MOA; d. Adverse effects/toxicity

a. Class: benzodiazepam

b. Use: sedation for painful procedures, used as induction agent or substitute for thiopental/propofol in high risk patients (CV or pulmonary issues). Provides CV stability.

c. MOA: potentiation at GABA-A receptors

d. Adverse effects: see class flash card.

89

Types of local anesthesia. What are advantages and disadvantages of each.

1. Topical: agent to surface of skin.

- Advantage: minimal systemic effect; Disadvantage: skin penetration difficult

2. Perineural infiltration: injection at one or more site around specific area where anesthesia is desired

- Advantage: specific area, ease of delivery; Disadvantage: large amounts of drug into small increases potential for systemic absorption / toxicity

3. Nerve block: injection around specific nerve to block conduction of sensory and motor fibers distal to block

- Advantage: less drug required to block larger area; Disadvantage: requires skill and knowledge of anatomy

4. Spinal block: injection into CSF in subarachnoid space to reach roots

- Advantage: more reliable (return of CSF ensures correct location), pt conscious with minimal disruption to resp and CV function; Disadvantage: time-limited, no titration, not reversible

5. Epidural block: injection into extradural space to block nerve root as it passes through space

- Advantage: not time limited, may be used post-op, can be titrated; Disadvantages: less reliable block?

90

Describe the mechanism(s) of action of local anesthetics

- Primary mechanism = blockade of VG Na channels = decrease in generation of AP

91

Types of local anesthetic agents. Name the drugs, describe metabolism of each.

1. Amides (two “I”s in name): lidocaine, articaine, mepivicaine, etidocaine, prilocaine, bupivacaine, ropivacaine, levobupivacaine

- Longer half-life and duration of action (P450s in liver). Pay attention in liver pathology patients.

2. Esters (one “I” in name): procaine, cocaine, chloroprocaine, tetracaine, benzocaine

- Short half-life and duration of action (rapid hydrolysis in plasma – enzyme is butyrylcholinesterase BChE). The metabolic metabolite PABA is prone to causing allergic reaction. Check if patient has had allergic rxn prior.

• Note: structural-activity is primary determinant of pharmacologic property. All LA are weak bases. Cationic form (LAH+) is most active form at Na receptor. Uncharged form is important for lipid penetration of membranes.

92

Do we need to know about receptor theory vs membrane disruption theory for local anesthesia?

Do we need to know about receptor theory vs membrane disruption theory for local anesthesia?

93

What factors influence local anesthetic onset and recovery?

- Before talking about factors, know about Cm. Cm is minimum anesthetic concentration = minimum [ ] of drug for standard block.

1. Fiber size: high fiber size = high Cm. Therefore smallest fibers are most sensitive. Myelinated are more sensitive too. Blocking effect: B fibers > C > A-delta > A-gamma > A-beta > A-alpha

2. Site of deposition: occurs first at outer fibers

3. pH: higher pH = lower Cm (need less drug)

4. Nerve stimulation rate: high frequency nerves (sensory) more sensitive

5. Ca concentration: higher [Ca] = higher Cm (need more drug)

6. Addition of vasoconstrictors: reduction of BF = increased duration of action = less toxicity systemically.

94

Should epinephrine with local anesthesia always be used?

- Never in areas with end arterioles such as digits, toes, ear lobe, nose and penis. Dt vasoconstrictor effect, there is a potential for gangrene / sloughing off of tissue.

95

What factors affect the reversal of local anesthesia?

1. Dilution by ECF

2. Absorption into circulation = most NB factor

3. Redistribution to other areas

4. Use of vasoconstrictors

96

What are potential adverse effects of local anesthetics?

- Hypersensitivity/allergic rxns

- Systemic toxicity: including CNS, CV effects. Less with esters d/t rapid metabolism in blood.

97

Describe treatment for local anesthetic toxicity (LAST).

- IV lipid emulsion of intralipid.

- Forms lipid sink to absorb circulating lipophilic anesthesia.

98

What is lidocaine used for? Toxicity?

- Use: reference std for anesthetics. Most commonly for epidural. Can be given topically and by injection for minor and major peripheral blocks. Note this!

- Toxicity: CNS excitation, TNS (transient neurologic symptoms) w/spinal administration leading to pain/increased sensitivity to touch

99

What is bupivacaine used for? Toxicity?

- Use: agent of choice for epidural infusion for labor analgesia and post-op pain. Excellent spinal anesthetic.

- Toxicity: CNS excitation and CV collapse. Levobupivacaine is less potent with less CV toxicity

100

What is articaine used for? Toxicity?

- Use: dental anesthetic

- Toxicity: potential for development of persistent paresthesias

101

What is cocaine used for? Toxicity?

- Use: topical anesthetic agent for ENT procedure

- Toxicity: CNS excitation, convulsions, cardiac arrhythmias, HTN, stroke

102

What is benzocaine used for? Toxicity?

- Use: topical only anesthesia

- Toxicity: potential to induce methemoglobin (reduced o2 affinity) – risk for hypoxia

103

What is chloroprocaine used for? Toxicity?

- Use: epidural agent for labor anesthesia (esp. c-section) d/t low risk for systemic toxicity or fetal exposure.

- Toxicity: CNS excitation and local neurotoxicity

104

What is exparel-liposome used for?

- This is encased bupivacaine that provides relief up to 72 hours post-op. High cost.

105

What is EMLA used for?

- Eutectic mixture of local anesthetics. This is mixture of LA in oil-water emulsions. Use as topical anesthetic on intact skin.

106

What is TAC used for?

- Tetracaine, adrenalin and cocaine. Use: topical in peds ER.

107

What agents are neurolytics? What are neurolytics? Use?

- Neurolytics = agents that are not reversible and achieve permanent local anesthesia.

- Agents include: ethyl alcohol and phenol. Use = terminal cancer or other chronic pain.

108

Define schizophrenia

- Severe type of psychosis characterized by disturbances in behavior and thought processing. Includes delusions (false beliefs) and hallucinations of various kinds.

109

Compare and contrast positive symptoms of schizophrenia

- Positive: manifestation of abnormal behavior.
o Delusions, hallucinations (auditory), agitation, paranoia, aberrant thinking, intrusion of thoughts

- Negative: absences of normal behavior
o Emotional apathy (flat affect), socially withdrawn, inattentiveness

110

What is the pathophysiology underlying schizophrenia?

1. DA hypothesis

- Hyperactivity of mesolimbic/mesocortical DA system = excess limbic DA activity = psychosis

- Not sure if we need to know serotonin hypothesis or glutamate hypothesis

111

Types of antipsychotic drugs. MOAs? What is a big difference between them?

- Typical: chlorpromazine, thioridazine, fluphenazine, haloperidol

o MOA: DA receptor antagonist (mostly D2 post-synaptic)

- Atypical: clozapine, olanzapine, risperidone, aripiprazole, quetiapine, ziprasidone

o MOA: antagonist at 5-HT(2a) receptors and D2 receptors (less than typicals)

- Typical agents produce a high incidence of extrapyramidal/PD-like symptoms. Atypicals have fewer EPS effects.

112

Therapeutic indications for antipsychotic agents

- Schizophrenia, psychotic behavior, severe mania (manic phase of bipolar), antiemetic

113

How are atypical antipsychotic agents metabolized?

- CYP450

114

Which antipsychotics tend to have higher hypotensive effects?

- Typical agents

115

What antipsychotic drugs lead to extrapyramidal symptoms? What are these symptoms?

- Typical antipsychotics

- Sx = PD-like (rigidity, tremor, bradykinesia), akathesia (motor restlessness and anxiety), dystonia (torticollis, spasm of back, eyes roll back, facial grimacing), tardive dyskinesia (involuntary movements of tongue, mouth, face and head) seen more in elderly group than younger group

116

Describe anti-dopaminergic effects seen with antipsychotics

- Antipsychotic effects

- EPS/motor behavior (see another card)

- Antiemetic

- Hyperprolactinemia: decreased testosterone, gynecomastia, changes in libido/impotence/infertility, galactorrhea, menstrual irregularities

- Weight gain (esp. clozapine and olanzapine).

117

What antipsychotics especially cause weight gain?

- Clozapine and olanzapine. These are atypical anti-psychotics

118

What are the adverse effects of antipsychotic meds?

1. EPS/motor behavior (see another card): esp with typical agents

2. Anticholinergic: dry picture

3. Antihistaminic: sedation, weight gain

4. Antiadrenergic: hypotension, reflex tachy, ED and impaired ejaculation

5. Weight gain (antihistaminic or 5-HT effect?): potential for increased risk of T2DM

119

What atypical antipsychotic agent is associated with EPS?

- risperidone

120

When is EPS risk highest in patient on antipsychotics?

- Typical agent use

- Rapid dose escalation

- Some patients are more vulnerable than others

121

Main characteristics of neurodegenerative disorders

- Irreversible loss of neurons (differ in regions depending on specific disorders)

- Genetic and environmental factors

- Aggregation of misfolded proteins

122

Patholophysiology of PD, HD and ALS. Include accumulations that occur

- PD: loss of dopaminergic neurons in basal ganglia leads to altered movement control, accumulation of intracytoplasmic aggregates of alpha-synuclein

- HD: loss of dopaminergic neurons in basal ganglia leads to altered movement control, accumulation of intranuclear inclusions of huntingtin protein

- ALS: degeneration of cortical and spinal motor neurons resulting in muscular weakness, accumulation of intracytoplasmic aggregates

123

Symptoms of AD

1. Cognitive: loss of short-term memory, aphasia, apraxia, agnosia, disorientation

2. Non-cognitive: depression, psychotic symptoms (hallucinations and delusions), behavioral disturbances

124

What is the most common cause of dementia?

- Dementia: decline in mental ability to the point it interferes with ADL

- Most common cause: AD

125

What biologically is AD? What accumulations are seen? What is the pathophysiology?

- AD is loss of hippocampal and cortical (temporal, frontal and parietal lobes) neurons that leads to impaired memory formation and cognitive deficits.

- Accumulations = extracellular beta-amyloid plaques and intracytoplasmic neurofibrillary tangles

- Pathophys

1. Deficiency of Ach: degeneration of subcortical cholinergic neurons (hippocampus)

2. Amyloid plaques: beta-amyloid is cleaved from amyloid precursor protein (APP) – unknown function. Imbalance between production and clearance of beta-amyloid. Genetic components identified with mutations in APP, PSEN1/2, APOE

3. Tau hypothesis: Tau provides support to microtubules and neuronal cytoskeleton. Hyperphosphorylation occurs in AD = aggregation and tangles.

126

Drug classes used to treat AD

- Cholinesterase inhibitors

- Glutamate antagonists

127

What cholinesterase inhibitors are used to treat A? a. Class; b. Specific treatments, c. MOA; d. Adverse effects/toxicity; e. Drug interactions

- Drugs: donepezil, rivastigmine, galantamine

a. Class: cholinesterase inhibitors

b. Tx:

- Donepezil: mild to severe AD

- Rivastigmine: AD, selective for activity in hippocampus and prefrontal cortex. Available as transdermal patch.

- Galantamine: mild to moderate AD

c. MOA: cholinesterase inhibitors. Specifics:

- Donepezil: inhibits primarily AChE

- Rivastigmine: both AChE and BChE

- Galantamine: ?

d. Adverse effects: nausea, vomiting diarrhea. Also cholinergic side effects – SLUDGE (salivation, lacrimation, urinary incontinence, diarrhea, GI cramples, emesis. Note donepezil causes bradycardia specifically.

e. Avoid TCAS d/t anticholinergic effects and orthostatic HoTN (esp in elderly)

128

What is memantine? a. Class; b. Clinical use; c. MOA; d. Adverse effects/toxicity

a. Class: glutamate antagonist

b. Use: moderate to severe AD, provides neuroprotection by reducing intracellular Ca influx and glut-induced excitotoxicity

c. MOA: non-competitive antagonist of the NMDA glut receptor with long half-life

d. Adverse effects: dizziness, HA, depression, anorexia, fatigue, insomnia, sedation, tremor

129

Other treatment strategies for AD besides cholinesterase inhibitors and NMDA receptor antagonists

- Estrogen

- Vitamin E

- Ginkgo biloba ? efficacy

130

What are the treatment options for psychosis/agitation in AD patients?

- Atypical antipsychotics: risperidone, olanzapine and quetiapine

131

What are the treatment options for depression/anxiety in AD patients?

- SSRIs (sertraline, citalopram). AVOID TCAs as they have anticholinergic effects. Can also cause orthostatic HoTN in elderly.

132

How to treat sleep disturbances in AD patients?

- Antidepressents (SSRIs, avoid TCAs)

- Atypical neuroleptics: clozapine, olanzapine, risperidone, aripiprazole, quetiapine, ziprasidone

- Avoid benzos (long-acting) and anti-histamines (anti-cholinergic effect)

133

Describe stages of AD

a. Mild cognitive impairment: cognitive impairment (not dementia)

b. Mild AD: memory loss, confusion, impaired judgment, decreased concentration

c. Moderate AD: language impairment, decreased comprehension, disorientation, sleep disorders

d. Severe AD: dependence, delusions, agitation, incapacitation

134

Signs/symptoms of PD

1. Cardinal motor symptoms: bradykinesia, muscular rigidity, resting tremor, postural instability

2. Non-motor: cognitive decline, anxiety/depression, sleep changes, etc.

135

Pathophysiology of PD

- Degeneration/loss of DA neurons in substantia nigra (of basal ganglia) that project to striatum

- Loss above is accompanied by increased activity of cholinergic pathways

- Genetic factors (alpha-synuclein accumulation forming Lewy bodies and increased production of free radicals)

- Environmental factors implicated

136

What are general tx strategies for PD

1. DA replacement

2. DA receptor agonists

3. L-DOPA degradation inhibitors

4. Increase in DA release

5. Anticholinergic agents

137

L-DOPA. a. Class; b. Clinical use; c. MOA; d. Adverse effects/toxicity; e. Drug interactions

a. Class: ?

b. Use: most common PD treatment. Give with carbidopa to increase entry into brain.

c. MOA: precursor to dopamine, crosses BBB

d. Adverse effects: dyskinesias (~80%), response fluctuations, GI disturbances, CV effects (postural hypotension, tachy, dysrhythmias), behavioral disturbances

e. Interactions: pyridoxine (B6), MAO-A inhibitors, antipsychotics (DA-receptor blockers), protein-rich meals (competition for absorption), anti-cholinergics

138

What is problematic about L-DOPA treatment?

- Tx effects often begin to diminish after 3-4 years of therapy as patients become less responsive. Must take drug holiday.

- Also peripheral conversion and loss. Requires carbidopa or COMT inhibitors.

139

Pramipexole, ropinirole, apomorphine. a. Class; b. Clinical use; c. MOA; d. Adverse effects/toxicity

a. Class: dopamine receptor agonists

b. Use: first-line or initial therapy for PD, generally effective as monotherapy for mild PD. Apomorphine: rescue treatment in levodopa-induced dyskinesia

c. MOA: DA-2 receptor agonists

d. Adverse effects: dyskinesias, response fluctuations (lower incidence overall of these than levodopa), GI, CV, HA, potential problems with impulse control disorders.

140

Rasagiline, selegiline. a. Class; b. Clinical use; c. MOA; d. Adverse effects/toxicity; e. Drug interactions

a. Class: L-Dopa degradation blockers. Non-selective MAO-B inhibitors.

b. Use: adjunct to L-dopa (esp with declining/fluctuating response) for PD at low dose, anti-depressant at high doses

c. MOA: inhibits MOA-B selectively at lower doses to decrease breakdown of DA. High doses inhibits MAO-A too.

d. Adverse effects: GI upset (minimal), serotonin syndrome (with meperidine and theoretically with SSRIs and TCAs)

e. Interactions: no wine and cheese interactions

141

Entacapone, tolcapone. a. Class; b. Clinical use; c. MOA; d. Adverse effects/toxicity

a. Class: L-dopa degradation blockers. COMT inhibitors

b. Use: PD (adjunct in those with response fluctuations to levodopa)

c. MOA: selective catecohol-O-methyltransferase (COMT) inhibitor in periphery = more L-dopa available

d. Adverse effects: hepatoxicity with tolcapone, other effects = increased levodopa toxicity, nausea, dyskinesias, confusion

142

Amantadine. a. Class; b. Clinical use; c. MOA; d. Adverse effects/toxicity

a. Class: dopamine releaser ☺, antiviral

b. Use: PD

c. MOA: antiviral agent that incidentally has anti-parkinsonian properties. Short duration of action and short-lived effectiveness (several to 12 months)

d. Adverse effects: LIVEDO RETICULARIS (red blotchy pattern usually on legs, clears w/in 1 month after stopping), others

143

What anticholinergic drugs are used in PD? MOA? Effects? Adverse effects?

- Benztropine and trihexyphenidyl.

- MOA: antagonist at muscarinic receptors in basal ganglia

- Reduces tremors and rigidity. Little effect on bradykinesia.

- Adverse effects: anticholinergic = dry

144

General effects of opioids

- Euphoria, analgesia, sedation, constipation (relief from diarrhea), anti-tussive, respiratory depression, miosis, emesis, urinary retention, CV (HoTN, brady), histamine release (mastocytosis)

145

Difference between opium, opiate, opioid and narcotic

- Opium: exudate from poppy including active components

- Opiate: drug extracted from exudate of poppy – morphine / codeine

- Opioid: natural or synthetic drug that binds opioid receptors

- Narcotic: compounds used to tx pain

146

Describe the opioid receptors

- Mu1: outside spinal cord – responsible for central interpretation of pain (known as supraspinal analgesia)

- Mu2: throughout CNS – responsible for supraspinal analgesia, spinal analgesia, respiratory depression, constipation, physical dependence, and euphoria

- Kappa: modest supraspinal and spinal analgesia

- Delta: modest supraspinal and spinal analgesia – least well understood

147

Describe metabolism of opioids

- Hepatic: glucuronidation

148

Describe mechanisms of analgesia

1. Mu receptors are Gi/o coupled

2. Pre-synaptic: activation of receptor = inhibition of AC = decrease cAMP = reduced opening of VG Ca = decrease in release of NTs

3. Post-synaptic: increased opening of K channels = hyperpolarization

4. Ascending pathway interneurons: activation of GABA (inhibitory) interneurons = reduced activation of afferent neurons = less pain registered in brain

5. Descending pathway interneurons: inhibition of GABA interneurons = more active descending pathways = enhanced inhibition of nociceptive processing in spinal cord = less pain registered

149

Therapeutic indications for opioids

- Analgesia

- Anesthetic (pre-med/adjunct)

- Cough suppressant

- Diarrhea

- Acute pulmonary edema (to reduce panic and anxiety)

150

Side effects of opioids

- Sedation, respiratory depression, N&V, behavioral restlessness, seizures, hypotension, constipation, increased ICP, urinary retention, urticarial

151

Drug interactions with opioids

- CNS depressants

- MES inducers??

- MAOI: hyperpyrexic rxn + HTN – contraindicated with meperidine. Caution with other opioids.

- Mixed agonist-antagonist

- Antagonist

152

What opioids are used for severe pain?

- Morphine, fentanyl, meperidine (Demerol), methadone, sufentanil, heroin (not really used), hydromorphone

153

Drug used to treat patients with opiate addiction (ie. heroin)?

- Methadone. Milder withdrawal symptoms.

154

What opioids are used for moderate pain?

- Codeine (also antitussive)

- Oxycodone (for breakthrough pain post surgical)

- Hydrocodone

155

What is dextromethorphan used for?

- Opioid cough suppressant

156

What is diphenoxylate used for?

- Antidiarrheal agent. It is opioid.

157

What is loperamide used for?

- Antidiarrheal agent. Opioid.

158

Example of mu agonist + 5-HT/NE uptake inhibitor

- Tramadol

159

What are mixed opioid agonist-antagonists? Names? Why use them? Cons?

- Act different at specific opioid receptors.

- Names: buprenorphine, butorphanol, nalbuphine, pentazocine

- They provide adequate analgesia with less risk of side effects and addiction than standard opioids. They have enhanced psychotropic (hallucinatory) effects.

160

Why use hydromorphone?

- Nearly 10 x more potent than morphine. Use in surgical settings for moderate to severe pain (cancer, bone trauma, burns, renal colic)

161

Which analgesic is available for transdermal use?

- Fentanyl

162

What is the most effective opioid analgesic used in clinical setting?

- Fentanyl. 10 x more potent than hydromorphone. 80 X more potent than morphine.

163

Opioid antagonists

1. Naloxone: short duration of action, used acutely – reverses CNS and resp depression within 30 seconds

2. Naltrexone: longer duration of action, maintenance drug for addicts in treatment programs

164

Describe mechanism of euphoria with opioids

- Opioids inhibit GABAergic inhibitor interneurons = increased activation of dopaminergic neurons (reward pathway) = feeling of euphoria

165

What is one of the leading causes of opiate dependence and abuse?

- Euphoria

166

Describe withdrawal symptoms from opioids

- Flu-like muscle aches, chills, diarrhea, nausea, vomiting, fever, insomnia, sweating, anxiety, hostility, increased BP, fearfulness, hyperventilation

167

Classification of CNS stimulants. Explain general use for each category. Name drug(s) in each category

1. Analpetics (respiratory stimulants)

- Doxapram

2. Methyxanthines: mild CNS, respiratory stimulant, bronchodilator, cardiac stimulator, diuretic properties

- Caffeine, theophylline

3. Sympathomimetic amides: psychomotor stimulants

- Amphetamine (methamphetamine, dexamphetamine, methylphenidate, dextroamphetamine), cocaine, modafinil, atomoxetime (not technically a stimulant)

168

What drugs must be avoided when one is on a CNS stimulant?

- Avoid MAOIs and SSRIs

169

What are the general clinical uses of CNS stimulants?

- ADHD, post-anesthesia/drug-induced respiratory depression, analgesia, performance enhancement/alertness, narcolepsy/sleep disorders, severe obesity

170

Doxapram. Use, MOA

- Use: respiratory stimulant to counteract post-anesthetic respiratory depression

- MOA: depression of inhibitory neurotransmission (GABA-A and glycine antagonists = decrease Cl influx and hyperpolarization)

171

Caffeine. Use, MOA

- Use: CNS stimulant (alertness), primary tx for apnea of prematurity in infant, analgesia as adjunct to other OTC agents

- MOA: inhibition of CNS suppressant (reduce adenosine activity by A1 receptor antagonist)

172

Theophylline. Use, MOA

- Use: COPD, asthma, apnea of prematurity

- MOA: inhibition of CNS suppressant (reduce adenosine activity by A1 receptor antagonist)

173

What are amphetamines clinically used for? MOA?

- ADHD, narcolepsy, obesity (short-term weight loss)

- MOA: competitively inhibits DA transporter and increases DA, Also interferes with VMAT causing increases to synaptic DA

174

What is methylphenidate used for?

- This is Ritalin and main choice for treating ADHD

- ADHD, narcolepsy

175

Dextroamphetamine. Use

- Use: ADHD, narcolepsy and sleep disorders, obesity

176

Cocaine. MOA

- Use: illegally (stimulant, appetite suppressant), topical anesthetic ENT

- MOA: enhancement of excitatory transmission (inhibition of monamine uptake via blockage of DAT, NET and SERT). Affects VTA reward circuitry in brain

177

Modafinil. Use, MOA

- Use: non-stimulant for ADHD (not for children), fatigue, narcolepsy (FDA approved)

- MOA: activates histamine neurons in TMN of hypothalamus – this is wake-promoter in brain

178

Atomoxetine. Use, MOA

- Use: non-stimulant for ADHD

- MOA: enhancement of excitatory transmission (selective NE transporter blockade)

179

Common side effects with psychomotor stimulants such as amphetamines, cocaine

- CNS: euphoria, dysphoria, insomnia, irritability, tremor, HA, loss of appetite

- CV: MI, CVA

- Others: anorexia, severe weight loss, addiction

180

Describe how ADHD is diagnosed

1. Inattention (6 or more of following must be present for 6 months)

- inattention to details, diff sustaining attention, easily distracted, avoids tasks requiring sustained attention, doesn’t listen, fails to finish tasks, difficulty organizing, loses things, forgetful

2. Impulsivity/hyperactivity (6 or more of following must be present for 6 months)

- blurts out answers before Q finished, difficulty waiting turn, interrupts/intrudes on others, talks excessively, squirms and fidgets, unable to stay seated, runs/climbs excessively, cannot play/work quietly, on the go

- Diagnosis based on predominance of either or or combined (majority of cases)

181

What area of brain is implicated in ADHD?

- Frontal lobe dysfunction. Dopamine deficit hypothesis.

182

Describe stimulants vs non-stimulant treatment of ADHD

- Stimulant: methylphenidate, amphetamine salts, dextroamphetamine

- Non-stimulant: atomoxetine, clonidine (alpha-2 agonist), modafinil, antidepressants

183

Common side effects in ADHD treatment

- Decreased appetite/weight loss, insomnia, headaches, stomach aches, irritability/moodiness rebound, motor tics

184

What are the main feelings/symptoms sought after for drug abusers? Also sugar abusers? ☺

- Euphoria, reward

185

What is the hallmark of drug addiction?

- Compulsive drug use

186

Compare and contrast dependence from addiction? What is physical vs psychological?

- Dependence (physical): drug is necessary for normal physiological function. Removal = withdrawal.

- Addiction (psychological): compulsive drug use to induce pleasure and / or escape from reality

187

What are common / generalized withdrawal symptoms?

- Dysphoria, depression, anxiety, strong craving, seizures and psychosis

188

Describe relative risk of addiction scale

- 1: non-addictive, 5: highly addictive

189

What biological system do addictive drugs activate?

- Mesolimbic dopamine system – reward pathway

- VTA (ventral tegmentum) – amygdala, nucleus accumbens, hippocampus, prefrontal cortex

190

Classification of drugs of abuse. Names of drugs and relative risk of addiction?

1. CNS depressants and sedatives: alcohol, benzodiazepines, barbs (pentobarbital), GHB. These are rated RR 3.

2. Psychostimulants: cocaine, amphetamines, methylphenidate, MDMA (ecstasy). These are rated RR 5.

3. Psychedelics: LSD, psiolocybin (mushrooms), ketamine, PCP (angel dust). These are rated RR 1.

4. Opioids: morphine, heroin, codeine, oxymorphone. These are rated RR 4.

5. Cannabinoids: THC. These are rated RR 2.

6. Nicotine, tobacco

7. Inhalants: volatile solvents, N2o2, ethyl ether

191

What is the drug used to encourage alcoholics to abstain from etoh abuse? How does it work?

- Disulfiram (antabuse): inhibits ALDH which converts acetaldehyde to acetate. When high, acetaldehyde causes facial flushing, nausea, vomiting, dizziness and headache.

- Naltrexone blocks reinforcing properties of etoh and reduces rate of relapse.

192

Describe etoh metabolism

1. ADH: alcohol dehydrogenase – ethanol to acetaldehyde. Also converts methanol to formaldehyde and antifreeze (ethylene glycol) to oxalic acid (CNS toxicity + other)

2. MEOS: microsomal ethanol-oxidizing system (induced during chronic alcohol consumptoion)

3. ALDH: aldehyde DH – acetaldehyde to acetate

193

How is etoh eliminated from body? What kinetics?

- Zero-order. Rate of elimination independent of time and concentration. ADH saturable. Constant amount of etoh eliminated per unit time. 7-10 g etoh per hour metabolized in avg adult, which is about 1 drink.

194

What does BAC of 0.08 mean?

- BAC: blood alcohol content. 0.08 % = 80 mg/dL

195

MOA of etoh

- GABA-A potentiation like barbiturates and benzos

- Also inhibits NMDA receptor inhibitor (this is excitatory)

196

What drugs should never be combined with etoh?

- Barbiturates, benzos and THC

197

What is Wernicke-Korsakoff syndrome?

- Aka wet brain or alcoholic encephalopathy. It is a neurological condition associated with B1 (thiamine) deficiency in combination with excessive etoh intake. Symptoms = ocular disturbances, changes in mental state, memory impairment, movement difficulties

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What are the effects of FAS (fetal alcohol syndrome)?

- Mental retardation, hyperactivity, antisocial behavior

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Withdrawal symptoms in alcoholic

- Hyperexcitability, seizures, toxic psychosis, delirium tremens

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Most commonly abused benzodiazepines?

- Diazepam (valium) and alprazolam (Xanax)

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Describe mechanism of addiction of benzos.

- Benzos are GABA-A receptor potentiators. Overall, result = disinhibition of VTA DA neurons and activation of mesolimbic reward pathway.

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What effects cause addiction to cocaine?

- Intense euphoric effect, increased energy and libido, decreased appetite, hyperalertness, increased self-confidence

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What is cocaethylene?

- Mixture of etoh and cocaine. Produces intensification of cocaine’s euphoric effect, most common two-drug combo resulting in drug-related death.

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What drug leads to strongest psychological dependence?

- Cocaine. Has strong reinforcing properties.

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What effects cause addiction to amphetamines? MOA?

- Increase in catecholamines = euphoria, increased arousal and reduced sleep. Meth easily pyrolyzed. Effects last 6-24 hours while cocaine only lasts 20-30 mins.

- MOA = DAT and VMAT blocker

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MDMA. Why is it abused? MOA? Toxicity?

- Designer/club drug. Evokes feeling of intimacy and empathy

- MOA: interferes with SERT = release of 5-HT from pre-synaptic terminals

- Toxicity: acutely – hyperthermia and dehydration

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LSD and psilocybin. Effects, MOA, adverse effects

- Effects: hallucinations, illusions, paranoia, euphoria/depression

- MOA: release glut in cortex via excitation of thalamus, also target 5-HT2a receptors = increase Ca

- Adverse effects: flashbacks, bad trip

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Does LSD & Psilocybin stimulate the mesolimbic dopamine release pathway?

- No. Therefore no dependence or addiction.

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Ketamine and PCP. Effects, MOA

- Effects: psychedelic effects – hallucinations, impaired memory, visual alterations

- MOA: block NMDA-type glut receptors = decrease activity of cortex and limbic system

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Most commonly abused opioids

- Codeine, heroin, morphine, oxycodone

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What medication is used for emergency overdose of opioids?

- Naloxone

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What is the active substance in cannabis? MOA for addiction?

- THC. Synthetic THC is available called dronabinol.

- MOA: disinhibits DA neurons in the VTA

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Therapeutic effects of THC

- Increased appetite, attenuation of nausea, decreased intraocular pressure, relief of chronic pain (big one… not the big D)

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Describe MOA of nicotine addiction. Describe treatment?

- MOA: activation of NAChR on VTA = DA release in nucleus accumbens and PFC

- Tx: transdermal nicotine patch, bupropion (antidepressant), varenciline (Chantix) – agonists of R