Neuro Drugs Flashcards
1
Q
Principles of Anti-epileptics: monitoring
A
Epilepsy patients need 24-hour coverage
- t 1/2 < 24 hours–> BID dosing
- t 1/2 < 12 hours–> TID dosing
- Some drugs have short t 1/2 but work on BID schedule- have secondary effects that exceed pharmacokinetic half-lives
Serum levels: often easured
- Therapeutic range= guideline, low-end more meaningful
- Seizure= level not enough
- Side effect= level too high
- Toxicity ALWAYS determined by patient symptoms, NOT serum level (high levels do not endanger patient)
Protein-binding:
- Phenytoin, Valproate= 90% protein bround
- Can measure bound and unbound levels
- free fraction is what’s relevant (change in protein binding, as in pregnancy, chronic liver disease, malnutrition) will change free but not total serum level
- Monitor interactions with other protein-bound drugs
2
Q
Principles of anti-epileptics: metabolism
A
Metabolism:
- Most AEDs metabolized by the liver
- Space out doses in pts w/hepatic failure
- Gabapentin, pregabalin, levetiracetam, oxcarbazepine’s active metabolite are renally excreted
- Reduce doses in renal failure
- Topiramate 2/3 kidney, 1/3 liver
Hepatic induction:
Barbiturates, phenytoin, carbamazepine are potent inducers of CYP450 system
- Induce metabolism of many other drugs
- Ex: oral contraceptives
- Another Ex: vitamin D (-> osteomalacia)
** Topiramate, oxcarbazepine induce only a couple of CYP enzymes (but same effect on OCP)
** CBZ autoinduces metabolism
- Valproate is a potent inhibitor of CYP450 enzymes
- Raises levels of other drugs
- All of these AEDs may also have their own levels changed, by each other (and sometimes by other drugs)
- Ex: erythromycin causes ↑ CBZ level
3
Q
IV epilepsy meds
A
Urgent use for seizures
- Phenytoin (and fos-phenytoin)
- Valproate
- Benzodiazepines
- Barbiturates
- Levetiracetam
- Lacosamide
4
Q
IV phenytoin, phenobarbitol
A
Long half-lives (30 hrs, 96 hrs), so can’t wait for steady state – must load IV
- Serum level = dose / volume of distribution (Vd)
For quick & dirty mgmt, assume Vd ~ 1. So, if you want a level of 20 ug/dl, load with 20 mg/kg
- Vd actually varies by pt, around 0.8
- Maintenance doses different story
5
Q
Benzodiazepines
A
Lorazepam, diazepam Rx of choice for acute seizures
- Lorazepam shorter half-life, but longer brain half-life than diazepam (diffuses into adipose tissue)
- Midazolam (ultrashort acting) for status
- Clonazepam used for chronic Rx, but benzos lose effect when given chronically (except for myoclonic sz)and can be addictive
MOA: Bind to an allosteric modulation site on the GABAA receptor, which is coupled to a Cl- channel
- Benzo causes channel to open more frequently –> hyperpolarization, greater inhibition
- Flumazenil: competitive antagonist at benzodiazepine receptor
- Can cause sz in pts taking benzos
6
Q
Barbituates
A
- Phenobarbital (t1/2 = 96 hrs)
- Used for acute & chronic sz Rx - Pentobarbital (PB pro-drug)
- Refractory status epilepticus
- Induction of deep coma - Primidone metabolized into PB + PEMA
- Epilepsy
- Essential tremor
MOA:
- Bind to another allosteric modulation site on the GABAA receptor
- Different from the one used by the benzodiazepines
- Barbiturate binding causes the Cl- channel to remain open longer (not to open more frequently)
AEs:
- Acute IV use: respiratory depression -
- Sedation
- Depression
- Cognitive impairment
- Hepatotoxicity
- Allergic rashes
- Not first-line drugs
- Exceptions: infants, severely financially challenged
7
Q
Gabapentin
A
Designed as a GABA-analog, but it’s not!
- Effective only for focal seizures
- Neuropathic pain major use: only 10% of prescriptions are for epilepsy
MOA:
- Binds to α2δ subunit of presynaptic Ca++ channel
- leads to (usually modest) reduction in release of a host of neurotransmitters (e.g. substance P)
AEs: Mild:
- Sedation
- Weight gain (at higher doses)
PK:
- Neutral AA transporter gets saturated
- Total dose limited by gastric absorption
- Renal elimination
** Pregabalin very similar, but much more potent, and not limited by gastric absorption (more AEs, still used for pain)
8
Q
Phenytoin
A
MOA:
- Voltage- and frequency-dependent block of Na+ channels
- Prevents high-frequency firing, allows firing at more typical frequencies
Works for GTC and focal seizures
* Ineffective for absence, myoclonic sz
Odd properties:
- Non-linear pharmacokinetics (CLOSE MONITORING REQUIRED)
- Induction of CYP450 enzymes
- 90% protein bound
- Half-life longer with higher doses
- Absorption erratic
- IV solution precipitates with dextrose
PK:
- T 1/2 24 - 30 hrs; QD dosing
AEs:
- Acute: sedation, ataxia, dizziness, diplopia
- Chronic: gingival hyperplasia, hirsutism, acne, coarsening of facial features, osteomalacia
- Dangerous: rash, hepatatoxicity, myelosuppresion
9
Q
IV Phenytoin
A
Diluted in ethanol & propylene glycol
AEs:
- Hypotension
- Cardiac arrythmias
- Thrombophlebitis,“purple glove” syndrome
- Fos-phenytoin: IV phenytoin pro-drug
- Water-soluble, doesn’t precipitate w/dextrose
- Less local irritation
10
Q
Carbamazepine
A
MOA:
- Tricyclic ring structure
- Blocks voltage-sensitive Na+ channels just like phenytoin
PK:
- Half-life 8 - 10 hrs;
- sustained release formulations can be given BID
- Induction of hepatic CYP450 enzymes
- Autoinduction of metabolism
Uses:
- Effective for partial and GTC seizures
- Can worsen absence, atonic, and myoclonic seizures Rx for bipolar d/o, trigeminal neuralgia
AEs:
- Acute side effects like phenytoin (ataxia, dizziness, diplopia, sedation)
- No cosmetic side effects
- Chronic: hyponatremia, leukopenia
- Serious: rash, aplastic anemia
11
Q
Oxcarbazepine
A
Carbamazepine has an epoxide metabolite that may contribute to toxicity
- Oxcarbazepine is very similar, but no epoxide metabolite
Better tolerated:
- No hepatic or hematologic toxicity
- Limited hepatic inducer (CYP3A4, 3A5)
- Hyponatremia more common
12
Q
Lamotrigine
A
Na+ channel drug, but also enhances slow inactivated state of channel
- Developed from cancer chemo drugs
Broad-spectrum:
- works on all seizure types
T 1/2= 18-30 hours (BID dosing)
AEs:
- Stimulating, not sedating
- Insomnia, headaches
- Rash
- Less common if titrated slowly
- Few drug interactions (inducers, VPA)
- Non-teratogenic?!
Uses:
- Effective for bipolar depression
13
Q
Lacosamide
A
Na+ channel: enhances SLOW inactivation through different mechanisms
- Available IV, same dosing
- Safe, well-tolerated
AEs: dizziness when combined with other Na+ channel blockers
14
Q
Ethosuximide
A
MOA: voltage-dependent block of “transient” T-type Ca+2 channels in thalamus
- Blocks corticothalamic interactiosn responsible for 3 Hz spike and wave in Absence seizures
Use: Absence seizures
** Patients with other concomitant seizure conditions will need more drugs
15
Q
Valproate
A
First broad-spectrum AED
** Most commonly used for bipolar disorder
MOA: ethosuximide-like effects on T-type Ca+2 channels
- Phenytoin-like effects on Na+ channels
- Increases brain GABA levels
- Unclear
AEs:
- GI upset, sedation, cognitive probs
- Weight gain, hair loss, tremor
- Serious: hepatic failure (mainly infants), pancreatitis, thrombocytopenia, hyperammonemia (transiently “out of it”)
- Causes reversible form of polycystic ovary syndrome
- 2% incidence of neural tube defects, cognitive teratogenicity
16
Q
Topiramate
A
Substituted fructose ring
MOA:
- Broad-spectrum; many (possible?) mechanisms
- Some effects on Na+ channels
- Inhibition of voltage-sensitive Ca2+ channels
- Benzo-like effects in GABA-induced Cl- currents
- Inhibits AMPA/kainate type Glu receptors
- Inhibits carbonic anhydrase
- Not clear which, if any, of these actions is relevant to anticonvulsant effects
PK:
- T1/2 20 hrs; dosed BID
Uses:
- Migraines, bipolar, essential tremor
AEs:
- Sedation, paresthesias, cognitive impairment (esp. aphasia- word finding problems)
- Can be very prominent, yet transient
- Nephrolithiasis (1%)
- Weight loss
- Few drug interactions
17
Q
Zonisamide
A
MOA:
- Broad-spectrum drug
- Phenytoin-like effect on Na+ channels
- Ethosuximide-like effect on Ca+2 channels
- Carbonic-anhydrase inhibition
PK:
- t1/2= 63 hours (QD dosing)
AEs:
- Sedation, dizziness, cog. impairment, decreased appetite
- Rash, nephrolithiasis (1%), agranulocytosis (very rare), oligohydrosis/hyperthermia
- No drug interactions
18
Q
Levetiracetam
A
MOA:
- Recently shown to tightly & specifically bind to a synaptic vesicle protein called SV2A
- Affinity of SV2A binding correlates with strength of antiepileptic effect
PK:
Effective at starting dose (within 72 hrs)
AEs:
Safe and well-tolerated; sedation, irritability, psychosis (1%)
Uses:
Effective for partial seizures, myoclonic seizures
19
Q
Prognosis of Refractory epilepsy
A
If focal epilepsy doesn’t respond to the first 2 or 3 drugs tried, chance of being seizure-free on medicine 10-20%
~50% of these may be candidates for resective epilepsy surgery
- In best-selected candidates, > 80% chance of long-term seizure freedom
20
Q
Treatment prognosis
A
Large majority (>95%) of pts with idiopathic generalized epilepsy can be made seizure-free with medication
Symptomatic generalized epilepsy is rarely controllable
- Minimize atonic and GTC seizures
Focal epilepsy fully medically controllable in 60-70% of patients
21
Q
Neurotransmitters of basal ganglia
A
Dopamine= Excitatory and inhibitory
- Striatonigral
Ach= Excitatory and inhibitory
- Striatal interneurons
GABA= Inhibitory
- Striatopallidal and pallidothalamic
Glutamate= Excitatory
- Corticostriatal, thalamocortical
22
Q
Biosynthesis of Dopamine
A
Dopamine is the most important and well studied neurotransmitter in movement disorders.
In the central nervous system, dopamine is synthesized from the amino acid tyrosine.
- Tyrosine is converted to L-dihydroxyphenylalanine by tyrosine hydroxylase. This is the rate limiting step and can be inhibited by Alpha-methyl-p-tyrosine.
- L-Dopa is converted to dopamine by dopa decarboxylase.
- In the periphery, we use carbidopa to inhibit DDC in the periphery which helps reduce the side effects of dopamine such as nausea, vomiting, and hypotension. - In the presynaptic neuron, dopamine is stored in vesicles and released in both a phasic and pulsatile manner across the synapse.
- Tetrabenazine and reserpine are dopamine depleters that inhibit synaptic storage and allow for degradation of DA. - DA is degraded in 3 fashions.
- DA reuptake across the synapse occurs through DAT and this process is inhibited by amphetamine or cocaine.
- Catechol-O-methyltransferase and monoamine oxidase B both degrade DA into HVA.
- Rasagiline and Selegiline are selective MAO-B inhibitors, while tolcapone and entacapone are COMT inhibitors.
23
Q
Competing Dopamine Pathways
A
In the presence of dopamine, D1 type receptors which project directly to GPi are activated, while D2 type receptors are inhibited. The indirect pathway projects
Direct Pathway:
- D1 (D1 and D5) receptors
- Project directly to GPi
- Activated by DA, increased cAMP
- “Accelerator”
- Shut off in Parkinson’s disease= lesion in Substantia Nigra Pars compacta (SNpc)
Indirect pathway:
- D2 (D2, 3, 4) receptors
- Project to GPe–> STN–> then GPi
- Inhibited by DA, decreased cAMP
- “Brake”
- Shut off in Huntington’s Chorea= lesion D2 receptor in Striatum
- Hemiballismus= lesion in subthalamic nucleus
24
Q
Levodopa
A
Replaces dopamine
There are several types of motor complications that we see:
- Wearing-off of the medication effect over several hours
- Delayed onset of the medication effect
- Random dose failures may occur
- Sudden ON-OFF, when medications stop working or kick-in abruptly
- Levodopa-induced dyskinesia, the overexpression of movement due to excess dopamine and receptor hypersensitvity.
MOA: Breaks on D1 and D2–> breaks on Subthalamic nucleus, GPi–> decreased VL/VA stimulation
25
Anticholinergics
Block central muscarinic receptors
26
Dopamine agonists
Stimulate dopamine receptor directly, bypass gut and neuronal metabolism
27
COMT inhibitors
Inhibit breakdown of dopamine by COMT
28
MAO-B inhibitors
Inhibit breakdown of dopamine by MAO
29
Deep Brain Stimulation
```
Microelectrode
Basal ganglia target
Implantable Pulse Generator (IPG) in clavicle
High frequency stimulation
Adjustable, reversible symptom control
```
30
Dopamine Receptor blockers/depleters
Antipsychotics, antiemetics
Risk for extrapyramidal side (EPS) effects:
1. Acute dystonia
2. Akathisia
3. Drug-induced Parkinsonism (DIP): reversible
- treat with anti-cholinergics
4. Tardive dyskinesia (TD): can be irreversible
- treat with anti-cholinergics, DA depleters
5. Neuroleptic Malignant Syndrome (NMS): Muscle rigidity, Altered mental state, Autonomic dysfunction (fever, tachycardia, BP)
- Features: Tremor, incontinence, metabolic acidosis, **CPK elevation**, leukocytosis may be secondary features
* * Other causes of fever need to be excluded
- Treatment: DA agonists, dantrolene, ECT, benzo
** Clozapine does NOT induce EPS, BUT can cause agranulocytosis
31
Botulinum Toxin
Toxin produced in anaerobic acidic conditions by clostridium botulinum
- One gram of crystalline toxin sufficient to kill one million people
7 Distinct serotypes:
- A (BOTOX®), B (MYOBLOC®), C-G
- 150 kD Inactive pro-polypeptide --> HC (100kD) and LC (50kD) --> LC internalized
- LC is a zinc protease that cleaves vesicular membrane proteins
- Inhibits the release of acetylcholine from the presynaptic nerve terminal
Used to treat:
- cervical dystonia
- hemifacial spasm
- oromandibular dystonia
32
Acute migraine meds
Non-specific
- NSAIDs
- Combination analgesics
- Opioids
- Neuroleptics/antiemetics
- Corticosteroids
* * Specific**
- Ergotamine/DHE (dihydroergotamine)
- Triptans
Rescue therapy (stop suffering, prevent ED visit):
- Opioids (or for pregnant patients- non-teratogenic)
- Neuroepileptics
- Corticosteroids
33
Drugs causing rebound headaches
High Probability
- Opioids
- Ergotamine
- Butalbital
- Caffeine
Low Probability
- ASA/APAP
- Triptans
Possibly
- NSAIDs
- Nasal decongestants
Unlikely
- DHE
- Neuroleptics
34
Triptans/Ergots
MOA:
- 5 HT1B/D Receptor Agonists
- Cerebral Vessel Vasoconstrictors
- Inhibit Neurogenic Inflammation
- Inhibit Pain Transmission in Trigeminal Nerve
35
Dihydroergotamine
Nonselective 5-HT1 agonist
Dosage forms
IV/IM/SC: 1mg/ml: -use up to 1mg
Nasal: 4mg/ml: -use 2mg
Pulmonary in development
AEs:
- Fewer side effects than ergotamine
- Less nausea, vomiting, leg cramps
- Low headache recurrence
- Rebound headache rare
* *Teratogenic**
36
Triptans
Effective:
- In migraine with and without aura
- Both early and late in attack
Best to give early:
- Improves response to therapy
- Prevents attack progression
- Do not wait for allodynia to develop
- Second dose not effective in same attack if initial dose failed
AEs:
- Very low risk of severe AEs
- Rare reports of angina, MI, stroke, and significantly increased BP
- Common minor AEs: Chest tightness, asthenia, dizziness, somnolence, paresthesia
- Chest symptoms rarely due to ischemia
* * Teratogenic**
Possible mechanisms for AEs:
- Activation of peripheral pain fibers
- Pulmonary vasoconstriction
- Not indicated for basilar or hemiplegic migraine
37
CGRP Antagonists in Migraine
NOT in current use
CGRP infusions triggers migraine
CGRP levels increase during migraine attacks and decrease with headache relief
Triptans and ergots inhibit CGRP release
CGRP receptor antagonists:
- Block CGRP in CNS and inhibit pain transmission
- Not direct vasoconstrictors
- AEs: comparable to placebo, lower than zolmitriptan
- Used for: cluster headache, rebound (med overuse) headache), patients with ergot/triptan contraindications
38
Indications for Migraine Prevention
1. Attacks significantly interferes with patients‘ daily routine, despite appropriate acute treatment
2. Frequency attacks (>4 attacks/month); risk of CDH
3. Acute Rx overuse (>2 days/week); risk of MOH
4. Contraindication, failure, or intolerance to acute Rx
5. Presence of certain disorders
- Prolonged, disabling, or frequent aura
- Hemiplegic Migraine
- Basilar Migraine
- Migrainous Infarction
6. Patient preference
Only 4 drugs in USA FDA-approved for prevention of migraine headaches:
- Divalpoex/Topiramate
- Propanolol/Timolol
- Methysergide
- Anabotulinum
39
Beta-blockers for migraines
Types:
- Propranolol
- Metoprolol
- Timolol
- Nadolol
- Atenolol
50% reduction in attack frequency
AEs:
- Drowsiness
- Nightmares
- Insomnia
- Depression
- Memory disturbances
- Decreased exercise tolerance
Contraindications:
- CHF
- Asthma
- Diabetes
40
Antidepressants for migraines
Mitriptyline (tricyclic): as effective as propanolol, superior to placebo
- Independent of depression, proven benefit
SSRI: fluoxetine
SNRI: duloxitine, venlafaxine
MAOIs: little evidence
AEs:
- Drowsiness, urinary retention, dry mouth, weight gain, constipation, mania, dizziness, tachycardia, blurry vision, tremor, confusion
Contraindications:
- Glaucoma, urinary retention; caution with heart block
41
Divalproex sodium
Valproic acid/sodium valproate (Depakote) 500-3000mg/d
Therapeutic level
50-120mcg/ml
AEs
Minor: Tremor, hair loss, weight gain, nausea, sedation
Major: Hepatotoxicity, pancreatitis
Comments
- Effective in 5 P-C, D-B migraine trials; used in, cluster, CDH
- Check LFTs before and as needed during therapy
42
Topiramate
Sulfamate-substituted monosaccharide
Fructose-1,6-diphosphate analog
Anticonvulsant: modulates kinase phosphorylation
Effective in migraine Positive trials in CM, and cluster headache
43
Opiate
Morphine-like activity
- Extracted from opium (poppy)
- Natural extracts: morphine, codeine
44
Opioids
```
Any molecule (ligand) that interacts with
opioid receptors
```
Includes – endogenous peptides (e.g.endorphins)
– Natural extracts
– Semisynthetic cogeners
May be agonists, antagonists, agonist-
antagonists, or “partial” agonists
- Believed to have no ceiling effect (but side effects may limit use)
Two different properties:
1. Narcotic: produces stupor, sleep
- Term associated with abuse
2. Analgesic: produces pain relief
- Refer to as opioid- poor amestics, better pain relief
45
Opioid receptor
```
G-protein coupled receptor
- Extracellular amino-terminal tail
- Intracellular carboxyl-terminal tail
7 hydrophobic regions
3 intracellular, 3 extracellular loops
```
Steps for painful stimulus and perception:
Mu receptors at each site can be blocked
Ascending Transmission
1. Peripheral neuron--> dorsal horn
2. Dorsal column--> thalamus
3. Thalamus--> cortex
Descending modulation:
1. Cortex--> Peri-aquaductal gray (PAG)
2. PAG--> Rostral Ventromedial Medulla (RVM)
Three major classes:
1. Mu: Beta-endorphin, morphine
2. Kappa: Dynorphin A
3. Delta: enkephalins
46
Mu receptors (OP-3)
Stimulation produces:
- Supraspinal analgesia
- sedation
- Euphoria
- Decreased GI motility (constipation)
- Respiratory depression
- N/V
- Miosis
- Tolerance
- Physical dependence
```
Agonist= Beta-endorphin, morphine
Antagonist= Naloxone (most specific for Mu)
```
47
Kappa receptors (OP-2)
Stimulation produces:
- Spinal analgesia
- Sedation
- Dysphoria
- Diuresis
- Psychomimetic effects
- Hallucinations
Peripheral effect: visceral pain relief
Central effect: dysphoria
Agonists: Dynorphin, pentazocine, oxycodone
Antagonists: naloxone (at high dose)
48
Delta Receptors (OP-1)
Stimulation produces:
- Spinal and supraspinal analgesia
Agonist: Enkephalines
Antagonist: Naloxone (at high dose)
49
Effects of opioids and metabolites
1. Analgesia
2. Convulsant:
- Neurotoxic metabolite (meperidine--> normeperidine) at high doses
- Metabolite renally excreted (avoid in renal dysfunction, seizure disorder)
3. Respiratory depression:
- Most feared opioid side effect
- Decreased sensitivity of chemo-receptors in medullar to CO2
- Respiratory drive reduced by pain
- Decreased rate, tidal volume, both
- High CO2 levels--> narcosis (beware in closed head injuries--> increased CSF pressure)
- Beware of sedated/obtunded patient--> impending respiratory arrest
* * Use with caution in obstructive sleep apnea (can worsen obstruction due to sedation, can also depress central component of respiratory drive)
4. Emetic/anti-emetic
5. Antitussive (at lower doses than for analgesia)
6. C-V system effects (bradycardia)
- Parasympathetic, histamine (morphine)
- Stimulates central vagal nucleus
7. GI: constipation, decreased motility
- Most common side effect
- Disrupt coordinated contraction of circular muscles
- Significant dose-limiting side effect (tolerance does NOT develop over time)
8. Miosis (pupillary constriction)
9. Immunological: t-cell suppression (infection risk, tumor growth)
10. Opioid-induced hyperalgesia
11. Tolerance, abuse, misuse, diversion
12. Tumor angiogensis: opioid-free anesthetic used in cancer surgery--> better survival
13. Hormonal suppression
- Other: pruritis, sedation
50
Opioid Dependence
Dependence is NOT the same as addiction
- Tolerance to analgesic effects
- See withdrawal, abstinence syndrome
```
Physical Dependence=
state of adaptation manifested by drug-class specific withdrawal syndrome produced by abrupt cessation/antagonism
```
```
Addiction:
Primary, chronic, neurobiologic disease with genetic, psychosocial, environmental factors
- Chronic use
- Impaired control over use
- Compulsive use
- Continued use despite harm
- Craving
```
Tolerance:
- Need more drug to produce same effects
51
Risk factors for drug-associated aberrant behaviors
Biological:
- Age > 45 years
- Family history of Rx drug/alcohol use
- Cigarette smoking
Psychiatric:
- Substance use disorder
- Preadolescent sexual abuse
- Major psychiatric disorder (personality, depressive, bipolar)
Social:
- Legal problems, MVA
- Poor family support
- Problematic subculture involvement (gang)
** NEVER withhold opioids from opioid-dependent patient (lead to withdrawal)
52
ADME of Opioids
Administration:
- PO (Oral)
- IV, IM, PCA (= Patient Controlled Analgesia)
- Epidural
- Spinal (Intrathecal)
- Transdermal
- Iontophoretic
- Transmucosal
- Rectal (can be variable; generally a poor route for most drugs)
- Sustained release vs Patient-controlled: get bolus dose to control pain, then administer PCA
- Controlled release drugs= increased risk of respiratory depression, never in new pain/opioid naive patient, no evidence it improves pain control
Distribution:
- Good distribution
- Crosses BBB; placenta; in salivary excretions; into enterohepatic circulation (more lipophilic opioids- fentanyl- cross BBB easier)
Metabolism:
- Hepatic enzymes
- Active and inactive metabolites (morphine--> M-3-G, M-6-G)
- Toxic metabolites (meperidine--> normeperidine)
Excretion:
- Renal (metabolite accumulation in renal insufficiency)
- Free drug and glucuronide conjugates excreted
- Enterohepatic circulation
53
Naturally occurring opioids
- Paragoric= old remedy for colic in babies
- Morphine
- Codeine (constipation!!)
54
Semi-synthetic opioids
Based on naturally-occurring opioids:
- Heroin
- Apomorphine
- Oxycodone
- Hydromorphone
- Oxymorphone
55
Synthetic opioids
- Meperidine
- Fentanyl, Sufentanil
- Diphenoxylate
- Loperamide (peripheral-acting opioid)
- Methadone
- Propoxyphene
56
Mixed Opioid Agonist-Antagonists
Pentazocine, Nalbuphine, Butorphanol
Partial agonists at mu receptors, but have
limited capacity for activation (“ceiling effect”)
In presence of full agonists, act as antagonists at mu receptors
Can precipitate withdrawal in physically
dependent patients
May be used to treat (antagonize) mu-opioid receptor side effects
Typically are agonists at peripheral Kappa receptors- analgesia (visceral pain)
- Central Kappa effect: dysphoria
57
Nalaxone
Pure antagonist
IV, short acting
- Use caution- acute reversal of opioid analgesia can precipitate acute withdrawal
- Naltrexone= oral, long-acting
* Both reverse analgesia (dose-dependent)
- Can be titrated slowly to reverse side effects (vs immediate for overdose in ER)
58
Buprenorphine
Partial agonist (ceiling effect)
- High affinity, long half-life
- Prevents withdrawal in opioid dependence
- Used to treat addiction /dependence
- Suboxone= buprenorphine with sequestered naltrexone (anti-abuse built in)
- Patch made available for pain management
59
Alvimopan, Methylnaltrexone
Selective opioid antagonism
- Peripheral acting mu-Opioid receptor antagonist
- Reduces constipation, bowel dysfunction after surgery (ileus), nausea
- Don't cross BBB (won't interfere with analgesia effects)
60
Tramadol
Dual action opioid:
- Weak μ opioid agonist
- Inhibits reuptake of norepinephrine and
sserotonin
- May precipitate serotonin syndrome
- Activates α-adrenergic receptors 2
- Multiple sites of action produce analgesia by several mechanisms
Parent compound is inactive; must be metabolized to active form by P450-2D6
- Not everyone has this pathway; codeine shares this problem.
61
Tapentadol
Recently approved dual-action analgesic
- μ opioid agonist= 2 to 4 times less potent than morphine
- Inhibits NE reuptake
- Parent compound is active (doesn’t require intact P450-2D6)
- No 5-HT activity –(no seizures)
- Reduced GI side-effects (nausea, constipation), less withdrawal when terminated
* May precipitate serotonin syndrome
62
Opioid rotation
Equianalgesic tables for opioids established for opioid naive patients
- When patients highly tolerant to one mu-opioid switch to another--> far more sensitive than anticipated
- Reduce dose 50-75% (methadone is extreme example)
- Why? incomplete cross-tolerance among mu opioid splice variants
Potency= term comparing doses of different agents
* Potency will vary between subjects, especially opioid naive vs opioid tolerant
Efficacy= intrinsic activity of agent at opioid receptor (binding)
63
Fentanyl vs Morphine
Morphine= pruritis, respiratory depression, nausea, somnolence, confusion in elderly
Fewer side effects with Fentanyl
64
Opioid-induced hyperalgesia
Opioids may increase pain sensitivity!
- Opioid exposure may produce progressive and lasting reductions of nococeptive thresholds.
- Paradoxical increased pain with opioids.
Ex:
- Former opioid addicts have lasting increased pain sensitivity that appears worsened by methadone maintenance.
- Evidence argues against opioids as a choice for preemptive analgesia.
- NMDA receptor antagonists (ketamine) may reduce or prevent opioid tolerance and hyperalgesia.
Opioid induced pain may be more diffuse, less defined in quality, beyond distribution of pre-existing pain
- May indicate presence of opioid-induced analgesia
65
Anesthetic agents: possible neural-circuit mechanisms
Drug blocks excitatory impulses, allows inhibition of:
- Hypothalamus
- Basal forebrain nucleus
- Ventral tegmental area
- Dorsal raphe nucleus
- Lateral dorsal tegmental nucleus
- Locus ceruleus
66
Drug targets of anesthetics
Ligand-gated ion channels
Ion channels (leak and voltage-gated channels: K+, Na+, Ca+2, ATP activated)
Intracellular: mitochondrial function
67
IV induction drugs (group I)
Barbiturates, propofol, benzodiazepines
Potent
Mainly act on gama-aminobutyric acid-A (GABAA) receptor
68
Volatile Anesthetic (group II)
Ethers, substituted hydro-carbons
Less potent
Molecular targets: GABAA , glycine, N-methyl-D- aspartate (NMDA), potassium channels.
Why continue to use inhaled agents?
- Can provide all needs: anesthesia, analgesia, immobility
- Low cost as single drug
- Great control (breath by breath) of anesthesia state
- Administration and elimination via lungs
- Always accessible route (respiration and gas exchange vital to life)
- Reliable means to control delivery/removal
Risks:
- Flammability
- Toxicity (liver, kidneys)
- Heart conduction changes
Halogenated anesthetics reduce AEs, increase potency
- but still have hepatotoxicity, myocardial sensitization to catecholamines
69
Xenon, NO, Ketamine (Group III)
Minimal effect on GABAA receptor
Marked blockade of NMDA action
70
Minimum alveolar concentration (MAC)
Measurement of potency
- Prevents movements in 50% of subjects in response to surgical stimulus (minimum concentration needed)
Effectiveness (MAC) decreased by increasing:
- Narcotics
- Age
- Temperature
71
Solubility of inhaled anesthetic
Relative concentration in two phases= affinity
Solubility= relative affinity of inhaled anesthetic for two phases (Blood/gas)
- Concentration in blood twice that of gas= affinity of anesthetic for blood is 2x the affinity in gas phase
Ex: halothane very soluble in blood compared to desflurane
Factors affecting uptake:
- Inspired concentration increase--> increased uptake
- Alveolar ventilation increase--> increased uptake
- Solubility (in blood) increased--> decreased uptake (by tissue)
- Cardiac output increase--> decreased uptake
* * lower solubility indicates rapid increase and decrease in alveolar conc. (rapid induction and rapid recovery)- high uptake in blood-> takes longer to take effect, lasts longer in blood
72
Respiratory effects of inhaled anesthetics
Halogenated hydrocarbons:
- Decrease bronchial smooth muscle tone
- Decrease PVR
- Depress mucocilliary function
- Reduce tidal volume and increase respiratory frequency
- Depress respiratory response to CO2
- Block respiratory drive due to hypoxemia
73
Cardiovascular effects of inhaled anesthetics
All volatile anesthetics depress myocardial contractility
Effects on BP and CO vary based on effects on heart rate and systemic vascular resistance
74
IV anesthetics
All CNS depressants can act as general anesthetics in high doses
Clinically used:
1. Ketamine
2. Propofol
3. Etomidate
75
Ketamine
- IV, IM, PO
- Metabolized via oxidation and demethylation
- Produces state called “dissociation anesthesia”. Patients are pain-free and unconscious, but show nystagmus and random movements
AEs:
- Increased intra-cranial pressure
- May produce emergence reactions, hallucinations
CV effects:
- Direct myocardial depressant
- Increases blood pressure and heart rate
Respiratory effects:
- Normal response to CO2 in anesthetic doses
- Bronchial smooth muscle is relaxed
- Used in large quantities in Haiti
76
Propafol
A di-isoproylphenol
Discarded after 6 Hr due to blend:
- 1% solution in an emulsion
- Soybean oil 1%
- Egg phosphatide 1.2%
- Glycerol 2.25%
pH – Neutral / slightly alkaline
Administered intravenously
- Widely used as an induction agent
- IV infusion provides a complete anesthetic
Benefits:
- Faster, cleaner recovery than barbituates and ketamine
- Anti-emetic
AEs:
- Depresses BP, respiration
77
Etomidate
Non barbiturate hypnotic
- Minimal cardiovascular effects
- Causes reversible adrenocortical suppression after a single dose
78
Anesthetic-induced neurotoxicity
It is well documented that anesthetics cause brain cell death, apoptosis, in rodents and primates and cause long-term neurocongnitive dysfunction
Administration of ketamine and propofol to rodent pups potentiated neonatal brain cell death and resulted in impaired learning and memory functions
79
Local anesthetic principles
Block sodium channel on nerves--> prevents Na influx--> block AP
- Can be administered topically or injection
- Can be restricted to localized area
- Administered IV--> effect other tissues
Ideal:
- Water soluble/stable in solution
- Non-irritating
- Low systemic toxicity
- Short induction period
- Adequate duration of action
- No post-anesthetic side effects
- Vasoconstrictive effect (prevent spread, bleeding)
Chemistry:
- Lipophilic group (aromatic ring)
- Connected by intermediate chain (ester/amide) to
- Ionizable group (tertiary amine)
pKa= affects onset (base/cation form)
Lipid solubility= affects potency
Protein binding= affects duration of action
- Increased protein binding--> duration of AP increased
Vasoconstriction= duration, potency
- Slows blood flow (prevents removal of anesthetic from region)
- Longer-acting agents less dependent on coadministration of vasoconstrictors
80
Cocaine
Precursor for local anesthetic
Used for intranasal surgery
- Strong addictive potential
ONLY local anesthetic that is a vasoconstrictor
- intrinsic sympathomimetic action by inhibiting norepinephrine reuptake into nerve terminals
81
Procaine
Reduce local irritation, tissue damage
- Minimize systemic toxicity
- Faster onset of action, longer duration of action
82
Lidocaine
Prototype local anesthetic
83
Esters
- Benzocaine
- Chloroprocaine
- Cyclomethycaine
- Dimethocaine/Larocaine
- Piperocaine
- Propoxycaine
- Procaine/Novocaine
- Proparacaine
- Tetracaine/Amethocaine
NO injectable ester anesthetic (only used topically
Metabolized by tissue esterases, shorter 1/2 lives than amides
84
Amides
- Articaine
- Bupivacaine (longer duration)
- Cinchocaine/Dibucaine
- Etidocaine
- Levobupivacaine
- Lidocaine/Lignocaine (2%)
- Mepivacaine
- Prilocaine
- Ropivacaine
- Trimecaine
Liver metabolism- use caution in liver dysfunction (increased 1/2 life)
85
Local anesthesia effects
Temporal progression:
- Interrupt transmission of autonomic impulses
- Block sensory impulses
- Block motor impulses (skeletal muscle)
C and B fibers are blocked first followed by A delta, A beta, A gamma fibers and finally A alpha fibers.
Order of blockage:
- Smaller fibers are blocked more easily than larger fibers
- Myelinated are blocked more easily than unmyelinated
- Peripheral fibers are blocked sooner than core fibers because they are exposed sooner to higher concentrations of anesthetic
** All drugs= mild vasodilators EXCEPT for cocaine
86
Local anesthetic additives
Epinephrine/ phenylephrine= added to cause vasoconstriction
- Little effect on rate of onset
- Reduces diffusion away from site, increases therapeutic duration
- NOT recommended on end-organ surgery (fingertips, low circulatory organs)
Risks:
- may contribute to cardiac dysrhythmias or accentuate hypertension in vulnerable patients
- Not recommended in patients with cardiac dysrhythmias, uncontrollable hypertension, unstable angina
87
Surface Anesthesia
- anesthesia of mucous membranes
- not submucosal structures
- produced by topical application
- mostly nose and mouth, eyes (optho)
88
EMLA
Eutectic mixture of local anesthetics (EMLA) is a topical anesthetic cream, that consists of lidocaine 2.5% and prilocaine.
- EMLA cream requires 45 to 60 minutes to exert its peak effect.
89
Nerve block anesthesia
produced by injection into specific areas or by infusion into vessel of a limb (tourniquet up to one hour)
- peripheral and extremity surgery
90
Spinal anesthesia
- produced by injection of LA into CSF of lumbar region
- spread of LA can be affected by gravities of the injected solution and position of the patient
- goal is to block somatic sensory and motor fibers
- diagnostic procedures and surgery of lower abdomen, perineum and extremities
Vs epidural anesthetics= longer-acting, leave catheter in spine
91
Epidural anesthesia
- produced by injection into epidural space from where it diffuses into subarachnoid space and paravertebral area
- doses injected can produce significant blood levels
- repeated injections cause tachyphylaxis
- child birth, post operative pain control
92
Interactions of anesthetics
Excess extracellular K= enhance local aesthetic activity
Excess extracellular Ca= antagonize anesthetic activity
93
Toxicity of anesthetics
Administration:
- systemic toxiciy,
- neurotoxicity and
- allergic reactions.
The most common cause of local anesthetic systemic toxicity is accidental, intravascular injection of local anesthetic solution during the performance of a nerve block
CNS effects:
- light headedness or sedation
- restlessness
- nystagmus
- tonic clonic convulsions
- coma and respiratory and cardiovascular depression
Cardiovascular effects:
- Vasodilation
- Arrrhythmia
- Hypotension (IV)
- Cocaine--> severe HTN, cerebral hemorrhage, cardiac arrhythmias, MI
Hematologic:
Prilocaine, benzocaine--> metabolized--> methemoglobinemia
- Signs and symptoms within 3-4 hours: lethargic, respiratory distress, cyanotic mucous membranes, nail beds, ashen skin
- Will not improve with 100% O2
- reverse with methylene blue: converts iron back to ferrous state
Ester-type anesthetics can cause antibody formation
94
Treatment of anesthetic toxicity
Severe toxicity is treated symptomatically
- Convulsions are treated with intravenous diazepam or short acting barbiturate
Hyperventilation with oxygen is useful
Bupivacaine overdose is difficult to treat and has caused fatalities in healthy young adults
95
Indications for anti-tussive agents
Appropriate for non-productive coughs:
- Where coughing results in sleep loss and contributes to debilitation
- To prevent visceral herniation due to increased pressure (e.g. Post-op)
- To reduce the spread of infection by droplet spray
- To facilitate repair of the tracheobronchial tree
- SOMETIMES recommended for nighttime treatment of a productive cough
96
Anodynes
Agents acting centrally to suppress cough center
- Non-specific reduction in excitability
Types:
1. Opioid
2. Non-opioid
3. Other
97
Codeine, Hydrocodone
Opioid antitussives
- Smaller dose needed for anti-tussive effect than analgesia effect
AEs:
- Respiratory depression
* * caution using codeine in children <2– more sensitive to this (OTHERS:)
- Constipation
- Miosis
- Sedation
- Addiction potential
98
Dextromethorphan
Non-opioid antitussive
- Isomer of opioid, doesn't bind to classical opioid receptors (mu, delta, sigma)
- Binds in cough center
- d-isomer of codeine analog
- Binds to receptors: NMDA antagonist; Sigma opioid agonist; nicotinic antagonist; serotonin reuptake pump block)
- Effective at suppressing cough with fewer side effects than codeine or opioids.
- Efficacy in children questioned
AEs:
- Dose-related side effects
- Confusion, excitation, nervousness, irritability, and respiratory depression can occur with high doses.
- Reduce doses for debilitated patients
- Do not use with MAOIs (dextromethorphan is a weak blocker of serotonin reuptake)
- Additive CNS depression with other sedating medications
* * Potential for abuse (esp. in teens): 6 oz taken to induce hallucinations, loss of motor control, out of body sensations, hyperthermia
- does NOT respond reliably to naloxone
99
Promethazine (+/- codeine)
Phenothiazine, antihistamine
- Used in combination cough syrups
- Antihistamine with sedative/antiemetic effects
100
Diphenhydramine
2nd line antitussive
| - May be useful when treating multiple symptoms
101
Peripherally-acting antitussives
Local anesthetics- act primarily on afferent input--> reduce input to cough center
102
Benzonatate
Chemically related to procaine (ester anesthetic)
MOA: Local anesthetic effect on the stretch receptors in the respiratory passages, lungs, and pleura (thus depressing the cough reflex at its source).
* No effect on respiratory center in recommended doses.
AEs:
- hypersensitivity reactions can occur—bronchospasm, laryngospasm, CV collapse.
* Contraindicated if hypersensitive to related drugs such as procaine and tetracaine.
* * Oropharyngeal anesthesia can occur if capsules are chewed or dissolved in mouth (don't chew!)
103
Mucokinetic agents
1. Expectorants= stimulate or modify mucous production in bronchi
- increase secretions, thin mucus (good for thick sputum coughs)
2. Mucolytics= break down sputum aggregates (mucopolysaccharides) to smaller components
3. Demulcents= sticky substances that protect lining of respiratory tract from irritation
- syrups, honey, hard candy (self-care)
** ALL can be also used with productive cough
104
Guaifenesin
Expectorant
MOA: Stomach irritant which reflexly affects the CNS to increase bronchial secretions.
Adverse reactions: GI tract (e.g., N/V, irritant to gastric mucosa).
** Frequently underdosed (esp due to common presence in combination dosing)
105
N-acetylcysteine
Mucolytic
MOA: The sulfhydryl groups of acetylcysteine splits the disulfide bridges of the mucopolysaccharides present in mucous secretions, thus lowering the viscosity of the mucus.
Administration: By spray (nebulizer) or directly with a bronchoscope.
AEs:
Bad taste, smell
Uses:
- Bronchopulmonary disease with viscous mucous secretions (cystic fibrosis)
- Antidote to acetaminophen poisoning
106
Pharmacologic methods to control emesis
1. Raise threshold/or decrease excitability of the neurons of the CTZ (central)
2. Directly depress the emetic center (central).
3. Modify input to emetic center, both by drugs that act peripherally and/or in the CNS (central).
107
Chlorpromazine
Prochlorperazine
Promethazine
Thiethylperazine
Dopamine Antagonists: phenthiazine derivatives
MOA:
1. depresses excitability of the CTZ by blocking dopamine (D2) receptors and transmission.
2. peripheral action blocking dopamine (D2) receptors in the GI tract.
* * Promethazine also binds H1 histamine receptors (antihistamine)
- Available as suppository, oral tablets, liquids, IM, IV
Uses:
- Radiation and drug-induced N/V in patients receiving mildly emetogenic drugs.
- Thiethylperazine is used for post-operative N/V.
AEs:
- Sedation
- Extrapyramidal symptoms (E.P.S.)
- Allergic
* * Caution with promethazine= IV risk of intra-arterial injection; contraindicated in children < 2
108
Droperidol
Dopamine antagonist: Butyrophenone derivative
MOA:
1. depresses excitability of the CTZ by blocking dopamine (D2) receptors and transmission.
2. peripheral action blocking dopamine (D2) receptors in the GI tract.
- Given orally, IV, IM
Uses:
- For preventing mildly emetogenic antineoplastic drug-induced emesis
- Premedication/ induction/ adjunct in anesthesia maintenance postsurgical emesis.
- Some tranquilization effects.
AEs:
- Sedation
- Extrapyramidal symptoms (E.P.S.)
- Allergic
109
Trimethobenzamide
Dopamine antagonist: benzamide derivative
MOA:
1. Antiemetic- Depresses CTZ by blocking dopamine (D2) receptors.
2. Antitussive- Suppresses laryngeal and pharyngeal reflexes to cough center in medulla (rarely used for this purpose)
- Given orally, rectal, IV
Uses:
- Postoperative N/V
- Postoperative coughing
AEs:
- CNS depression
- Extrapyramidal side effects
- Reye’s syndrome in children (cause? association?)
110
Metoclopramide
Dopamine antagonist: benzamide derivative
MOA:
1. Prokinetic action stimulates motility of the upper GI tract by sensitizing gut to the action of ACh.
2. Anti-emetic action appears to result from its antagonism of dopamine (D2) receptors in the CTZ and GI tract.
- Oral, IV
Uses:
- Symptomatic gastroesophageal reflux
- Diabetic gastric stasis
- Radiologic examination of GI tract
- N/V associated with cisplatin therapy, other antineoplastic agents and radiation therapy.
AEs:
- CNS depression
- Extrapyramidal side effects (Dopamine antagonism)
111
Scopalamine
Anticholinergic agent
MOA:
- Blocks Ach receptors in CTZ, vestibular nuclei, GI tract
- Dermal patch
Use:
- Motion sickness
AEs:
- Sedation
- Blurred vision
- Reduced GI bladder tone/urinary retention
112
Dimenhydrinate,
| Diphenhydramine
Antihistamines: ethanolamine derivatives
Used in motion sickness: anticholinergic activity
MOA: block Ach receptors in vestibular nuclei, CTZ
Uses:
- Motion sickness
- Mild N/V
AEs:
Sedation, blurred vision, dry mouth.
113
Hydroxyzine
Meclizine
Cyclizine
Antihistamines: 1st generation piperazine derivatives
MOA: block Ach receptors in vestibular nuclei, CTZ
Uses:
- Vertigo
- Motion sickness
114
Ondansetron
Granisetron
- Setron drugs
Serotonin receptor antagonist anti-emetics
MOA: Selectively blocks serotonin receptors (5-HT3 subtype) in GI tract and CTZ
- Do not produce extra-pyramidal side effects
Uses:
- Post-op N/V for highly emetogenic surgical procedures (abdominal surgery, cholecystectomy, eye/ear surgery)
- N/V due to highly emetogenic agents (NO, ketamine, opioids, antineoplastics)
- N/V due to radiation therapy
* * No effect on motion sickness
AEs:
- Headache, diarrhea, constipation, phlebitis, asthenia (weakness)
115
Aprepitant
Neurokinin-1 antagonist (anti-emetic)
MOA:
- Selective, high affinity antagonism of human substance P/ neurokinin 1 recepts
AEs:
- CYP3A4 inhibitor
116
Dronabinol
THC synthesized drug (schedule II)
MOA: binds to cannabinoid receptors in CTZ, vomiting center, cortex
Uses:
- N/V due to emetogenic antineoplastic drugs
- Anorexia-associated weight loss in AIDS patients
AEs:
- Impairs cognition, motor performance
- Induce dysphoria, psychotomimetic behavior
117
Dexamethazone
| Methyprednisone
Glucocorticoids used for N/V
MOA:
- Inhibits proinflammatory PGs in CNS--> blocks cortical projections to emetic center
Uses:
- IV with other antiemetics for highly emetogenic agent administration
118
Bezodiazepines: alprazolam, lorazepam
Used for N/V due to emotional factors (anticipatory N/V)
119
Treatment for Alzheimer's Disease
Ach-Esterase Inhibitors:
- donepezil, rivastigmine, galantamine
NMDA antagonists:
- Memantine
