Lecture 36/37 Flashcards
Nicotinic, Ganglionic, Neuromuscular Blockers
1
Q
Nicotine as an Agonist
A
- Stimulates parasympathetic and sympathetic ganglia resulting in:
1. Increased BP due to symp. NS - epi. release from adrenal and NE from nerve terminals on blood vessels not innervated parasympathetically
2. GI and Urinary Tract - increases peristalsis and secretions due to parasympathetic activation over sympathetic - *Rapidly enters CNS - addictive**
2
Q
Ganglionic Blockers
A
- Specifically block parasymp. and symp. ganglia’s nicotinic receptors
- No selectivity over one over the other, makes responses complex and unpredictables
- No effect on NMJ
- Drug class = non-depolarizing, noncompetitive ganglia antagonist (Mecamylamine)
- RARELY used therapeutically
3
Q
Predominating System
A
-Ganglionic blockers uncover the dominant system since it blocks ALL autonomic ganglia
4
Q
Tissue + Dominant System/Effect
A
- Arterioles/Veins ==> Symp./Vasodilation (Thera. use)
- Sweat glands ==> Symp./Anhidrosis (can’t sweat)
- Heart ==> Parasymp/Tachycardia
- Iris/Ciliary Muscle ==> Parasymp./Mydriasis/Cycloplegia
- GI Tract ==> Parasymp./Hypomotility
- Urinary Bladder ==> Parasymp./Urinary Retention
- Salivary Glands ==> Parasymp./Xerostomia (dry mouth)
5
Q
Mecamylamine
A
- Inversine
- Oral ganglion blocker that decreases BP in normal and hypertensive patients
- Noncompetitive antagonists of nic. ACh receptors in ganglia
6
Q
Mecamylamine Therapeutic Uses
A
- Moderately severe to severe essential hypertension
- Malignant hypertension (sudden and rapid development of extremely high BP) - diastolic raises up to >130 mmHg, 1% of hypertensive patients have this and can be related to women with toxemia of pregnancy and those with kidney/collagen vascular disorders
7
Q
Mecamylamine SE/Information
A
- Start at low dose and adjust up to dose that is just below causing mild, postural hypotension
- D/C slowly since it may cause fatal cerebral vascular accidents or acute CHF; sub. with other hypertensives
Side Effects
- GI: Ileus, constipation, dry mouth, N/V
- CV - orthostatic hypotension, dizziness
- NS/Psychiatric - Convulsions, tremor, sedation
- Urogenital - Urinary retention
8
Q
Drug Classes + Muscle Function
A
- NM Blocking Drugs - competitive (non-depolarizing) or non-competitive (depolarizing)
- Centrally acting muscle relaxants (antispasmodics)
- Peripherally acting skeletal muscle relaxants (dantrolene)
9
Q
Skeletal Muscle Relaxants - Nic. Antagonists
A
-Block neurotransi=mission of nic. chol. receptor
Two Types:
1. Nondepolarizing blocking agents - competitive antagonists for ACh at nicotinic receptor in skeletal muscle
2. Depolarizing blocking agents - Initially stimulate at junction to get contraction and then create NM blockade
10
Q
ACh Receptor in NMJ
A
- (Alpha1)2/(Beta1)yo
- Abundance of these receptors and AChE in NMJ
11
Q
Curare
A
- Used in poison dart by South American indians in early 1800s, causes respiration to shut down
- Developed to be used in tetanus/spastic disorders and muscle relaxation during anesthesia in 1932 and 1942 respectively
- Substitutes and more potent version of the drug discovered in the late 40s into the 60s
12
Q
Non-Depolarizing Blockers
A
- Competitive
1. Pancuronium (Pavulon) - increases HR
2. Tubocurarine - prototype replaced by other drugs due to side effects
3. Cisatracurium (Nimbex) - spontaneously degrades in plasma, no dose adjustment needed in renal failure
4. Atracurium (Tracrium)
5. Rocuronium (Zemuron) - rapid onset (1 minute), used for tracheal intubation
6. Vecuronium (Norcuron) - commonly used for mechanical ventilation in the ICU
13
Q
Non-Depolarizing Blocker Uses
A
- Used in anesthesia during surgery to relax skeletal muscle
- “Balanced” anesthesia so that a lower dose is needed
- Shorter acting drugs used to facilitate tracheal intubation
- Provide skeletal muscle relaxant in ICU
14
Q
Plane 2
A
Initial signs of paralysis of intercostals
15
Q
Plane 3
A
Full paralysis of intercostals
16
Q
Plane 4
A
Paralysis of diaphragm
17
Q
Sequence of Paralysis
A
Fingers, Orbit (Small muscles) ==> Limbs ==> Trunk ==> Neck ==> Intercostals ==> Diaphragm
Recovery goes in reverse
18
Q
Breathing Muscles
A
- Intercostal muscles - contract and pull rib cage out to draw air in and relax to push air out
- Diaphragm - contracts to bring air in and relaxes to push air out
19
Q
NM Blockade in ICU
A
- Limited use due to prolonged weakness and complications
- Want to maximize use of sedative and analgesic infusions first
- Vecuronium - commonly used
20
Q
Vecuronium
A
- Norcuron
- Facilitates in mechanical ventilation
- Assist in control of elevated intracranial pressures
- Decreases oxygen comsumption
- Prevents muscle spasms in neuroleptic malignant syndrome, tetanus, etc.
- Protects surgical wounds or medical device placement
21
Q
Long-Term Complications with NM Blockers
A
- Associated with inactivity - muscle wasting, edema, corneal drying
- Associated with inability to assess patient - recall, anxiety, unrelieved pain
- Associated with loss of respiratory function - asphyxiation from ventilation malfunction or atelectasis, pneumonia, etc.
- Prolonged paralysis or acute NM blockade myopathy - decreases membrane excitability or muscle necrosis, increased risk if used with steroids
22
Q
Non-Depolarizing Blockers + Doses
A
- Prevents ACh binding at low doses and inhibits skeletal muscle contraction - can be overcome by high concentrations of ACh, ChE inhibitors can also decreases its duration (Neostigmine, Pyridostigmine, or Edrophonium)
- High doses - may block ion channel and weaken NM transmission - decreases the ability of ChE inhibitors to reverse the drug action
23
Q
Comp. NM Blocker Drug Choice
A
-Depends on how quickly you need the muscle relaxation
Factors to Consider
- Liver: Vercuronium and Rocuronium are deacetylated in liver, CL prolonged with liver disease
- Renal - Pancuronium is excreted unchanged in urine, CL prolonged with kidney disease
- Cisatracurium - spontaneously degrades in plasma, is safe to use in liver and renal diseased patients
All drugs possess 2+ Quat. amines, must be given IV, no oral effectiveness or CNS effects
Adverse Effects - minimal, Pancuronium increases HR
24
Q
Drug Interactions (Comp. NM Blockers)
A
- ChE Inhibitors - may cause depolarizing block, low doses may inhibit response
- Halogenated hydrocarbon anesthetics - Isoflurave sensitizes the NMJ to blockers
- Aminoglycoside Antibiotics - Gentamycin and Tobramycin inhibit ACh release
- Calcium channel blockers - decrease ACh release and AChE inhibitors can still reverse the blockage
25
Q
Sugammadex
A
- Bridion
- For reversal of blockade by rocuronium and vercuronium
- Forms a complex with these drugs to decrease the amount available to form blockade
- Renally excreted unchanged so not good for renal diseased patients
- Adverse reactions: N/V, hypotension, pain, headache
- Avoids the need to use AChE inhibitors and mus. antagonists
26
Q
Depolarizing NM Blockers
A
- Non-competitive
- Main example is Succinylcholine
27
Q
Succinylcholine
A
- Quelicin
- Short-acting
- Phase I - binds to receptor and causes contraction (fasiculations), explains SE of sore muscles
- Phase II - therapeutic, high concentrations still in cleft provide constant stimulation which inactivates the receptor
- Result is flaccid paralysis, AChE inhibitors increase the effect
28
Q
Quelicin Uses
A
- Primary indication - facilitate tracheal intubation, very fast onset and duration (few minutes)
- Adjunct to general anesthesia
- Provide skeletal relaxation during surgery or mechanical ventilation
- Electroconvulsive Shock Therapy (ECT)
29
Q
Quelicin Black Box
A
- Acute rhabdomyolysis with hyperkalemia followed by ventricular dysrhythmia,cardiac arrest, and death in those with undiagnosed skeletal muscle myophathy
- Usually Duchenne’s muscular dystrophy
30
Q
Quelicin Facts
A
- IV bolus or continuous infusion
- Metabolism by plasma ChE
- Action terminated by diffusion from synapse
- Genetic variations in plasma ChE can prolong the paralysis
31
Q
Quelicin Adverse Effects
A
- Patients deficient in plasma AChE have malignant hyperthermia and prolonged apnea
- Hyperkalemia - dangerous in burn patients or those with serious tissue damage where lots of K+ is rapidly loss from cells
32
Q
General Warnings - NM Blockers
A
- Should only be used by those skilled in airway management and respiratory support
1. Should be immediately available for endotracheal intubation and support of ventilation
2. Respiration assured by assisted or controlled ventilation
3. AChE reversal agents should also be immediately available - Use peripheral nerve stimulator to measure NM function and monitor drug effect and recovery
- ONLY use on patients once they are unconscious to reduce distress
- *NO KNOWN EFFECTS ON CONSCIOUSNESS, PAIN THRESHOLD, OR THINKING**
33
Q
Nicotine
A
- Tertiary amine found in tobacco plant leaves
- No therapeutic benefit
- Highly lipid soluble and rapidly absorbed by lungs when smoked, enters CNS
- Absorbed through skin and mucous membranes in the mouth too
- Can cause intestinal cramps, diarrhea, and increased BP
34
Q
Smoking
A
- Cigarettes contain ~3000 chemicals, 250 are carcinogenic or toxic
- ~50 compounds in second hand smoke are possible carcinogenic too
- Nicotine boils at ~250 degrees Celsius but cigarettes burn at about 800 degrees, more heat causes more damage
- ~90% of nicotine is absorbed
- Inhaled nicotine reaches brain in about 7 seconds and has a quick onset and duration - positive reinforcement for smoking
- Initial effect - mild buzz, tolerated in chronic smokers
- Negative reinforcement - avoiding withdrawal symptoms
35
Q
Chewing Tobacco
A
- Buccal Absorption
- Slowly reaches peak in plasma levels
- 75% destroyed in first pass metabolism if swallowed
36
Q
Smoking + Pregnancy
A
Effects child by:
- Decreasing lung function
- Increasing risk of asthma
- Lowering birth weight which can lead to heart disease, type 2 diabetes, increased BP in adulthood
- Increased risk of childhood obesity and overweight
37
Q
Cotinine
A
- Major metabolite of nicotine
- Measured in serum, saliva, urine, and hair
- Half life of 16-20 hours (compared to nicotine’s 2 hours), making it the best biomarker of tobacco use
- Second hand smokes only gives cotinine levels of 1-10 ng/mL if heavily exposed, chronic smokers can have levels of >500 ng/mL
38
Q
High Cotinine Doses + Effects
A
- N/V
- Excess salivation
- Stomach pain
- Pallor
- Sweating
- Hypertension
- Tachycardia
- Ataxia
- Tremor
- Headache
- Dizziness
- Muscle fasiculation
- Seizure
39
Q
Smoking Mechanism of Action
A
- Acts on Alpha4/Beta2 nic. ACh receptors in CNS
- Larger toxic doses required to stimulate nic. receptors on skeletal muscle and ganglia
- Half of smokers die early from lung cancer or coronary heart disease, lose ~8 years of their life
- Stopping at ANY age helps and has immediate health benefits
- Releases dopamine and opiate peptides onto nucleus accumbens, leads to dependence and cravings
40
Q
Nicotine Addiction + Behaviors
A
- Time to first cigarette - <5 minutes in morning
- Waking at night to smoke
- Number of cigarettes a day
41
Q
Smoking Facts
A
- Age of onset and tobacco use - most hooked adults started as teens
- About half of 12-17 year olds use menthol cigarettes
- Act passed in 2009 that banned flavoring cigarettes except for menthol
- Menthol decreases the harshness and irritation from smoking nicotine, tobacco industry’s opposition prevented the menthol ban
42
Q
Dependence
A
- Physical in nicotine use
- Withdraw isn’t apparent in all smokers, but the biggest barrier to quitting in those where it is
- Symptoms of cessation: craving nicotine, restlessness, irritability, anger, anxiety, depression, inability to concentrate, insomnia, increased appetite, weight gain, and headaches
43
Q
Nicotine Accumulation
A
- First cigarette of day - arousal but tolerance begins to develop
- Nicotine accumulates through day and tolerance builds, withdraw symptoms increase between cigaretttes
- Primary euphoric effects of nicotine decrease through day
- Abstinence allows considerable re-sensitization to nicotine actions
44
Q
Nicotine Replacement Therapy
A
- Replacing with synthetic nicotine in step-wise manner over 6-8 weeks
- Clean pharmaceutical source
- Helps prevent withdrawal and removes from environment and social cues
45
Q
First Line Replacement Therapy
A
- Smaller dose and slower rate than cigarettes
- Double smoking cessation rates
- Oral pills are susceptible to first pass metabolism
- Nicotine gum, lozenges, and patches are OTC and some Rx versions like nasal sprays and inhalers exist
- Take regularly to avoid withdrawal symptoms
46
Q
Nicotine Patches
A
- Slowest delivery to CNS, 6-8 hour peak
- Standard and high dose available
- Start treatment BEFORE quitting
- Can produce pruritus, insomnia, vivid dreams
- Remove before bed to avoid sleep problems and try different brands if pruritus occurs
47
Q
Nicotine Oral Options
A
- Absorbed via buccal mucosa
- Gum, lozenges, and inhalers have intermediate CNS delivery, peak reached in 20-60 minutes
- If swallowed, first pass metabolism will eliminate their bioavailability
- May irritate mouth and cause N/V or indigestion if swallowed
48
Q
Nicotine Nasal Spray
A
- Fastest onset, peak in CNS at 5-20 minutes
- Increases cessation rate by about or over double when used in combination with patch
- May cause transient burning, stinging, throat irritation, rhinorrhea, and nausea
49
Q
E-Cigs
A
- Contain nicotine, flavor, and chemicals
- Introduction product for preteens
- Nicotine ranges from 5-60 mg, NOT FDA controlled
- No conclusive evidence that it helps as a smoking cessation agent
- FDA now regulates it manufacturing, import, labeling, packaging, advertising, promoting, sale, and distribution so that minors can’t buy them in stores or online
50
Q
Bupropion SR
A
- Catecholamine reuptake inhibitor - treats depression
- Bupropion (Zyban) - FDA approved for smoking cessation
- Start 7-14 days before target quit date
- Patch + Bupropion - 36% cessation rates
- Adverse effects - most commonly insomnia (21-35%) and dry mouth
- Don’t take if you have a history of seizures, strokes, brain injuries, tumors, or surgeries
51
Q
Varenilcine Tartrate
A
- Chantix
- Partial agonist that stimulates Alpha4/Beta2 nic. AChR
- Relieves cravings and withdrawal symptoms
- New guidelines on initial use and smoking for first 12 weeks
- Greater affinity for receptor than nicotine, decreases reward for smoking
52
Q
Chantix Effects and Warning
A
Adverse Effects - usually well tolerated like Bupropion, but can cause nausea, sleep disturbances, weird dreams, and headaches
Warning: Neuropsychiatric symptoms and exacerbation of psychiatric illness may occur (depression, suicidal thoughts)
53
Q
Clonidine
A
- Catapres
- NOT approved by FDA for smoking cessation
- Used if patients don’t tolerate or want other options
- Mixed clinical results
- Inhibits symp. NS activation from CNS
- Causes dry mouth, dizziness, sedation, and hypotension
54
Q
Nortryptyline
A
- Panelor
- TCA that improves cessation
- When used with patch cessation rates raise to 23%
55
Q
Nicotine Vaccine
A
- Phase I-III trials show some success
- Antibodies bind to free nicotine and prevent crossing into CNS and BBB
56
Q
Rimonabant
A
- Acomplra
- Antagonist of cannabinoid type I receptors
- Decrease nicotine self administration
- Not approve in US
57
Q
Have SSRIs, MAOIs, and Topiramate been show to help smoking cessation?
A
No.
58
Q
Smoking Treatment + Pregnancy
A
- Counseling is the preferred treatment
- Nicotine is a Category D drug
- Nicotine replacement therapy is probably safer than smoking itself
- Smoking increases incidences of low birth weights, deliveries, and many peri and post-natal complications
- Bupropion and Varenicline - Pregnancy Category C (risk cannot be ruled out)
