1
Q
Properties of ANS
A
- all output from CNS to body except motor / skeletal muscle
2
Q
List the processes which the ANS controls
A
- Heart function
- Visceral organ function
- Breathing
- Digestion
- Blood flow to organs
- Contraction / relaxation of smooth muscle
- Exocrine and endocrine hormones
3
Q
Preganglionic pathways
A
- ACh synapse on nicotinic receptors which releases NT to synapse on post-ganglionic receptors
- Every preganglionic neuron is releasing ACh
- ACh that synapse on nicotinic receptors in adrenal medulla causes it to release Epi and NE
- ACh can directly synapse on nicotinic receptors on skeletal muscle
4
Q
Prostganglionic pathways
A
- ACh (from nicotinic) synapse on muscarinic receptors on cardiac & smooth muscle, gland & sweat cells, and nerve terminals
- NE (from nicotinic) synapse on alpha and beta receptors on cardiac & smooth muscle, gland cells, and nerve terminals
- Dopamine (from nicotinic) synapse on D1 receptors on vascular smooth muscle
5
Q
Neurotransmission mechanism
A
Ion channels open at nerve terminal -> Ca influx trigger vesical to release content via fusion of SNAPS and VAMPS
6
Q
What muscle is located in the iris?
A
Pupillary dilator and constrictor muscle
7
Q
Which muscle is responsible for mydriasis?
A
- mydriasis: pupil dilation
- contraction of radial pupillary dilatory muscle
8
Q
What does β adrenoceptor activation do to the eye?
A
- Increase secretion of aqueous humor from the ciliary epithelium
- Increases intraocular pressure
9
Q
Mechanism for glaucoma
A
- inability to drain fluid
- increase in intraocular pressure
- damaged optic nerve
10
Q
Identify the neurotransmitter acetyl choline and the steps involved in its synthesis, storage, release and termination of acetylcholine.
A
- Choline transporter (CHT) cotransports choline and Na into the nerve terminal
- AcCoA + Choline -> ACh
- VAT transports this into storage vesicle
- Increase in intracellular Ca2+ causes VAMPs and SNAPs to merge -> release of ACh
- AChesterase breaks down ACh into acetate and choline
- Choline transported into nerve terminal
11
Q
List the drugs that target each of these steps as a mechanism of neuromodulation.
A
- Hemicholinium blocks CHT
- Vesamicol blocks VAT
- Botulinum toxin blocks release of ACh from vesicles
- Latratoxin and Carbachol increases release of ACh
12
Q
M2 receptor tissue distribution
A
- myocardium
- smooth muscle
- CNS neurons
- “some presynp. sites”
13
Q
M3 receptor tissue distribution
A
- exocrine glands
- vessels
- CNS neurons
14
Q
M2 mechanism
A
- opening of K channels
- inhibition of adenylyl cyclase
15
Q
M3 mechanism
A
- formation of IP3 and DAG
- increased intracel. Ca
16
Q
Acetyl Choline as a Cholinomimetics
A
- Low doses = only M receptors
- High doses = both M and N receptors
- Used to produce miosis during ophthalmic surgery
17
Q
Bethanechol as a Cholinomimetics
A
- Only choline ester with common clinical use
- Used for: post-operative therapy, esophageal reflux
- Resistant to inactivation by AChE
18
Q
Methacholine as a Cholinomimetics
A
- Partially resistant to AChE inactivation
- In the past, used for diagnostic tool for asthmatics
19
Q
Carbachol as a Cholinomimetics
A
- Resistant to AChE inactivation
- Bind and activate M receptors
- Releases ACh from nerve endings
- Used to produce miosis in patients with glaucoma
20
Q
Nicotine as a Cholinomimetics
A
- Activates ALL nicotinic receptors
- If given at high doses, it will block nicotinic receptors
21
Q
Muscarine as a Cholinomimetics
A
Activates all muscarinic receptors
- Atropine is the antidote for this
22
Q
Pilocarpine as a Cholinomimetics
A
- Stimulates muscarinic receptors
- Can cross BBB
- Used to treat glaucoma
23
Q
Reversible AChE inhibitor agents property
A
allow the regeneration of AChE within hours
24
Q
Physostigmine
A
- reversible AChE inhibitor
- Binds to both sites on AChE
- Can cross BBB
- Used for glaucoma; increase amounts of ACh -> miosis
25
Neostigmine
- reversible AChE inhibitor
- Cannot cross BBB
- Directly stimulate nicotinic sites on skeletal muscle
- Used for Myasthenia Gravis (MG)
26
Pyridostigmine
- reversible AChE inhibitor
- Used for MG
- Potent AChE inhibitor
27
Ambenonium
- reversible AChE inhibitor
- Used for MG
- Potent AChE inhibitor
28
Edrophonium
- reversible AChE inhibitor
- Bind only to anionic site
- Short acting / short duration of action
- Used to diagnose MG
- Helps with titration of longer acting anticholinesterase
29
antidote to curare poisoning
All reversible AChE inhibitors are antidotes
30
Which drugs are used to attempt to treat cognitive dysfunction?
- Tacrine
- Donepezil
- Rivastigmine
- Galantamine
- These are reversible AChE inhibitors
31
Irreversible AChE inhibitor agents property
- Contains phosphorous -> phosphorylate esteratic site on AChE (covalent bond)
- lipid soluble; absorbed through skin
32
Echothiophate
- irreversible AChE inhibitor
- Potent miotic
- used for glaucoma
33
Parathion
- irreversible AChE inhibitor
- Insecticides / pesticides
- Converts to paraxon in liver
- Potent AChE inhibitor
34
Malathion
- irreversible AChE inhibitor
- Insecticides / pesticides
- Converts to malaoxon in liver
- Potent AChE inhibitor
- Quickly inactivated in mammals and birds
35
What is the name for the potent war gases?
- Sarin
- Soman
- Tabun
- cannot be reversed UNLESS given RIGHT AFTER exposure
36
List one drug available for treatment of toxicity from overdose of anticholinesterase inhibitors and its mechanism of action.
Pralidoxime (2-PAM): releases the organophosphate from the esterase
37
Explain why ACh itself is not a good drug
- Non-selective
- Fast hydrolysis
- Poor bioavailability
38
Explain the studies to understand the impact to “stereochemistry of Ach”
- Wanted to know which conformer was physiologically active
- Hypothesized that anti-periplanar was because it has less steric hindrance
- Found that the anticlinal form had stronger affinity
39
Methacholine structure
- introduction of methyl group reduce activity
| - Higher affinity for mACh than nACh
40
Carbachol structure
Have carbomyl group -> less electrophilic carbonyl carbon -> tolerant to / slows down hydrolysis
41
Explain why norepinephrine itself is not a good drug
- Non-selective
- Poor oral bioavailability
- Undergoes fast metabolism
• MAO & COMT in intestine and liver (1-2 min duration of action)
• 3’-O-glucuronidation / sulfation
42
Anti-muscarinic mechanism
- Interfere with synapse on muscarinic receptors (receives innervation from Nn)
- Muscarinic receptors present on/in: cardiac & smooth muscle, gland cells, sweat glands, nerve terminals
43
Ganglion blockers mechanism
Interfere with synapse on nicotinic neuronal receptors
44
Neuromuscular blocking agents mechanism
- Interferes with synapse on Nm
| - Inhibited irreversibly by snake alpha-bungarotoxins
45
Atropine
- anti-muscarinic
- Cross BBB; CNS stimulant
- Effects on eye: mydriasis (dilation), cycloplegia (where eye cannot focus)
- Decreased GI & urinary motility
- Low dose -> bradycardia
- High dose -> tachycardia
- Toxic dose -> vasodilation
- Clinically used for: anti-spasm, anti-secretory (for dentists), antidote for cholinomimetic poisoning
- Can lead to: dry eyes, xerostomia, hyperthermia, hallucinations, delirium, coma
46
Scopolamine
- anti-muscarinic
- Cannot cross BBB; CNS depressant
- Prevent motion sickness
- Can produce euphoria
47
Tropicamide and Cyclopentolate
- anti-muscarinic
| - Less potent; useful for ophthalmic exams
48
Ipratropium
- anti-cholinergic
- Does not cross BBB
- Treat COPD, bronchitis, and emphysema
- dose QID
49
Tiotropium
- anti-cholinergic
- Does not cross BBB
- Treat COPD, bronchitis, and emphysema
- dose QD
50
Benztropine and trihexyphenidyl
- anti-muscarinic
- CNS acting agents
- Used for Parkinson’s patients
51
Nicotine
- ganglion blocker
- Low dose = stimulate Nn receptors; used for tobacco cessation
- High dose = blocks ganglia
- Acute overdose leads to: CV & CNS stimulation, increased GI activity, N/V, abdominal pain, dizziness, confusion, muscle weakness
52
Hexamethonium
ganglion blocker
53
Varenicline (Chantix®)
- nicotinic agonist
- Smoking cessation
- Side effects: headache, nausea, insomnia
54
Competitive Nondepolarizing neuromuscular blocking drugs
- Low doses = compete with ACh to bind to the Nm receptor to prevent depol
- High doses = block ion channels in the endplate -> cannot undergo neuromuscular transmission -> paralysis of muscle
55
D-Tubocurarine (curare)
- neuromuscular blocking agents
- Also blocks autonomic ganglia -> hypotension
- Releases histamine from mast cells -> bronchoconstriction
56
Doxacurium
- neuromuscular blocking agents
- Doesn’t block ANS ganglia, doesn’t release histamine
- If cannot clear due to renal failure -> prolonged muscle relaxation
57
Pancuronium
- neuromuscular blocking agents
- has a steroid nucleus
- Doesn’t block ANS ganglia, doesn’t release histamine
- If cannot clear due to renal failure -> prolonged muscle relaxation
58
Atracurium
- neuromuscular blocking agents
- Intermediate acting
- Release histamine from mast cells
- Metabolite can provoke seizures
- Preferably given to asthmatic patients
59
Cistacurium
- neuromuscular blocking agents
| - Isomer of atracurium but does not have seizure side effects
60
Vecuronium & Rocuronium
- neuromuscular blocking agents
| - Doesn’t block ANS ganglia nor release of histamine
61
Mivacurium
- neuromuscular blocking agents
- Shortest acting
- Mainly used in surgery
62
Succinylcholine
- neuromuscular blocking agents
- Short acting depol blocks muscle for 5 minutes
- Releases histamine
- Stimulates autonomic ganglia -> elevation of blood pressure
- Increase CSF & GI pressure
- Contraindicated in glaucoma patients, patients with brain tumors, immediately after a meal
- Drug of choice to relax laryngeal muscles prior to intubation
- Adverse effects: bradycardia, fasciculations, muscle pain, hyperkalemia, increase IOP, hyperthermia
63
EPI
- Immediate relief from hypersensitivity reactions (anaphylactic shock)
- Adjuvant with anesthesia and topical hemostatic agent due to its vasoconstrictor effect
64
DA
- used in CHF patients; an adjuvant to reduce periph. Resistance
- infusion has been used to treat certain conditions where renal blood flow is compromised
65
Isoproterenol (ISO)
- Nonselective β-adrenoceptor agonist
- relieve bronchoconstrictive episodes in asthmatic patients and COPD
- Sometimes used in emergencies to stimulate heart rate in patients with bradycardia or heart block.
66
Ephedrine
- Nonselective β-adrenoceptor agonist
- used orally for bronchial asthma (β effect)
- decongestion
- used for its α effects as a pressor agent -> produce short lasting mydriasis without cycloplegia
67
Pseudoephedrine
- Nonselective β-adrenoceptor agonist
- Decongestant
- Must not be taken in patients with HTN risk
68
Dobutamine
- Selective β2-adrenoceptor agonists
69
Metaproterenol
- Selective β2-adrenoceptor agonists
| - used primarily to treat bronchial asthma
70
Terbutaline
- Short-acting β2-adrenoceptor agonists
71
Albuterol
- Short-acting β2-adrenoceptor agonists
- Treatment of asthma
- Long acting; fewer cardiac side effects
72
Ritodrine
- Selective β2-adrenoceptor agonists
- β2-adrenoceptor agonist
- some cardiac effects possible
- approved to relax smooth muscle of the uterus to delay premature labor
73
Phenylephrine
- Selective α1-adrenoceptor agonist
| - α-adrenergic stimulants -> local vasoconstriction in nose -> less leakage of fluid
74
Methoxamine
- Selective α1-adrenoceptor agonist
- used to produce mydriasis
- treat paroxysmal atrial tachycardia
75
Clonidine
- Selective α2-adrenoceptor agonist
- Crosses BBB
- Decrease sympathetic tone to the blood vessels and heart
- Treat excessive sympathetic activity experienced during withdrawal from opioid and ethanol addiction (gives synergy effect with opioid opioid dose can be decreased)
76
α-Methyl Dopa
- Selective α2-adrenoceptor agonist
- Crosses BBB
- Metabolite is potent α2-agonist
- Decreased sympathetic tone
- Not metabolized by MAO -> longer CNS effect than NE
77
Tyramine
- causes a massive release of NE from sympathetic nerve endings
-
78
Amphetamine and Methamphetamine
- Produce temporary increased mood but decreased appetite
- Patients suffering from narcolepsy.
- Some hyperkinetic children respond to amphetamines more sedated and thus ↑ their attention span.
79
Methylphenidate (Ritalin)
- CNS stimulant large doses = CNS excitations, can cause convulsions
- Used in children with ADHD
80
Tricyclic antidepressants
potent inhibitors of catecholamine reuptake into adrenergic nerve terminals
81
Drug-drug interaciton between sympathomimetics and MAO inhibitors
Pre-treatment with cocaine or TCA -> Inhibits effects of Tyramine, amphetamine, guanethidine and 6-hydroxy Dopamine
82
αadrenoceptor antagonists
- α-Adrenoceptor antagonists prevent sympathetic tone to the blood vessels.
- Sympathetic innervation to the heart is functional (β1 receptor-mediated).
- Side effects: orthostatic htn, reflex tachycardia, nasal congestion, failure to ejaculate
83
β-adrenoceptor antagonists
- Antagonism of the innervated β1-adrenoceptors
- Eliminate sympathetic neural effectiveness to heart and JDA in kidney (which decreases renin release)
- Consequences: bronchoconstriction, vasoconstriction, lipolysis, glycogenolysis
84
Recognize and list the clinical uses of all drugs targeting the adrenergic system
- Hypertension
- Essential tremor
- Glaucoma
- Post-infarction prophylaxis
- Angina
- Congestive heart failure
- Migraine
- Stage fright
- Cardiac arrhythmias
- Pheochromocytoma
- Autonomic hyper-reflexia
- Raynaud’s
- Benign prostatic hypertrophy
- Hyperthyroidism
85
Phentolamine
- α-adrenoceptor Antagonists
- antagonist that competes with NE on the α- adrenoceptors
- selective: a1 > a2
- short duration of action due to competition with NE
86
Phenoxybenzamine
- α-adrenoceptor Antagonists
- Potent
- Higher affinity for a1 than phentolamine
- Long duration of action b/d dual mechanism of blockade; first starts as competitive antagonist -> after 30-60 minutes it becomes non-competitive
87
Prazosin
tension -> some people lose consciousness with first administration
88
Terazosin and Doxazosin
- α-adrenoceptor Antagonists
- Prazosin-like drugs with a longer half-life which permits once daily dosing
- Commonly used to treat the symptoms of benign prostatic hypertrophy/hyperplasia (BPH).
89
Yohimbine
- α-adrenoceptor Antagonists
- Selective for a2
- Experimental tool; prevents hypotensive effects in clonidine and α-methyldopa
90
Propranolol
- β-adrenoceptor Antagonists
- Blocks both beta1 and beta2
- Potent local anesthetic
91
Metoprolol
- β-adrenoceptor Antagonists
- High affinity beta1 > beta2 and therefore called cardioselective
- Decreases plasma renin levels
- Less affinity to beta 2 less metabolic and bronchial effects
- Side effects: fatigue, dizziness, headache, insomnia
92
Atenolol
- β-adrenoceptor Antagonists
- Cardioselective
- Longer half life
- Less side effects than metoprolol
- Excreted by kidney and therefore should not be given to patients with renal failure / disease
93
Esmolol
- β-adrenoceptor Antagonists
- Cardioselective
- Short half-life when given IV b/c of RBD esterases
- Used for acute emergency control of ventricular heart rate in patients with atrial fibrillation or atrial flutter
- Safer to use in critically ill patients
94
Betaxolol
- β-adrenoceptor Antagonists
- Cardioselective
- Long half-life; once daily administration
95
Pindolol
- β-adrenoceptor Antagonists
- Has ‘intrinsic sympathomimetic’ activity
• Non selective beta antagonist but stimulates beta1 as well
- Less cardiac depression than other drugs
- Better tolerated during exercise
96
Timolol
- β-adrenoceptor Antagonists
- Potent; non-selective
- Reduces formation of aq. humor in eye; less side effects than other drugs
- Open angle glaucoma
97
Nadolol
- β-adrenoceptor Antagonists
- Long half life; once daily administration
- Not selective
98
Labetalol
- α and β-adrenoceptor Antagonists
- nonselective β-AR antagonist & α1 selective blocker
- Higher potency for beta but alpha dominates because they are located on the blood vessels
- some β2 stimulating properties
- post. hypotension is a problem in some patients
- decrease TPR with little effect on HR and CO
99
Carvedilol
- α and β-adrenoceptor Antagonists
- nonselective β-AR antagonist & α1 selective blocker
- Has “free radical scavenger” antioxidant properties
• can bind to and scavenge reactive oxygen species
• decrease biosynthesis of ROS and oxygen radicals
- Very lipophilic -> protects cell membranes from lipid peroxidation
- Prevents LDL oxidation
OU PDA
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