Autonomic Drugs Part 2 Flashcards
What class of drugs are Parasympathetic effects mimicked by?
- Muscarinic Receptor Agonists (promote parasympathetic effects)
- AChE Inhibitors (relax muscle instead of stimulate)
Parasympathetic activity can be blocked by?
- Muscarinic receptor antagonists
- Skeletal NMJ Blockers
What are some typical therapeutic uses of Parasympathetic drugs?
- Reduce intraocular pressure in the eyes
Eg) Pilocarpine opens the trabecular meshwork and allows the aqueous humour to drain. - Increase the motility of GI tract
- Bethanecol - Increase Motility of the Urinary Tract:
- Bethanecol
- Causes the constriction of the detrusor muscle, relaxation of the sphincter and allows urine to exit the bladder. - Increases Salivary Secretions
- ->Pilocaprine used to treat xerostomia
What is the role of Cholinesterase Inhibitors? (ChE)
- Allows for an increased time ACh is available in the synapse
- ->Drugs can cause paralysis.
What are the 2 types of Cholinesterase Inhibitors?
- AChE (Acetylcholineasterase)
- Breaks down ACh
- BuChE (Butyrlcholinesterase)
- Breaks down Succinylcholine
What is an Aceylation Drug Interaction?
- Drug causes Acetylation of the enzyme (caused by ACh)
- Quick recovery/ reversible binding
What is a Carbomylation Drug Interaction?
- Reversible Inhibition (Carbamylation of enzyme takes 3-4 hours to overcome)
- Enzyme is still available to ACh but there is competition due to drug.
- Can be overcome by more ACh present at the synapse.
What is a Phosphorylation Drug Interaction?
- Irreversible binding due to Covalent Bonds
- ->ACh is unable to unbind from the synapse (can easily cause poisoning.
–>After some time, phosphorylated drugs undergo Aging (phosphorylated enzyme loses chemical group and new chemical created has no enzymatic activity)
What type of drug is Neostigmine?
- Reversible AChE inhibitor
- Carbamylation (3-4 hours)
- Can be overcome by adding more ACh
What type of drug is DFP?
- Irreversible AChE inhibitor
- Takes VERY long for enzyme to dephosphorylate.
What can overcome Aging in a Phosphorylation drug reaction?
- Oxime, such as 2-PAM
- Binds enzyme before aging- donates phosphate moiety cause enzyme inhibition to be reversed.
What is the result of reversible cholinesterase inhibition?
-Increased cholinergic activity where it is lacking (decreased Acetylcholinesterase activity= more frequent contractions, increased GI motility, ect.)
Cholinesterase Inhibition results in:
Inhibiting AChE/ BuChE release
- Increase motility of GI tract
- Increased activity of the Urinary bladder
- To treat symptoms of Alzheimer’s disease
- Can be used to diagnose/ treat Myasthenia gravis
- To improve skeletal muscle contraction
- Can topically be used to treat conjunctiva causing miosis.
- Cause aqueous humour outflow/ a decrease in intraocular pressure
What is the downside of using a ChE inhibitor on the eyes?
- ->Allow ChE inhibitor can be used to treat glaucoma, it can cause cataracts with long-term use
- ->Only used in aphakic patients
What is the effect of ChE Inhibitors on competitive neuromuscular blockers, as a tubocurarine?
Reverses their antagonism (lessens their blocking effects?)
Clostridium botulism mechanism of action?
Blocks ACh release from the synapse
- Acts as a depolarizing neuromuscular blocker
- Causes muscle paralysis in muscles with involuntary muscle tone
Clinical Uses of BOTOX include: -Removes wrinkles -Strabismus (corrects unaligned lines of visions of the eyes) -Blepharospasm (Contracted eyelids) Hemifacial Spasms (relaxes spasms)
Muscarinic Receptor Blockers:
Two different Types:
Belladonna Alkaloids- Scopolamine and Atropine
Semisynthetic/ Synthetic: Oxybutynin
What kind of drug is Atropine?
Muscarinic Antagonist
-Acts to prevent ACh from binding at the synapse (anti-spasmic drug)
What effects do Muscarinic Antagonists have on the body?
- Mydriasis (Pupil Dilation)
- Relaxation of smooth muscle in the GI tract, bronchi and urinary bladder.
- Inhibit secretions of various exocrine glands.
- In high doses, muscarinic antagonists act to completely block parasympathetic effects of ACh (for example, atropine- a muscarinic antagonist, can bind all available enzymes and actually cause an increase in heart rate.
What drug can be used to treat motion sickness?
Scopolamine (Muscarinic Antagonist Effects)
-Blocks the M1 receptor of the vestibular apparatus.
What is the difference between Atropine and Scopolamine?
- ->(Scopolamine is 10x more potent for producing CNS effects than atropine)
- More scopolamine is unionized at physiological pH than atropine, allowing it to easily pass through the skin.
Would a muscarinic antagonist promote Miosis or Mydriasis?
- ->Would indirectly promote sympathetic activity by inhibiting parasympathetic activity
- -> Mydriasis (pupil dilation)
Would a muscarinic antagonist cause an increase or decrease in GI motility/ secretion?
Decrease in parasympathetic GI activity
–>Decreased secretions/ GI motility
(Treat IBS)
What types of Urinary Incontinence would a muscarinic antagonist treat?
Overactive bladder problems
- Daytime urinary frequency
- Nigh time urinary frequency (Nocturia)
- Urgency
- Incontinence (unable to control bladder)
Oxybutyrin is used to treat which condition?
- -> Semi-synthetic/ synthetic muscarinic antagonists
- ->Anti spasmic drug
- Can be used to treat an overactive bladder.
- ->Binds M2 and M3 (uroselective)
Which muscarinic antagonists are used to treat COPD? (Emphysema, asthma and chronic bronchitis?)
- ->Ipratropium and Tiotropium - derivatives of atropine
- Decrease bronchial secretions and cause bronchodilation
- Not absorbed into systemic circulation
What is the main cause of COPD physiologically?
-Increased bronchial secretions
What are 2 drugs used to treat Parkinson’s disease?
Trihexyphenidyl and Benztropine
–>Muscarinic antagonists which reduce ACh binding in the synapse- less frequent contractions which cause tremors in patients.
What are the side effects caused by Muscarinic Antagonists?
- Urinary retention (due to supressed Urinary Bladder)
- Constipation (due to supressed GI tract)
- Tachycardia (When all ACh receptors are bound)
- Dry Mouth (supressed secretions)
- Mydriasis (Supressed miosis)
- Blurred Vision (inadequate AH drainage?)
- Inhibition of sweating (reduced secretions)
- Toxic Psychosis
Neuromuscular Junction Blockers?
Block ACh from binding Nicotinic receptors.
What is the mechanism of ACh binding nicotinic receptors?
-ACh binding the nicotinic receptors leads to an influx of Na+ ions, membrane depolarization which causes the release of Ca2+ from the sarcoplasmic reticulum, leading to muscle contraction.
What is the mechanism of a Competitive Neuromuscular Blocker?
- Competitively antagonizing the actions of the agonist (ACh) at the nicotinic receptor.
- Produce flaccid paralysis
- Chemical structure is different than ACh.
- Block can be overcome by increasing ACh in synapse.
- ->Main example is Curare (tubocurarine)
What is the mechanism of a Depolarizing Neuromuscular Blocker?
- Irreversibly binds nicotinic receptor
- Prevents repolarization and makes the muscle fibre’s refractory period during further nerve impulses (this is called depolarizing block)
- Chemical structure resembles ACh
- Main drug used is Succinylcholine
Contraction is partially impaired when what fraction of receptors are bound to a competitive drug?
75-80%
Contraction is fully impaired when what fraction of receptors are bound to a competitive drug?
90-95%
Which drugs are commonly used to reverse competitive neuromuscular blockers?
- ->ChE inhibitors
- Neostigmine
- Edrophonium
- Pyridostigmine
- Reduces acetylcholinesterase in the synapse and allows for more ACh to overcome drug competition.
What is the sequence of Competitive Neuromuscular Blockers?
-Small, rapidly moving muscles are paralysed first.
Then moves to the Limbs, Trunk, Intercostal Muscles, the Diaphragm which would lead to respiratory failure.
–>Recovery occurs in the reverse order.
What are the main side effects of Competitive Neuromuscular Blockers?
- Ganglionic Blockade
- (Fall in BP and tachycardia)
- Block of the vagal response
- Histamine release
Which is the only Depolarizing neuromuscular junction blockers used clinically?
Succinylcholine
- Binds nicotinic receptors
- IS NOT metabolized by AChE
- ->Metabolized by Butyrylcholinesterase (BuChE)
What is a common problem with succinylcholine breakdown?
-Several patients display isoforms of BuCHE, which can lead to prolonged synaptic transmission/ more extensive neuromuscular block.
What are common side effects of depolarizing NMJ blockers?
- Can release excess K+ from intracellular sites.
- Can lead to hyperkalemia (elevated blood K+ levels, rhamdomyolysis and cardiac arrest.
Why is Hyperkalemia dangerous in patients on digoxin or diuretics?
-Digoxin is a cardiac contraction stimulant drug which is supposed to increase contractions of the heart. Increasing K+ concentrations could lead to heart failure/ blocking this drugs effects.
What is Malignant Hyperthermia a common symptom of?
- Depolarizing NMJ blocker side effect
- Due to genetic abnormality of the ryanodine receptor
(1: 3000) - Causes Ca2+ release from SR into the skeletal muscle which can lead to contracture, rigidity, heat production from muscles, hyperthermia, accelerated muscle metabolism, metabolic acidosis and tachycardia.
Which drug is Malignant Hyperthermia treated by?
Dantrolene (Blocks Ca2+ release)
What are some of the main uses of Neuromuscular blockers?
- Surgical anesthesia
- Orthopedic procedures to realign bone fractures and dislocations.
- To facilitate tracheal intubation*
- To prevent trauma during electroshock therapy
Sympathetic effects can be mimicked by which classes of drugs?
- Adrenergic receptor agonists (Epi, albuterol)
- Norepinephrine Uptake Blockers (Cocaine, imipramine)
- Monoamine Oxidase and COMT inhibitors
- NE releasing agents
What is the mechanism of Monoamine Oxidases and COMT inhibitors ?
-Delay the breakdown of NE and prolong it’s action
Which drugs can block sympathetic effects?
Adrenergic Receptor Antagonists
Examples include: Prazosin and Propranolol
How is NE removed from the synapse?
Uptake of NE occurs in the presynaptic terminal of the synapse.
-Re-uptake can be blocked by several drugs, including cocaine.
What is the effect of increasing Re-uptake blockers?
Sympathetic activity at the synapse
NE can’t be removed
What is the role of Baroreceptors?
- Sense changes in arterial pressure & cause activation of the sympathetic/ parasympathetic systems.
- Increase in blood pressure causes vasodilation (Parasympathetic Activity)
- Decrease in blood pressure causes vasoconstriction (Sympathetic Activity)
What are examples of Adrenergic Receptor Agonists?
- Epinephrine (binds Alpha and Beta receptors)
- NE- Can bind Alpha1 and Beta 2- has little effect binding Beta2
- Isoproterol- Most POTENT sympathomimetic amine
- Acts on BETA receptors - Dopamine (Activates BETA1 receptors)
What is the result of Epinephrine binding B2 receptor?
Vasodilation
Epinephrine brining properties?
- ->Binds Beta1 to cause an increase in HR
- ->Binds Beta2 to cause vasodilation
- ->Binds Alpha 1 and causes vasoconstriction
Norepinephrine brining properties?
- ->Binds Beta 1 and causes an increase in HR
- ->Binds Alpha 1 and causes vasoconstriction
Clinical uses of Adrenergic Agonists?
- Allergic reactions–> Epinephrine (EPIPEN)
- Bronchodilators (asthma)
- As presser agents (Hypotension- increase CO and HR)
