Flashcards in Drugs modulating the autonomic nervous system III and IV Deck (28):
What is atropine? What affect do do increasing doses of atropine have on the parasympathetic system?
- Atropine is well absorbed orally and also reaches the brain
- When applied locally in the eye, it has longer-lasting effects because it binds to pigments in the iris, which slowly releases the drug over many days
- Increasing doses of atropine produce increasing block of parasympathetic effects as follows:
Depress salivary (dry mouth) and bronchial secretions, and sweating
Pupil dilates, accomodation of the eye inhibited, heart rate increases
Tone and motility of GI tract and urinary bladder are inhibited
Gastric acid secretion and motility are inhibited
Atropine blocks ACh more readily at sites where less neurotransmitter is released (e.g., salivary glands) than at sites where more is released (e.g., sinoatrial node)
Low doses of scopolamine are more sedative than low doses of atropine
What is scopalamine and what is the major important difference from atropine?
Scopolamine is well absorbed orally, and also reaches the brain more readily than atropine
REMEMBER: Scopolamine is approximately 10 times more potent at producing CNS effects
When applied locally in the eye, it has longer-lasting effects because it binds to pigments in the iris, which slowly releases the drug over many days
A greater fraction of scopolamine is present in a unionized form at physiological pH than atropine - facilitates its absorption through the skin
Scopolamine is used for motion sickness as a transdermal patch placed behind the ear – duration of action 3 days
What are semisynthetic and synthetic muscarinic receptor agonists?
Dicyclomine is used to relax intestinal smooth muscle (antispasmodic) in irritable bowel symptoms (intestinal cramping)
Glycopyrrolate - given preoperatively to inhibit excessive salivary and respiratory tract secretions
Pirenzepine - selective for M1 receptors – used to reduce gastric acid secretion in patients with peptic ulcers - blocks M1 receptors on paracrine cells and inhibits the release of histamine, a potent gastric acid stimulant (available in Canada but not in the United States)
Oxybutynin, tolterodine, darifenacin, solifenacin, and trospium - relatively selective for M2/M3
Appear to have a more selective action on the urinary bladder ("uroselective“) and cause fewer adverse effects such as dry mouth and blurred vision
Used to reduce the four major symptoms of overactive bladder : daytime urinary frequency, nocturia (frequent urination at night), urgency, and incontinence
What are ipratropium and tiotropium?
Semisynthetic and synthetic muscarinic receptor antagonists
Ipratropium and tiotropium - derivatives of atropine - are administered by inhalation to patients with obstructive lung diseases (asthma, emphysema and chronic bronchitis)
Not absorbed into the systemic circulation - they produce few adverse effects
E.g. they do not impair the ciliary clearance of secretions from the airways
What is tropicamide? what are trihexyphenidyl and benztropine used for?
Tropicamide - is a tertiary amine
used topically in the eye as a mydriatic (pupillary dilator) to facilitate examination of the peripheral retina
Short duration of action (about 1 hour) used for short-term mydriasis
Muscarinic receptor antagonists, such as trihexyphenidyl and benztropine, are used for Parkinson's disease
Some antihistamines, tricyclic antidepressants, and antipsychotics, have prominent antimuscarinic side effects
What are some muscarinic receptor antagonist side effects?
Urinary retention, constipation, tachycardia, dry mouth, mydriasis, blurred vision, inhibition of sweating, toxic psychosis.
Contraindicated in patients with atony of the bowel, urinary retention, or prostatic hypertrophy.
Ophthalmological use contraindicated in the elderly and in patients with narrow angles.
What are CNS muscarinic receptors like?
Muscarinic receptors in the brain play an important role in learning, memory, control of posture, and temperature regulation
Excessive activation of central muscarinic receptors causes tremor, convulsions, and hypothermia.
what are nicotinic cholinergic receptors for neuromuscular junction blockers?
The nicotinic receptor is an acetylcholine-gated sodium channel. The channel is a polypeptide pentamer composed of varying combinations of α, β, δ, and ε subunits. ACh binding to the receptor causes sodium influx, membrane depolarization, release of calcium from the sarcoplasmic reticulum, and muscle contraction. Nicotinic receptors at autonomic ganglia and in the brain have a different subunit composition.
What are the two types of neuromuscular junction blockers?
(II.b) Neuromuscular junction blockersTwo types based on electrophysiological differences in their mechanism of action
- Competitively antagonizing the actions of ACh at nicotinic acetylcholine receptors
- Chemical structure different than that of ACh
- e.g. curare
- The drug occupies and activates the nicotinic receptor for a prolonged period of time, prevents repolarization and makes the muscle fibre refractory to further nerve impulses – known as a depolarizing block
- Chemical structure resembles that of ACh
- e.g. succinylcholine
What did the native south americans use as a competitive neuromuscular blocker?
- The native South Americans used certain plant extracts as arrow poison, which would cause muscle paralysis in the animal
- Curare – a generic term for various South American arrow poisons
- d-tubocurarine was isolated from these plant (Strychnos species) extracts
1932 – West used purified extracts in patients with tetanus and spastic disorders
1942 – curare used for muscle relaxation in general anesthesia
What is the classification system based on duration of action for competitive neuromuscular blockers?
Classification – based on duration of action
- Short acting
- Intermediate acting
- Long acting
What is the classification system based on chemical structure for competitive neuromuscular blockers?
- Natural alkaloids
- Ammonio steroids
Pancuronium – no histamine release
- Benzylisoquinolines – devoid of vagolytic and ganglionic blocking actions, may cause histamine release
What do competitive neuromuscular blockers do?
Block the action of ACh at the nicotinic receptor
produce flaccid paralysis
Contraction is partially impaired when 75% to 80% of receptors are occupied
Contraction is inhibited totally when 90% to 95% receptors are occupied
Block can be reversed by increasing the concentration of ACh
ChE inhibitors - neostigmine, edrophonium, and pyridostigmine are used clinically to reverse neuromuscular block caused by competitive blockers
What is the sequence of muscle paralysis with competitive neuromuscular blockers?
I.v. competitive blocker – motor weakness progressing to total flaccid paralysis
Small rapidly moving muscles paralyzed first
- Eyes, jaw, larynx
- Respiration stops
Recovery occurs in reverse order
What are the main side effects of competitive nueromuscular blockers?
- Ganglionic blockade
Fall in blood pressure
Tachycardia (vagal block)
- Block of vagal responses
- Histamine release
↑ bronchial and salivary secretions
What are the depolarizing neuromuscular blocker that is currently in clinical use?
Only one currently in clinical use
Binds to and activates muscle nicotinic receptors
Not metabolized by AChE
Causes persistent receptor stimulation
Succinylcholine is hydrolyzed primarily by butyrylcholinesterase (also known as pseudocholinesterase) in the plasma
what happens after a single i.v. dose of 10-30 mg siccinylcholine?
After a single i.v. dose of 10-30 mg succinylcholine
Muscle fasciculations occur briefly
- Chest and abdomen muscles
Relaxation occurs within 1 min
Becomes maximal within 2 min
Disappears within 5 min
Transient apnea occurs at the time of maximal effect
Longer duration relaxation can be achieved by continuous i.v infusion
What is the clinical problem with succinylcholine?
Succinylcholine - short duration of action
Rapid hydrolysis by plasma butyrylcholinesterase
Clinical problem: Certain patients exhibit several variants of this enzyme, which lead to prolonged and potentially dangerous durations of neuromuscular block
What are the side effects of depolarizing blockers?
Depolarizing agents can release K+ rapidly from intracellular sites
Cause hyperkalemia, rhabdomyolysis and cardiac arrest
Hyperkalemia can be dangerous in heart failure patients on digoxin or diuretics
Depolarizing blockers should be avoided in patients with soft tissue trauma or burns
Also avoid in rhabdomyolysis, ocular lacerations, spinal cord injuries with paraplegia or quadriplegia or muscular dystrophies
Not given to children under 8 years of age
What is meant by malignant hyperthermia?
Seen after certain anesthetics (haolthane, isoflurane, sevoflurane) and neuromuscular blockers (succinylcholine)
Can be life-threatening
Due to a genetic abnormality with an incidence of 1:3000 -mutations in the ryanodine receptor
↑ Ca2+ release from the sarcoplasmic reticulum of skeletal muscle
Contracture, rigidity, heat production from skeletal muscle, hyperthermia, accelerated muscle metabolism, metabolic acidosis and tachycardia
Treatment – i.v. dantrolene – blocks Ca2+ release
Wat are the therapuetic uses of neuromuscular blockers?
In surgical anesthesia to obtain relaxation of skeletal muscle, particularly in the abdominal wall
Reduces the need for deeper anesthesia and the associated respiratory and cardiovascular depression
Correction of dislocations and alignment of fractures
To facilitate tracheal intubation – laryngoscopy, bronchoscopy, eosphagoscopy (alongwith an anesthetic)
To prevent trauma during electroshock therapy
Administered mostly i.v. by trained anesthesiologists and trained clinicians
Facilities for respiratory cardiovascular resuscitation should be available
What drugs mimick the sympathetic nervous system?
Sympathetic effects can be mimicked by:
Adrenergic receptor agonists (Direct acting, e.g. Epinephrine, albuterol )
Norepinephrine uptake blockers [indirect acting, e.g. cocaine, imipramine (non-specific blocker, also blocks serotonin uptake)]
Monoamine oxidase and COMT inhibitors (these drugs delay the breakdown of NE and prolong its action) (indirect acting, e.g. pargyline, entacapone)
NE releasing agents (from the nerve terminal, indirect acting, e.g. amphetamine)
What drugs can block the sympathetic nervous system effects?
Adrenergic receptor antagonists (e.g. Prazosin, Propranolol)
What happens with termination of NE action at the synapse - reuptake into nerve terminal?
The released transmitter is taken up back into the presynaptic nerve terminal
Uptake 1 can be blocked by several drugs including cocaine
Uptake 1 blockers will increase sympathetic activity
What are some adrenergic receptor agonists?
(I.a) Adrenergic receptor agonistsRelative activity of sympathomimetic amines at adrenoceptors
Epinephrine – equipotent at α and β receptors
NE – Can activate α and β1 receptors, has little activity at β2 receptors. It is a little less potent than epinephrine at α receptors
Isoproterenol – most potent sympathomimetic amine – acts exclusively on β receptors
Dopamine – activates cardiac β1 receptors, dopamine receptors in kidneys cause ↑ in renal blood flow
what are the clinical uses of adrenergic drugs?
Allergic reactions – anaphylactic shock, e.g. epinephrine (EPIPEN autoinjector)
Uterine relaxant (e.g. to prevent premature labour)– e.g. ritodrine, a β2 agonist
Bronchodilators (asthma) – albuterol, a β2 agonist
Nasal decongestion – e.g. ephedrine
CNS stimulants – for ADHD or narcolepsy
Anorectic – phentermine
Cardiac stimulants – e.g. dobutamine, a β1 agonist
As pressor agents (hypotension) – e.g. Epi or NE
For local vasoconstriction – e.g. epinephrine
What are two classes of adrenergic receptor blockers?
α1 – prazosin, terazosin, tamsulosin doxazosin
α2 – yohimbine
β1 – metoprolol, atenolol, esmolol
β2 – butoxamine (no clinical use)
α1, α2 – phentolamine
β1, β2 – propranolol, timolol
α1, β1, β2 – labetalol, carvedilol