Subject: Pharmacology Topic: ANS 2 Lecturer: Maria Luisa D. Delacruz, M.D.

Date of Lecture:August 3, 2011 Transcriptionist: Anonymous Pages: 16

Review and definitions: (Integration with previous knowledge from previous lectures and in first year) **Please double check when in doubt! know some of the info here are pretty much duh for some people but I put them in anyways for the flow of info to be nice.. I hope you can apply these general concepts to facilitate memorization and understanding I. ALL ABOUT ACETYLCHOLINE (usually parasympathetic with a few exceptions LIKE SWEAT GLANDS sympathetic cholinergic) 1. Acetylcholine neurotransmitter whose release may be accompanied by VIP (vasoactive intestinal peptide) 2. Cholinergic - pertaining to acetylcholine 3. Cholinergic receptors acetylcholine receptors have two types a) muscarinic (designated as letter M1-M5) and b) nicotinic *in other words, if you say muscarinic receptor, it is a cholinergic receptor and it is a receptor for acetylcholine *same goes for nicotinic ALL ABOUT NOREPINEPHRINE (usually sympathetic) 1. epinephrine, norepinephrine, and dopamine are all derived from tyrosine and they have similar structures. Their similar structures imply that they may bind to similar substrates or receptors depending on the selectivity of s uch. **in other words if something is not picky, it may bind with various things because they look alike. If the selectivity is hi gh, it is picky, it can distinguish one from the other despite similarities in structure, so it will reject the others. 2. Epinephrine is synonymous to adrenaline; norepinephrine is synonymous to noradrenaline 3. Release of norepinephrine may be accompanied by ATP, and neuropeptide Y 4. Adrenergic pertaining to adrenaline (or epinephrine) 5. Adrenergic receptors - receptors for epinephrine or norepinephrine have 4 types: a) alpha 1 b) alpha 2 c) beta 1 d) beta 2 *in other words, if u say alpha 1 receptor, it means its a form of adrenergic receptor and its a receptor for epinephrine o r norepinephrine *use the same logic for b,c and d *dopamine receptors sometimes have a special name, that is, dopaminergic receptors (in renal) II. SYNTHESIS 1. So why bother giving different names for different receptors if there are only 2 types of neurotransmitters in this module? Because these receptors have different EFFECTS, LOCATIONS, and SECONDARY MESSENGER MECHANISMS of producing effects WHOSE TABLES NEED TO BE MEMORIZED before you proceed to the next parts (they only look unimportant but they really are important!) 2. Antagonist anti; Agonist pro 3. Acetylcholine and epinephrine oppose each other (its often BUT NOT ALWAYS acetylcholine VS epinephrine) 4. Thus in general (but there may be certain exceptions): a. When you say acetylcholine agonist, promote effects of acetylcholine b. Acetylcholine antagonist, inhibit effects of acetylcholine and promote effects of epinephrine because its effect goes unchecked (you can think of it as magkaawaaysi epinephrine and acetylcholine, yungmga drugs they pick a side, they can either help acetylcholine or fight epinephrine to promote acetylcholine effects, or they can help epinephrine or fight acetylcholine effects Promote acetylcholine effects: acetylcholine agonist (ANS 1 Lecture) norepinephrine antagonist Promote norepinephrine effects acetylcholine antagonist (ANS 2 Lecture) norepinephrine agonist (ANS 3 Lecture) 5. General effects: (there are certain exceptions which are not stated here) a. Sympathetic (usually Norepinephrine/Epinephrine) (fight or flight) When u wanna fight or run you want lots of blood in ur muscles so u c an move, heart up and beating to pump blood, bronchioles dilated so u can breathe in lots of O2 and breathe out CO2, see clearly (lots of light going in: mydriasis, sphincter relaxation + see far things: far accommodation, ciliary relaxation). You also do nt want to suddenly pee or poop while youre on the run so constrict GIT and urinary sphincters, but relax the walls. b. Parasympathetic (usually Acetylcholine) (rest and digest) - When your just chilling, your body has the luxury of digesting food and you h ave the time to go to the bathroom to do ur stuff so promote GIT and urinary. You dont need to run so decrease heart activity, bronchioles are constricted (smaller opening less air cause u dont need them). Pupillary constriction/miosis + near accommodati on (ciliary contraction)

SY 2011-2012

The M1, M3 and M receptors are stimulatory and couple primarily to the mobilization of intracellular Ca2+. An increasein cytoplasmic Ca2+ results from the coupling of these receptors with the heterotrimeric G proteinGq, which leads to stimulation of the effector enzyme phospholipase C (PLC) and the release ofinositol-(1,4,5)-trisphosphate [Ins(1,4,5)P3]. The M2 and M4 receptors are inhibitory andnegatively modulate adenylyl cyclase (AC) to reduce cytoplasmic concentrations of cAM

Cholinergic Antagonists Types of Cholinergic Antagonists(in correlation with the classification above) 1.M scarinic receptor antagonists 2.Nicotinic receptor antagonists Neuromuscular blockers Ganglionic blockers

What is different between the two types? Muscarinic receptors are metabotropic (silayung may mga Q i, IP3/Ca, camp etc.) Nicotinic are ligand gated. When activated they let Na ions pass through. Remember in the muscles?

MUSCARINIC RECEPTORS

Muscarinic Receptor Antagonists 1. Naturally-occurring Alkaloids Atropine* Atropa belladonna Daturastramonium Scopolamine Hyoscyamusniger 2. Semi-synthetic Quarternary amines Methscopolamine bromide Homatropinemethylbromide Glycopyrrolate Tertiary amines Benztropinemesylate Biperiden Trihexyphenidyl hydrochloride Diphenhydramine hydrochloride

Five muscarinic acetylcholine receptors mediate the effects of acetylcholine.

Classification of Cholinergic Receptors. A. M scarinic Receptors (M M a. Smooth m scles b. Cardiac M scles c. Exocrine/Endo d. Glands/CNS B. Nicotinic Receptors a. ANS ganglia b. NMJ c. CNS

3. Synthetic Quarternary ammonium compounds Methylatropine Ipratropium bromide Tiotropium Tertiary amine compounds Pirenzepine HomatropineHbr Telenzepine Propantheline bromide Oxybutinin Tolterodine Muscarinic Receptor Antagonists Therapeutic Classification: I. Specific (muscarinic) M1 Receptor Blocker Pirenzepine Telenzepine II. As Bronchodilators Ipratropium bromide Oxytropium bromide Tiotropium III. Anti-arrhythmic Atropine IV. Anti-motion sickness Scopolamine V. Mydriatics and Cycloplegics Atropine Homatropinehydrobromide Cyclopentolate hydrochloride Tropicamide VI. As Antispasmodic Homatropinemethylbromide Propantheline bromide Dicyclomine hydrochloride Oxybutinin chloride VII. Centrally-acting Anticholinergics Benztropinemesylate Trihexyphenidyl hydrochloride VIII. As Anti-Urinary Incontinence (experienced in U.T.I.) Tolterodine

Atropine
(A discussion on atropine, an example of antimuscarinic compound) Tertiary amine also known as hyoscyamine, belladonna alkaloid Highly selective for muscarinic receptors Negligible effect on nicotinic receptors May act as inverse agonist Nonselective for all muscarinic receptor subtypes toxic doses produce initial stimulation followed by depression

Mechanism of action: compete with Acetylcholine for a common binding site in the muscarinic receptor prevent Ach effects by blocking Ach binding to muscarinic receptors antagonism can be overcome by increasing sufficiently the concentration of Ach at the receptor sites. Distribution of Muscarinic Receptors M1: (ganglionic) brain (cortex, hippocampus), salivary glands, sympathetic ganglia M2: (effector cell) heart, hindbrain, smooth muscle M3: blood vessels, smooth muscle, salivary glands, brain M4: brain (forebrain, stratum) M5: brain (substantianigra), eye M1: central nervous system (CNS) neurons, sympathetic postganglionic cell bodies, and many presynaptic sites M2: myocardium, smooth muscle and some neuronal sites, e M3: effector cell membranes, especially glandular and smooth muscle cells, endothelium M4: CNS M5: CNS
What is the importance of knowing the distribution of receptors? If know which receptors are affected by the drug, what the drug does to the receptor, and where these receptors are located, the n you know the effects of the drug. There are mus carinic receptors in the eye (M3).These receptors are cholinergic and promote miosis. Atropine inhibits these receptors. So one of the effects of atropine is mydriasis. Thus if there are receptors for the drug in the organ, then the drug may have an effect on that organ if the drug can reach t he organ.

Pharmacologic Actions of ATROPINE:

To study the next part, recall where the muscarinic receptors are located because atropine will have an effect on them. Muscarinic receptors are located in effector organs of the parasympathetic system . Also it is found in the sweat glands (remember this is the exception in that it is sympathetic but still cholinergic) Also Atropine is a muscarinic antagonist = sympathetic effects are not balanced out by parasympathetic , so sympathetic is promoted and so next, recall sympathetic effects.

1.Central nervous system

mild stimulant effect (medullar centers) slower, longer-lasting depressant Toxic doses: central excitation, restlessness, agitation, hallucinations, and coma SCOPOLAMINE Pharmacologic Actions:CNS more marked central depressant effects even at therapeutic doses manifested as drowsiness, amnesia, fatigue and dreamless sleep with a reduction of REM sleep produces euphoria in the presence of pain may occasionally cause excitement, restlessness, hallucinations, delirium prevents motion sickness thru its action on either the cortex or the vestibular apparatus

2. Ocular blockade of muscarinic receptors in the constrictor pupilllae unopposed sympathetic dilator pmydriasis abolition of normal pupillary constriction in response to light p photophobia decrease lacrimal gland secretions p dry, sandy eyes relaxation of ciliary muscles pparalysis of accommodation (cycloplegia) lens fixed for far vision, near objects are blurred and may appear smaller(**recall, mydriasis less light refraction for far vision) may induce acute glaucoma in patients with narrow anterior chamber angle Increase intraocular pressure by blocking drainage of aqueous humour

OCULAR ACTIONS OF ATROPINE

Muscarinic (M )
3
Accomodations 1 & 2

Relaxed Ciliary musclespcycloplegia

Atropinelimits focusing to near objects

Alpha 1

Control of Pupillary size

Accomodation is blocked by Atropine
systemic doses of Atropine have little ocular effects, equivalent systemic doses of Scopolamine definitely causes mydriasis and loss of accomodation topicalAtropine or Scopolamine produce ocular effects of long duration (7-12 days) muscarinic receptor antagonist with shorter duration of action are preferred as mydriatics Sympathomimetics produce mydriasis without cycloplegia
Eye muscle Receptor Effects of blocking parasympathetic cholinergic Effects of promoting sympathetic Adrenergic

Cholinergic Adrenergic Sphincter/circular iridial M3 Prevent contraction results to mydriasis muscle Radial iridial muscle Alpha 1 Ciliary muscle (circular muscarinic Prevent contraction results to orientation as well) cycloplegia with blurring of near view Above is the explanation for the effects discussed previously..

Promote contraction results to mydriasis

Cholinergic agonists (Pilocarpine, choline esters, acetylcholinesterase inhibitors) can partially or fully reverse ocular effects of Atropine **Atropine is an antagonist. Ingestion of an agonist would cancel out the effects.

3. Cardiovascular System initial slowing which is attributed to: central vagal stimulation may be due to blockade of prejunctional M1 receptors (autoreceptors) on vagal postganglionic fibers that normally limit acetylcholine release in the sinus node and other tissues

dominant response is increase in heart rate (tachycardia) due to blockade of vagal effects on the M2 receptors in the SA node increase by 35-40 beats/min in young men given 2 mg of Atropine intramuscularly maximal heart rate in response to exercise is not altered
**The mechanism of atropine is only promoting sympathetic effects. In exercise the body naturally induces maximal sympathetic stimulation already so atropine wont have an effect anymore.

blockade of vagal effects on the heart may facilitate AV conduction pshortening of refractory period of the AV node pincrease the ventricular rate in patients with atrial fibrillation or flutter Blood vessels counteracts the peripheral vasodilatation and decrease BP produced by cholinergic agonists no significant effects Toxic doses: ERYTHEMA (cutaneous vasodilatation, especially in the blush area atropine flush)

4. Respiratory System plays a major role in regulating bronchomotor tone blockade of M3 receptors in bronchial smooth muscles and submucosal glands RELAXATION OF BRONCHIAL SMOOTH MUSCLES DECREASE SECRETION OF TRACHEOBRONCHIAL GLANDS inhibit secretions in the nose, mouth, pharynx and bronchi p dryness of the mucus membranes of the respiratory tract basis for use of Atropine and Scopolamine as pre-anesthetic medication reduction in mucus secretions and mucociliary clearance may result in mucus plugs that aggravate bronchoconstriction in patients with airway disease inhibits bronchoconstriction induced by histamine, bradykinin and eicosanoids basis for use in asthma 5. Gastrointestinal tract blocks M3 receptors in the gastric parietal cells to inhibit secretion of gastric acid M1 receptors in intramural ganglia cause inhibition of motility and secretions DECREASED G.I. MOTILITY partially attributed to inhibition of vagal effects other neurotransmitters or neuromodulators e.g. 5-Hyrdroxytryptamine, dopamine and peptides are also involved acting through M3 receptors, abolish the copious, watery secretions induced by cholinergic agonists NO EFFECT ON GASTRIC PEPTIC DISEASE 6. Genitourinary tract decrease normal tone and amplitude of contractions of the ureter and bladder BLADDER RELAXATION M2(M2) is prevalent in the bladder, M3(M3) mediates detrussor muscle contraction constriction of sphincters 7. Sweat glands low doses inhibit activity of sweat glands innervated by sympathetic cholinergic fibers hot and dry skin DECREASE SECRETION depressed sweating p increase body temperature cause atropine fever in infants and children
Dose 0.5 mg 1 mg 2 mg 5mg >10 mg Effects slight cardiac slowing; some dryness of mouth; inhibition of sweating definite dryness of mouth; thirst; acceleration of heart, sometimes preceded by slowing; mild dilation of pupils rapid heart rate; palpitation; marked dryness of mouth; dilated pupils; some blurring of near vision all the above symptoms marked; difficulty in speaking and swallowing; restlessness and fatigue; headache; dry, hot skin; difficulty in micturition; reduced intestinal peristalsis above symptoms more marked; pulse rapid and weak; iris practically obliterated; vision very blurred; skin flushed, hot, dry, and scarlet; ataxia, restlessness, and excitement; hallucinations and delirium; coma

Tissue Sensitivity to Muscarinic Receptor Blockers HIGH salivary, bronchial, sweat glands other secretory glands MEDIUM pupil, ciliary body, heart urinary bladder, and GUT LOW gastric parietal cells

Atropine Pharmacokinetics: well absorbed from the GIT and from mucosal surfaces widely distributed in the body. significant levels are achieved in the CNS within 30 minutes to 1 hour the elimination of atropine from the blood occurs in two phases: rapid phase - T is 2 hours slow phase - T is approximately 13 hours hepatic metabolism accounts for the elimination of about half of a dose the remainder is excreted unchanged in the urine effect on parasympathetic function declines rapidly in all organs except the eye effects onthe iris and ciliary muscle persist for 72 hours. Pharmacodynamic and Pharmacokinetic Differences (between quarternary and tertiary) 1. Quarternary ammonium more peripheral effects, less CNS effects poor absorption from GIT and conjunctival membrane Less distributed longer duration of action 2. Tertiary amines lipid soluble more effects on eyes and CNS well absorbed from GIT and conjunctival membrane widely distributed shorter duration of action

Therapeutic Uses of Muscarinic Receptor Blockers

(discussion of muscarinic receptor blockers in general. The previous section was specifically on atropine) 1. Ocular Mydriatic for thorough examination of the retina and optic discs Cycloplegia is attained at higher concentration or more prolonged application cycloplegia: paralysis of the ciliary muscles of the eye complete cycloplegia for accurate measurement of refractive errors Therapy of iridocyclitis and keratitis
Nice to know: Iridocyclitis is an inflammation of the uvea. Scolopamine and atropine immobilizes the iris and decreases pain. Keratitis is an inflammation of the cornea. Atropine dilates the pupil and stops spasms off the iris .

Diagnostic: accurate measurement of refractive error examination of fundi and retina Therapeutic: prevent synechiae formation Drugs used: Atropine, HomatropineHbr, Cyclopentolate and Tropicamide

Antimuscarinic Drugs used in Ophthalmology

Drug
Atropine Scopolamine Homatropine Cyclopentolate Tropicamide

Duration of Effect (days)

7-10 3-7 1-3 1 0.25

Usual conc.(%)
0.5-1 0.25 2-5 0.5-2 0.5-1

2. Gastrointestinal Antisecretory/ Antispasmodic: Hypermotility, diarrhea; Peptic ulcer disease decrease gastric acid secretion delay gastric emptying time Pirenzepine and Telenzepine both drugs are used in the treatment of acid peptic diseases relative selectivity for M1 - marked improvement over Atropine more potent in inhibiting gastric acid secretion produced by neural stimulation than by muscarinic agonists

3. Respiratory tract - Ipratropium / Tiotropium - COPD, Bronchial asthma Ipratropium bromide quartenary ammonium compound blocks all subtypes of muscarinic receptors blocks the presynaptic muscarinic inhibition of Ach release produces BRONCHODILATATION, tachycardia and inhibition of secretion similar to Atropine given parenterally minimal inhibitory effects on mucociliary clearance compared to Atropine frequent side effect is dry mouth administered by aerosol or solution for inhalation action is confined to the mouth and airways maximal response observed in 30-90 minutes duration of action 4-6 hours 90% of inhaled dose is swallowed most of swallowed drug excreted in the feces moderately protects against histamine, bradykinin and PGF2a less protection against bronchoconstriction induced by serotonin and leukotrienes used for treatment of chronic obstructive pulmonary disease less effective in asthmatic patients Tioropium also a quarternary ammonium compound bronchoselective slower onset of action; longer duration of action(~24 hours) shows some selectivity fro M 1 and M3 receptors lower affinity for M 2p less presynaptic effect on Ach release

4. Cardiovascular system - Atropine - forBRADYARRHYTHM AS , ARRHYTHM AS POST M , HEART BLOCK (**speeds up the slow heart) initial treatment of patients with acute myocardial infarction associated with excessive vagal tone Sinus bradycardia is most common arrhythmia in acute myocardial infarction of the inferior and posterior wall restores heart rate to a level sufficient to maintain adequate hemodyamic status and to eliminate AV nodal block Dosing must be judicious very low doses can cause paradoxical bradycardia very high doses cause tachycardia that may extend infarctby increasing oxygen demand.

5. Central nervous system - MOTION SICKNESS : Scopolamine - Parkinsons Disease: Benztropinemesylate, Trihexyphenidyl Parkinsons disease used to be the only agents helpful in the treatment of Parkinsonism

Centrally acting agents are effective in preventing dystonias or parkinsonian symptoms in patients treated with antipsychotic drugs Motion sickness Scopolamine is the most effective prophylactic agent for short (4-6 hours) exposures to s evere motion and prolonged exposure less effective if given after severe nausea or vomiting has developed a transdermal preparation of Scopolamine is shown to be highly effective when used prophylactically the drug is incorporated into a multilayered adhesive unit and applied to the postauricular mastoid region, an area where transdermal absorption of the drug is especially efficient, and over a period of about 72 hours approximately 0.5 mg of the drug is delivered side effects include dry mouth, drowsiness, blurring of vision

6. Anesthesia - Scopolamine: Twilight anesthesia

**Twilight anesthesia is a type of anesthesia wherein a mild general anesthesia affects both the brain as well the body. The patient is not unconscious but sedated.

- Atropine: Pre-anesthetic medication, PREVENT VAGAL REFLEXES induced by surgical manipulation of organs 7. Genitourinary system Urolithiasis Renal colic Enuresis in children Urinary incontinence synthetic derivatives of atropine are preferred such as Tolterodine andTrospiumchoride also reduce urinary frequency in spastic paraplegia
**recall, paraplegia paralysis of the lower body caused by lower spinal injury or disease S2-S4 segments are in charge of urinary continence so they are affected too.

8. Anticholinesterase poisoning(ANTIDOTE) used in large doses for the treatment of carbamate and organophosphate poisoning antagonize parasympathomimetic effects of Neostigmine and Pyridostigmine

ADVERSE EFFECTS Muscarinic Receptor Blockers Adverse Effects: 1.dryness of the mouth and mucous membarne 2.palpitation 3.blurring of vision 4.urinary retention 5.constipation Toxicity to Muscarinic Receptor Blockers Atropine Toxicity Red as a beet: dilation of superficial vessels leads to flushing Blind as a bat:cycloplegia and mydriasis Dry as a bone: decreased sweating, lacrimation and salivation Hot as a hare: Atropine fever due to decreased perspiration Mad as a hatter: delirium and hallucinations Atropine Other Toxic Effects: 1.Hypotension 2.Convulsions 3.Paralysis and coma 4.Respiratoryfailure

NICOTINIC RECEPTORS

NICOTINIC RECEPTOR ANTAGONISTS

Nicotinic Cholinergic Receptors Presynaptic CNS controls release of neurotransmitters Postsynaptic neuromuscular junction peripheral autonomic ganglia Nicotinic Receptor Antagonists 1. Neuromuscular Blockers 2. Ganglionic Blockers
(**recall, there are two types of nicotinic receptors according to where theyre found muscle type and neural type)

Neuromuscular Blocking Agents Classification based on Mechanism of Action 1. Depolarizing (Non-competitive) Succinylcholine Dexamethonium 2. Non-depolarizing (Competitive) Tubocurarine Pancuronium Vecuronium Atracurium Mivacurium

Neuromuscular Blocking Agents Classification based on Duration of Action 1. Short-acting Succinylcholine Mivacurium 2. Intermediate-acting Vecuronium Rocuronium Atracurium 3. Long-acting Tubocurarine Doxacurium Pancuronium

Neuromuscular Blocking Agents Classification based on Chemical Structure 1. Dicholine ester Succinylcholine 2. Natural alkaloid (Cyclic Benzylisoquinoline) d-Tubocurarine 3. Benzylisoquinoline Atracurium Doxacurium Mivacurium

4. Ammonio steroid Pancuronium Pipecuronium Rocuronium Vecuronium Nicotinic II (N M) Receptors located at neuromuscular junction drugs that act here are neuromuscular blockers or skeletal muscle relaxants Events on the activation of receptors 1. Ca +2induces fusion of vesicles with nerve terminal membrane. (in presynaptic mebrane) 2. ACh is released and diffuses across synaptic cleft. 3. ACh binds to its receptor on the postsynaptic membrane 4. Binding of ACh opens channel pore that is permeable to Na + and K+. 5. ACh unbinds from its receptor so the channel closes. 6. ACh is hydrolyzed by AChE into Choline and acetate 7. Choline is taken up into nerve terminal 8. Choline resynthesized into ACh and repackaged into vesicle

One can inhibit the effects of acetylcholine by getting in the way of any of the above events.

NEUROMUSCULAR BLOCKERS (two examples are to be discussed: tubocurarine and succinylcholine) Tubocurarine Mechanism of action: bind with nicotinic receptors at the motor end plate and prevent Ach binding to the receptor p inhibit cholinergic transmission in the MOTOR END PLATE 90-95% of receptors must be blocked for complete interruption of contraction Tubocurarine and Anti-ChE agents act in opposite directions increasing the duration of Ach retention in the synapse favor the occupation of the receptor by the transmitter and displace Tubocurarine Pharmacologic Action: 1. Skeletal muscles given IV in human beings produce motor weakness that progress to total flaccid paralysis small, rapidly moving muscles such as those of the eyes, jaw and larynx relax before those of thelimbs and trunk followed by the intercostal muscles and finally the diaphragm recovery of the muscles usually occurs in the reverse order diaphragm is the first muscle to regain function 2. Ganglia ganglionic blockade HYPOTENSION TACHYCARDIA 3. Histamine release when injected intradermally orintraarterially produces typical histamine-like wheals bronchospasm, hypotension, excessive bronchial and salivary secretions may also be observed less likely with other NMB direct action on the mast cell not IgE mediated

4. CNS does not penetrate the blood brain barrier devoid of CNS effects Adverse Effects: 1. Hypotension 2. Histamine release : skin rashes, bronchospasm, anaphylaxis 3. Tachycardia

Succinylcholine Mechanism of action: binds to nicotinic receptor and depolarizes the neuromuscular end plate membrane prevents transmission of another action potential

Two phases:
Phase I depolarization of receptor (fasciculations) Phase II persistent depolarization q neuromuscular blockade(paralysis)

Phase I depolarization of the membrane by opening channels in the same manner as Ach persists at the neuromuscular junction primarily because of resistance to Acetylcholinesterase results in a brief period of repetitive excitation that may elicit transient muscle fasciculations Phase II persistent depolarization results to blockade of neuromuscular transmission producing flaccid paralysis due to released Ach that binds to receptors on an already depolarized end plate the change in end-plate potential elicited by the transient increase in Ach triggers the action potential Pharmacologic Action single IV dose of 10-30 mg produce muscle fasciculations particularly over the chest and abdomen which occur briefly followed by relaxation within 1 minute then disappears within 5 minutes transient apnea usually occurs at the time of maximal effect muscle relaxation of longer duration can be achieved by continuous intravenous infusion after discontinuation of infusion, the effects of the drug usually disappear rapidly because of hydrolysis by plasma and hepatic butyrylcholinesterase

Adverse effects: 1.cardiac arrhythmias 2.hyperkalemia 3.post-operative muscle pains 4.Increase intraocular pressure 5.Respiratory failure

Pharmacologic Properties of NMB

Neuromuscular Blockers
(in general) Therapeutic Uses: 1. As an adjunct to surgical anesthesia relaxation of skeletal muscle to facilitate surgery lessen dose of general anesthetics decrease risk for respiratory and cardiovascular depression not used to substitute for inadequate depth of anesthesia due to increase risk of reflex responses to pain stimuli and conscious recall 2. Orthopedic procedures Muscle relaxation for correction of dislocations and alignment of fractures 3. Facilitate endotracheal intubation 4. Facilitate laryngoscopy, bronchoscopy and esophagoscopy in combination with a general anesthetic agent 5. Control of muscle spasms to increase functional capacity relieve discomfort Life-threatening Complications of Neuromuscular Blockers: 1. Apnea prolonged apnea in patients given Succinylcholine or Mivacurium due to the presence of atypical plasma cholinesterase or a deficiency of the enzyme, hepatic or renal disease or a nutritional disturbance 2. Hyperkalemia attributed to Succinylcholine avoid using in patients with: - Extensive soft tissue trauma or burns - Non-traumatic rhabdomyolysis, ocular lacerations, spinal cord injuries with paraplegia or quadriplegia or muscular dystrophies - CHF patients on digoxin and diuretics - Children < 8 years unless in an emergency situation 3. Malignant hyperthermia manifests as muscular contraction, rigidity, increase heat production resulting in severe hyperthermia, accelerated muscle metabolism, metabolic acidosis and tachycardia initiating event is uncontrolled release of Ca ++ from the sarcoplasmic reticulum autosomal dominant trait - susceptibility is associated with certain congenital myopathies such as central core disease Treatment: Dantrolene sodium given IV Dantrolene blocks Ca++ release from the sarcoplasmic reticulum of skeletal muscle by limiting the capacity of Ca ++ and calmodulin to activate RYR-1 rapid cooling inhalation of 100% oxygen control of acidosis

4. Respiratory failure due to paralysis of respiratory muscles Treatment: Positive pressure artificial respiration with oxygen Maintenance of a patent airway Neostigmine or Edrophonium IV if caused by Competitive NMB Neuromuscular BlockersDrug Interactions Anti ChE agents such as Edrophonium, Neostigmine andPyridostigmine preserve endogenous Ach and act directly on the neuromuscular junction used in the treatment of overdosage with Competitive NMB not used to reverse neuromuscular blockade by Succinylcholine Inhalational anesthetics such as Halothane, Isoflurane and Enflurane exert a stabilizing effect on the postjunctional membrane p synergism with competitive NMB Aminoglycoside antibiotics produce neuromuscular blockade by inhibiting Ach release from the preganglionic terminal by competition with Ca ++ and to a lesser extent by noncompetitively blocking the receptor Tetracyclines, Polymyxin B, Colistin, Clindamycin and Lincomycin also possess neuromuscular blocking action Calcium channel blockers enhance neuromuscular blockade

GANGLIONIC BLOCKERS
GANGLIONIC RECEPTOR BLOCKERS 1. Noncompetitive (Depolarizing) Nicotine 2. Competitive (Non-depolarizing) Hexamethonium MecamylaminE Trimethaphan

Ach

N-Rc
SITE PREDOM NANT TONE EFFECT OF GANGLIONIC BLOCKADE

Predominant tone Blood vessels Heart Pupils Ciliary muscle GIT GUT Salivary glands Sweat glands Sexual function Sympathetic Parasympathetic Parasympathetic Parasympathetic Parasympathetic Parasympathetic Parasympathetic Sympathetic S and P

Ganglionic stimulants: Nicotine, Lobeline Ganglionic Blockers: Nicotine, Trimethaphan

Hexamethonium Mecamylamine

Effect/s vasodilatation, hypotension tachycardia mydriasis cycloplegia constipation, decrease secretions urinary retention xerostomia anhidrosis decrease stimulation

Therapeutic uses: 1. Hypertension 2. Acute dissecting aortic aneurysm 3. Autonomic hyperreflexia

Adverse Effects: 1. Orthostatic hypotension 2. Blurring of vision 3. Dry mouth 4. Constipation 5. Urinary retention 6. Sexual dysfunction The truth of being human is gratitude, the secret of existence is appreciation, and its significance is revealed in reciprocity. Mankind will not die for lack of information; it may perish for lack of appreciation.

End! Study to learn not just to pass! Good luck haha