ANS

Dr. Karun Kumar

JR – II

Dept. of Pharmacology

Nervous system hierarchy

Enteric Nervous System

ENS (3rd division of ANS)

• Submucosal, myenteric, and subserosal nerve plexuses, is innervated by the sympathetic and parasympathetic nervous systems.

• Synchronize propulsive contractions of gut muscle (peristalsis).

• Parasympathetic activates the ENS

• Sympathetic inhibits the ENS

• ENS functions independently of autonomic innervation after autonomic denervation

NeurotransmittersAch All autonomic ganglia, at parasympathetic neuroeffector junctions, and at somatic NMJ, few sympathetic neuroeffector junctions (sweat glands and vasodilator fibers in skeletal muscle)

NE Sympathetic postganglionic neuroeffectorjunctions

E Released from the adrenal medulla in activation of sym.n.s.

Other neurotransmitters NPY, VIP, enkephalin, substance P, serotonin, ATP, NO (vasodilatation)

In some tissues, ATP adenosine (activate adenosine receptors) Nitric oxide is an important

M3 Smooth musc. Contraction (except sphincters) & gland secretion

Cholinergic neurotransmission

• Ach synth. from choline and acetate in neuronal cytoplasm by chAT

↓

Autonomic regulation of structures associated with the eye

Dominant tone = Parasympathetic

Iris radial – contracted via alpha-1

Iris circular –contracted via M3

Ciliary muscle –contracted via M3

Regulation of the heart

Dominant tone = parasympathetic

Sympathetic

Increases heart rate and contractility via beta-1 and 2 (primarily beta-1)

Parasympathetic

Decreases heart rate and atrial contractility via M2

Regulation of the blood vessels

Veins

Dominant tone = parasympathetic

Arterioles/arteries

Dominant tone = sympathetic

Contraction via alpha1

Relaxation via beta-2

Regulation of the liver

• Sympathetic• Increase gluconeogenesis and glycogenolysis

• Provide glucose to fuel “flight or fight” response

• Primarily beta-2, possibly alpha-1

Control of stomach acid

Parasympathetic

• Increase histamine release from ECL cell via M3

• Increase H+ production from parietal cell in fundus via M3

• Decrease somatostatin release from D cell in antrum• Increases

gastrin release from G cell

Regulation of the bladder

Parasympathetic

• Bladder wall• Constriction via M3

• Relaxation via beta-2

• Sphincter• Relaxation via M3

• Constriction via alpha-1

Glandular secretion

Sweat

Salivary

Appocrine – increased via alpha-1Eccrine – increased via M

Increased via M3

Lacrimal gland (tear production) – increased via M

Predominant tones of major organ systems

• Heart - parasympathetic• Arterioles/arteries - sympathetic• Veins - sympathetic• Iris - parasympathetic• Ciliary muscle - parasympathetic• GI tract (ENS) - parasympathetic• Smooth muscle - parasympathetic• Bladder - parasympathetic• Sweat glands - sympathetic• Salivary glands – parasympathetic• Lacrimal glands – parasympathetic

Physiological effects of autonomic innervation and receptors that govern the effect

Parasympathetic Sympathetic

• Contracts the ciliary muscle via M-3

• Decelerates the sinoatrialnode via M-2

• Decreases heart contractility via M-2

• Releases EDRF in the endothelium via M-3, M-5

• Contracts bronchiolar smooth muscle via M-3

• Contracts GI walls via M-3

• Relaxes GI sphincters via M-3

• Increases GI secretions via M-3

• Contracts the uterus via M-3

• Causes erection of the penis

• Contracts the iris radial muscle via alpha-1

• Relaxes the ciliary muscle via beta

• Accelerates the sinoatrial node via beta-1,2

• Accelerates ectopic pacemakers via beta-1,2

• Increases cardiac contractility via beta-1,2

• Relaxes bronchiolar smooth muscle via beta-2

• Relaxes GI walls via alpha-2, beta-2

• Contracts GI sphincters via alpha-1

• Relaxes bladder wall via beta-2

• Contracts bladder sphincter via alpha-1

• Contracts uterus via alpha, relaxes uterus via beta-2

• Contracts pilomotor smooth muscle via alpha

• Activates sweat glands via alpha, M

• Increases gluconeogenesis and glycogenolysis in liver via beta-2 and alpha

Ach receptor agonists

1. Direct acting agonists Bind & activate Ach rec.

a) Choline esters Ach, Bethanechol, Carbachol

b) Plant alkaloids Muscarine, Nicotine,

Pilocarpine, Arecoline

c) Synthetic drugs Cevimeline, Varenicline,

Tremorine, Oxotremorine

2. Indirect acting agonists (Anti-chE)

i) Reversible anti-chE

a) Natural alkaloid Physostigmine

b) Others Edrophonium, Neostigmine,

Pyridostigmine, Donepezil, Galantamine,

Rivastigmine, Ambenonium, Demecarium

ii) Irreversible anti-chE OPs, Echothiophate,

Isoflurophate, Malathion,

Propoxur, Paraoxon, Carbaryl

Direct acting AchR agonists

1. Choline esters Quaternary ammonium compds. (poorly abs. from GIT n BBB)

• Ach & CarbacholM + N; BethanecholM only

• Resp. tract effects ↑ mucus secretion & bronchoconstriction (caution in asthma, COPD)

• Cardiac effects ↓ impulse formation in SAN by ↓ the rate of diastolic depolarization (↓ HR) & ↑ PR interval (Time from SAN to AVN)

• Vascular eff. Vasodilation (NOS & cGMP); M3

• GIT eff. ↑ GI motility & secretions

• UT eff. + bladder detrusor muscle, relax the internal sphincter of the bladder, and these effects promote emptying of the bladder (micturition).

Urinary bladder

Loc. of receptors in bladder

• α1A bladder neck, urethra and prostate to enhance bladder outlet resistance, in BPH

• β3- and β2-subtypes are important in the human bladder and urethra, respectively.

• Contraction of the bladder involves direct contraction via M3 receptors and an indirect ‘re-contraction’ via M2-receptors whereby a reduction in adenylate cyclase activity reverses the relaxation induced by β-adrenoceptor stimulation.

• 3 Muscarinic receptors are also located on the epithelial lining of the bladder (urothelium) where they induce the release of a diffusible factor responsible for inhibiting contraction of the underlying detrusor smooth muscle. The factor remains unidentified but is not nitric oxide, a cyclooxygenase product or adenosine triphosphate.

Effects of pilocarpine and atropine on the eye. A, The relationship between the iris sphincter and ciliary muscle is shown in the normal eye. B, When pilocarpine, a muscarinic receptor agonist, is administered, contraction of the iris sphincter produces pupillary constriction (miosis). Contraction of the ciliary muscle causes the muscle to be displaced centrally. This relaxes the suspensory ligaments connected to the lens, andthe internal elasticity of the lens allows it to increase in thickness. As the lens thickens, its refractive power increases so that it focuses on close objects. C, When atropine, a muscarinic receptor antagonist, is administered, the iris sphincter and ciliary muscles relax. This produces pupillarydilatation (mydriasis) and increases the tension on the suspensory ligaments so that the lens becomes thinner and focuses on distant objects.

When the ciliary muscle is relaxed, the choroid acts like a spring pulling on the lens via the zonule fibers causing the lens to become flat.

When the ciliary muscle contracts, it stretches the choroid, releasing the tension on the lens and the lens becomes thicker.

Acetylcholine

• Choline ester of acetic acid

• Uses

1. During cataract surgery (Miosis) NO topical

2. Diagnostic coronary angiography intracoronary injection to cause coronary artery spasm

3. Vasospastic angina pectoris, however, intracoronary injection of acetylcholine can provoke a localized vasoconstrictive response, and this helps establish the diagnosis of vasospastic angina

Clinical uses of direct acting AchR ag.

• Bethanechol

1. Urinary retention (Postoper. Or neurogenic bld.)

2. GIT atony (Expel gases, paralytic ileus)

3. Xerostomia (Salivary gland malfunc., Sjogren’s)

• MethacholineMCT (bronchial asthma)

• CarbacholMiosis during ophthalmic surgery

• Pilocarpine (Tertiary amine) sel. For Muscarinic R

1. Ophthalmic Glaucoma, mydr., break adhesions

2. Sialagogue Xerostomia (laryng. surg., radioth.)

• Nicotine Smoking cessation programs (gum, t.d)

• Pilocarpine Xerostomia, Glaucoma

• Cevimeline Xerostomia (Sjogr., radiation ther.)

• Varenicline Smoking cessation (Nicotinic ag.)

Indirect acting AchR agonists

1. Drugs that inhibit AchE1. Reversible chE inhibitors (shorter acting)

• Edro, neo, pyrido, physo, done, galant., rivast.

2. Quasi-reversible chE inhibitors (long acting)

• OP (Echothio, isofluro, malathion)

2. Type 5 PDE inhibitors

Reversible chE inhibitors

1. Edrophonium (+vely charged alc. that reversibly binds to a –vely charged anionic site on AchE)

• Duration of action 10 mins.

• Patients with myasthenia gravis may experience muscle weakness from either undertreatment or overtreatment with a cholinesterase inhibitor drug.

• Untreated - Edr ↑ Ach levels and muscle strength

• Overtreated - muscle weakness caused by ↑ Ach at NMJ depol blockade similar to Sch (cholinergic crisis) test dose of edrmuscle weakness ↑ patient’s dose of chE inhibitor should be ↓

Neo, pyrido (Q. amine), physo 3oa

Clinical uses of reversible ChEinhibitors

• Edrophonium Diff. b/w myasthenic & c. crisis

• Donepezil, Galantamine & Rivastigmine (t.a.) AD

• Neost., Pyridostigmine Myasthenia gravis

• Neo, pyrido, and edro Reverse eff. of curariformdrugs when muscle relaxation is no longer required

• Neostigmine (NO CNS penetration – Quat. Amine)

Muscarinic

1. Postop. Paralytic ileus

2. Postop. urinary retention

Nicotinic

1. Myasthenia gravis (Oral 15-30 mg; 0.5-2.5 mg i.m/s.c)

2. Cobra bite

3. Curare poisoning

• Physostigmine (CNS penetr. – Tertiary amine)

1. Antidote in atropine poisoning (2 mg i.m./i.v.)

2. Ophthalmic (Glaucoma, mydr., adhesions break)

Poisoning• Organophosphates (lipid soluble)

1. Insecticides Malathion (lice-p.c.), Parathion, Dyflos

2. Nerve gases Soman, Sarin

3. Ophthalmic agents Echothiophate (glaucoma, strabismus), Isoflurophate

• Carbamates

1. Reversible Physostigmine, Neostigmine, Pyridostigmine, Edrophonium,

Rivastigmine, Donepezil, Galantamine

2. Irreversible Carbaryl, Propoxur

OPs form a tight covalently bound intermediate with the catalytic site of chEThe phosphorylated intermediate is then hydrolyzed very slowly by the enzyme, accounting for the long duration of action of these compounds. The covalently bound intermediate is further stabilized by a spontaneous process called aging, in which a portion of the drug molecule (the “leaving group”) is removed

• OPs augment cholinergic neurotransmission at both central and peripheral cholinergic synapses

• Excessive activation of nicotinic receptors by organophosphate compounds leads to a depolarizing neuromuscular blockade and muscle weakness.

• Seizures, respiratory depression, and coma can result from the overactivation of acetylcholine receptors in the central nervous system.

Anti-chE poisoning

M Miosis

U Urination

S Sec. ↑ (Salivation, lacrimation & sweating)

C Cardiac contraction & conduction slows

A Abdominal cramps

R Redn. In i.o.t. (esp. in glaucoma)

I Inc. (↑) GI motility

N NO dependent vasodilatation

I Inc. sec. from GIT & tracheobronchial tract

C Constriction of tracheobronchial tract

Treatment

1. Termination of further exposure to the poison

2. Maintain patent airway PPV

3. Supportive measures

4. Specific antidotes

a) Atropine (musc.) Counteracts muscarinic symptoms

Dose 2 mg i.v. every 10 mins. Till atr. Signs

b) ChE reactivator Pralidoxime (nicotinic, Diacetylmonoxime; Dose 1-2 gms slow i.v.infusion

Acetylcholine

• Choline ester of acetic acid

• Uses

1. During cataract surgery (Miosis) NO topical

2. Diagnostic coronary angiography intracoronary injection to cause coronary artery spasm

3. Vasospastic angina pectoris, however, intracoronary injection of acetylcholine can provoke a localized vasoconstrictive response, and this helps establish the diagnosis of vasospastic angina

Atropine & Scopolamine (t.a.)

• t1/2 2 hrs (oral route)

• After topical ocular administration, they have longer-lasting effects because they bind to pigments in the iris that slowly release the drugs.

• People with darker irises bind more atropine and experience a more prolonged effect than do people with lighter irises. The ocular effects gradually subside over several days.

• “dry as a bone, blind as a bat, red as a beet, and mad as a hatter.” Atr. toxicity

Effects

• Ocular eff. Myd. + cycloplegia

• Cardiac eff. ↑ HR & AV conduction velocity by blocking the effects of the vagus nerve on SAN,AVN

Low i.v. atropine paradoxical slowing of HR (stimulation of the vagal motor nucleus in the brain stem). After full dose heart rate ↑

• Resp. tract eff. bronchial smooth muscle relaxation and bronchodilation, inhibitors of secretions in the upper and lower respiratory tract.

Indications

• Ocular Indicationsmydriasis (facilitate peripheral retina), cycloplegia (refractive errors), iritis and cyclitis (↓ muscle spasm and pain)

• Cardiac Indications Sinus bradycardia after MI. AV block to ↑ AV conduction velocity

• Respiratory Tract Indications ↓ salivary and respiratory secretions & prevent airway obstruction in patients who are receiving general anaesthetics. Glycopyrrolate is often used for this purpose today

• GIT Indications Relieve intestinal spasms & pain

• UT indications Relieve urinary bladder spasms in persons with overactive bladder.

• CNS Indications A transdermal formulation of scopolamine can be used to prevent motion sickness (blocking Ach neurotransmission from the vestibular apparatus to the vomiting center in the brain stem). Also, PD.

• Other Indications

1. Prevent muscarinic side effects when chEinhibitors are given to patients with myasthenia gravis.

2. Reverse the muscarinic effects of cholinesterase inhibitor overdose.

Atropine

Uses (ATROPA)

1. As mydriatic-cycloplegic in refraction error testing, fundoscopy, iridocyclitis

2. Traveller’s diarrhea

3. Rapid onset mushroom poisoning

4. Organophospohorous poisoning

5. Preanaesthetic medication

6. Arrhythmias (brady-arrhythmias)

MUSCARINIC effects (OP poisoning)

M Miosis

U Urination

S Secretions ↑ (salivation, lacrimation, sweating)

C Cardiac contraction & conduction slows

A Abdominal cramps

R Redn. In i.o.t. esp. in glaucoma

I ↑ GI motility

N NO dependent vasodilatation

I Inc. secretion from GIT & tracheobronchial tract

C Constriction of tracheobronchial tract

Adverse effects of Atropine (DHATURA)1. Dry mouth, difficulty in swallowing & speaking

2. Hot dry skin & hypotension

3. Accommodation paralysis (blurring of near vision)

4. Tachycardia

5. Urinary retention & fecal retention (constipation)

6. Respiratory depression

7. Ataxia & acute congestive glaucoma may precipitate

Type 5 PDE inhibitors1. Sildenafil & Tadalafil ED, BPH, PAH

Ach activates M3 rec. in vascular endothelial cells

↓

↑ NO

↓

NO diffuses into vascular smooth muscle cells in the corpus cavernosum

↓

NO activates g. c. & ↑ cGMP,

↓

Muscle relaxation and vasodilation

• Also, inhibit the breakdown of cGMP by type 5 PDE

BPH cGMP-mediated vasodilation in prostate and bladder tissue, as well as relaxation of prostate and bladder smooth muscle in a way that reduces obstruction to urine outflow

PAH Due to impaired release of NO by vascular endothelial cells, resulting in deficient cGMP levels in pulmonary vascular smooth muscle. Sildenafi and tadalafi increase levels of cGMP by inhibition of type V phosphodiesterase, causing relaxation of pulmonary vascular smooth muscle and decreasing pulmonary artery pressure. Other treatments for PAH include epoprostenol (prostacyclin) and endothelin receptor antagonists such as bosentan

A/E of PDE 5 inh.

• headache, nasal congestion, dyspepsia, myalgia, back pain, and visual disturbances

• Concurr. Admin. of 5-PDE inhibitors and NG can cause profound hypotension, reflex tachycardia, and worsening of angina pectoris.

• augment the hypotensive effects of other vasodilators, including α-adrenoceptor antagonists (e.g., doxazosin), that are used to treat symptoms of urinary obstruction in men with BPH

AchR antagonists

• Drugs that selectively block either muscarinic or nicotinic receptors.

• Muscarinic receptor blockers Relax smooth muscle, decrease gland secretions, or increase heart rate

• Nicotinic receptor antagonists Neuromuscular blocking agents that are used to relax skeletal muscle during surgery.

Musc. Rec. ant.,Anti-chol.,psymly.

• Belladonna Alkaloids Extracted from Atropabelladonna (the deadly nightshade), Daturastramonium (jimson weed), and Hyoscyamus niger.

• Belladonna, which is an Italian expression meaning “beautiful lady,” refers to the pupillary dilatation (mydriasis) produced by ocular application of extracts from these plants to women, which was considered cosmetically attractive during the Renaissance.

• Atropine, scopolamine, and hyoscyamine are examples of belladonna alkaloids.

• In fact, atropine was named after Atropos, one of the Fates in Greek mythology, who was known for cutting the thread of life.

Atropine & Scopolamine (t.a.)

• t1/2 2 hrs (oral route)

• After topical ocular administration, they have longer-lasting effects because they bind to pigments in the iris that slowly release the drugs.

• People with darker irises bind more atropine and experience a more prolonged effect than do people with lighter irises. The ocular effects gradually subside over several days.

• “dry as a bone, blind as a bat, red as a beet, and mad as a hatter.” Atr. toxicity

Effects

• Ocular eff. Myd. + cycloplegia

• Cardiac eff. ↑ HR & AV conduction velocity by blocking the effects of the vagus nerve on SAN,AVN

Low i.v. atropine paradoxical slowing of HR (stimulation of the vagal motor nucleus in the brain stem). After full dose heart rate ↑

• Resp. tract eff. bronchial smooth muscle relaxation and bronchodilation, inhibitors of secretions in the upper and lower respiratory tract.

• GIT eff. Atropine ↓ lower esophageal muscle tone (GERD), relaxed GI muscle (except sphincters), intestinal motility, thereby increasing gastric emptying time and intestinal transit time. They also inhibit gastric acid secretion. Sufficient doses of these drugs can cause constipation.

• UT eff. Atropine relaxes the detrusor muscle of the urinary bladder and can cause urinary retention.

• CNS eff. Sedation and excitement. Scopolamine is more sedating than is atropine and has been used as an adjunct to anesthesia. Standard doses of atropine typically cause mild stimulation,followed by a slower and longer-lasting sedative effect. With higher doses delirium & hallucinations.

• Other Effects Inhibit sweating, which can reduce heat loss and lead to hyperthermia, especially in children. The increased body temperature can cause cutaneous vasodilatation, and the skin can become hot, dry, and flushed.

Indications

• Ocular Indicationsmydriasis (facilitate peripheral retina), cycloplegia (refractive errors), iritis and cyclitis (↓ muscle spasm and pain)

• Cardiac Indications Sinus bradycardia after MI. AV block to ↑ AV conduction velocity

• Respiratory Tract Indications ↓ salivary and respiratory secretions & prevent airway obstruction in patients who are receiving general anaesthetics. Glycopyrrolate is often used for this purpose today

• GIT Indications Relieve intestinal spasms & pain

• UT indications Relieve urinary bladder spasms in persons with overactive bladder.

• CNS Indications A transdermal formulation of scopolamine can be used to prevent motion sickness (blocking Ach neurotransmission from the vestibular apparatus to the vomiting center in the brain stem). Also, PD.

• Other Indications

1. Prevent muscarinic side effects when chEinhibitors are given to patients with myasthenia gravis.

2. Reverse the muscarinic effects of cholinesterase inhibitor overdose.

Hyoscyamine

• levorotatory isomer of racemic atropine is responsible for the pharmacologic effects of atropine

• Formulations for oral or sublingual administration are used to treat intestinal spasms and other gastrointestinal symptoms

Semisynthetic & Synthetic MuscarinicReceptor Antagonists

• Ipratropium & Tiotropium (Q.a.) OLD(Obstr. Lung disease) not well absorbed from the lungs into the systemic circulation (Few A/E)

• Unlike atropine, they do not impair the ciliary clearance of secretions from the airways.

• Dicyclomine, Oxybutynin, Solifenacin Dicyclomine is a synthetic amine used to relax intestinal smooth muscle and thereby relieve irritable bowel symptoms, such as intestinal cramping.

• Oxybutynin, tolterodine, darifenacin, solifenacin, and trospium are used to reduce the four major symptoms of overactive bladder:daytime urinary frequency, nocturia (frequent urination at night), urgency, and incontinence.

• Glycopyrrolate Blocks musc. rec.

1. preop. inhibit excessive salivary and respiratory tract secretions.

2. It is also used during anesthesia to inhibit the secretory and vagal effects of cholinesterase inhibitors (e.g., neostigmine) that are used to reverse nondepolarizing neuromuscular blockade induced by curariform drugs (e.g., vecuronium).

3. Reduce chronic severe drooling in cerebral palsy.

• TropicamideMydriatic (pupillary dilator) Dur. Of action (about 1 hour) and preferable to atropine and scopolamine for short-term mydriasis.

• Pirenzepine Blocks M1 receptors on paracrine cells and inhibits the release of histamine, a potent gastric acid stimulant.

NICOTINIC RECEPTOR ANTAGONISTS1. Ganglionic blocking agents

• Their lack of selectivity for sympathetic or parasympathetic ganglia & A/E Stopped

2. Neuromuscular blocking agents

N.m. Blocking Agents (Paralytics)

• Bind to NM & inhibit neurotransmission at skeletal NMJ muscle

weakness and paralysis. Divided into :-

1. Nondepolarizing (Competitive) blockers

2. Depolarizing blocker Sch

• Extremely dangerous compounds (resp. failure in a patient lacking external ventilatory support).

• Responsible for the rare occurrence of “anesthesiaawareness” during surgery, because they render a patient immobile without affecting mental status

Nondepolarizing NeuromuscularBlocking Agents (Curariform drugs)• atracurium, cisatracurium, pancuronium,

rocuronium, and vecuronium.

• Tubocurarine From plants used by native South Americans as arrow poisons (curare) for hunting wild game.

• +vely charged quaternary amines admin. only i.v.

• Eliminated by renal and biliary excretion (except Cisatracurium elim. by Hoffman degradation & given in impaired hepatic and renal function).

Mechanisms & effects

• Competitive antagonists of Ach at NMJ

• Paralysis sequence - Small & rapidly moving muscles of the eyes and face Paralysis of larger muscles of limbs & trunk. Intercostal muscles and diaphragm resp. stops

• Respiratory function closely monitored

• Stimulate histamine release from mast cells & block autonomic ganglia and muscarinic rec. bronchospasm, hypotension, and tachycardia

• Doxacurium, cisatracurium, rocuronium, and vecuronium Less histamine & autonomic s/e

Interactions

• Potentiated inhalational anesthetic agents (e.g., sevoflrane), aminoglycoside, tetracycline,CCBs, m.g.

• Reversed neostigmine

• Sugammadex Reversing rocuronium.

Indications

1. Induce muscle relaxation during surgery & facilitate surgical manipulations.

2. Adjunct to ECT to prevent injuries that might be caused by involuntary muscle contractions.

3. Facilitate intubation of the respiratory tract so as to enable ventilation and endoscopic procedures (e.g., bronchoscopy).

• Degree of neuromuscular blockade small limb contraction

Drug Selection

• Atracurium, cisatracurium, rocuronium, and vecuronium provide duration of action (30 to 60 minutes).

• Doxacurium or pancuronium Longer duration of action is required.

• Tubocurarine No longer used

Depolarizing Neuromuscular Blocking Agents• Succinylcholine 2 molecules of Ach

• Binds to NM transient muscle contractions (fasciculations) Sustained muscle paralysis short

• duration of action 5 to 10 minutes

• sequence of muscle paralysis same as curare

• No antidote

• Indications Muscle relaxation before and during surgery and to facilitate intubation of the airway (emergency)administered in

• Nonemergent Interviewed (personal or family history suggestive of atypical cholinesterase)..

Adverse effects

• Succinylcholine can cause hyperkalemia (burns and, paralysis caused by spinal cord injury (up-regulation of AchR at NMJ)

• Postoperative myalgia Muscles of neck, back, and abdomen. (muscle fasciculations)

• Malignant hyperthermia

Regulation of the heart

Dominant tone = parasympathetic

Sympathetic

Increases heart rate and contractility via beta-1 and 2 (primarily beta-1)

Parasympathetic

Decreases heart rate and atrial contractility via M2

PREDOM

1. Ach Cardiac effects ↓ impulse formation in

SAN by ↓ the rate of diastolic depolarization (↓

HR) & ↑ PR interval (Time from SAN to AVN)

2. Atr Cardiac eff. ↑ HR & AV conduction velocity

by blocking the effects of the vagus nerve on sa,av

• Low i.v. atropine paradoxical slowing of HR

(stimulation of the vagal motor nucleus in the brain

stem). After full dose heart rate ↑

CVS eff. Of NE, E, Isoprenaline

• NE Activation of α1 receptors (V.c. & ↑ TPR)

Reflex bradycardia if blood pressure increases

sufficiently to activate the baroreceptor reflex

• E ↑ SBP but can ↑ or ↓ DBP

• Isoproterenol Activates β1 and β2 receptors

• Propranolol Blockade of β1 receptors

Baroreceptor reflex

Dopamine

• Low doses (< 2 μg/kg per min) D1 dopaminergic

receptors in renal, mesenteric, and coronary

vascular beds. (vasodilation)

• Moderate dose (2–10 μg/kg per min) β1 recept.

• Higher dose (10 μg/kg per min) α1 receptors

Adrenaline

Uses (ABCD)

1. Anaphylactic shock (DOC) 0.5 mg (0.5 ml of 1 in 1000 solution for adult) i.m.

2. Bronchial asthma

3. Cardiac arrest 10 ml of 1:10000 i.v.

4. Control of local bleeding Adr 1 in 10,000

5. During LA combined with Lignocaine (1:50,000 or 1:2,00,000)

Adrenoceptor agonists

• Adrenoceptors α or β (potency of agonists)

• E & NE > iso at (smooth muscle) α

• Iso > E & NE (cardiac tissue) β

1. Direct-acting Bind and activate adrenoceptors.

2. Indirect-acting a↑ stimulation of adrenoceptors (↑ conc. of NE at neuroeffectorjunctions)1. Cocaine inhibits the catecholamine transporter ↑

conc.

2. Amphetamine inhibit storage of NE

3. Mixed-acting agonists (e.g., ephedrine) have both direct and indirect actions.

Direct acting agonists

• Catecholamines Naturally occurring (E, NE, DA) & Synthetic (isoproterenol and dobutamine)

Drugs with large alkyl group (e.g., isoproterenol) have greater affinity for β-adrenoceptors than do drugs with a small alkyl group (e.g., epinephrine)

Effects on CVS

1. NE Activation of α1 (vasoconstr. & ↑ TPR [↑SBP & DBP]). Reflex bradycardia

2. E ↑ SBP (↑ HR & CO), ↑/↓ DBP (α1 and β2) Lower doses E Gtr stimulation of β2 (Vasodil. & ↓ DBP) High dose V.c. &↑SBP & DBP

3. Isoproterenol β1- and β2 (↓ DBP, MAP, ↑SBP)

4. Dobutamine ↑ myocardial contractility & SV (HR unaff) ↓ vasc. resistance (β2 receptors)

5. Dopamine low doses (D1 receptors);slightly higher doses (β1); more higher doses (α1)

Respiratory Tract Effects

• E & Iso potent bronchodilators.

• Nowadays more selective β2 agonists

Adverse Effects

1. Exc. V.c. (tissue ischemia and necrosis)

2. Reduce blood flow to vital organs, such as the kidneys

3. Exc. cardiac stimulation that leads tachycardia and other cardiac arrhythmias

4. β agonists (hyperglycemia) so NOT in diabetes

Shock

• Shock Circulation to vital organs is profoundly reduced as a result of

1. inadequate blood volume (hypovolemic shock)

2. inadequate cardiac function (cardiogenic shock)

3. inadequate vasomotor tone (neurogenic shock and septic shock).

• Septic shock is associated with massive vasodilation secondary to the production of toxins by pathogenic microorganisms (“warm shock”)

4. Anaphylactic shock (immediate hypersensitivity reaction) hypotension and bronchoconstriction

• Catecholamines that ↑ BP vasopressors

• Hypovolemia should always be corrected by i.v.fluids coz vasopressors will not be effective if hypovolemia is present.

• Cardiogenic shock, mechanical devices (e.g., the intra-aortic balloon pump) are usually superior to pharmacologic agents in their ability to improve coronary artery perfusion and cardiac performance while reducing myocardial ischemia and cardiac work. Such devices are often used in conjunction with vasopressor drugs in the treatment of this condition.

• Dobutamine (inotropic agent) that also produces vasodilation. cardiac stimulant during heart surgery, acute HF and cardiogenic shock.

• Dopamine septic or cardiogenic shock (2 mg/kg/ min) with i.v. fluids & vasopressors

• Norepinephrine septic & cardiogenic shock. Also hypotension caused by exc. Vasodilators (Phenylephrine)

• In anaphylaxis epinephrine (DOC) counteracts the effects of histamine and other mediators that are released from mast cells and basophils during immediate hypersensitivity reactions, reduce bleeding during surgery and to prolong the action of local anesthetics by retarding their absorption into the general circulation. Epinephrine is also used as a cardiac stimulant in the treatment of cardiac arrest and ventricular fibrillation.

• Isoproterenol Refractory bradycardia & AV block when other measures have not been successful.

• Noncatecholamines Do not contain a catechol moiety, and they are not substrates for COMT. Some of the noncatecholamines are also resistant to degradation by MAO. For this reason, noncatecholamines are effective after oral administration and have a longer duration of action than do catecholamines.

1. Phenylephrine

2. Midodrine

Phenylephrine (α1-receptors (smooth muscle contraction)• Indications

1. Nasal decongestant in patients with viral rhinitis, allergic rhinitis

2. Eye allergic conjunctivitis ocular decongestant ophthalmoscopic exam. of the retina.

3. hypotension and shock (hypotension caused by excessive doses of vasodilator drugs, drug-induced shock, septic shock, and neurogenic shock such as resulting from spinal cord injury).

4. Phenylephrine is also used to maintain blood pressure during surgery (e.g., when hypotension is induced by anesthetic agents)

Terbutaline• Management of preterm (premature) labor, < 37

wks Delays delivery to enable corticosteroids to be given to prevent neonatal respiratory distress syndrome.

• The adverse effects of albuterol and other selective β2- adrenoceptor agonists include tachycardia, muscle tremor, and nervousness caused by activation of β2-adrenoceptors in the heart, skeletal muscle, and central nervous system.

Imidazoline Drugs

• Activate α and imidazoline receptors.

1. Oxymetazoline and similar drugs α1. never be used for more than 3 to 5 days, to avoid rebound congestion that results from excessive vasoconstriction and tissue ischemia. Also cause CNS & CV depression if they are absorbed into the systemic circulation and distributed to the brain. (used with caution in children under 6 years of age and in the elderly)

2. Apraclonidine and Brimonidine. (α2 receptors in ciliary body); high rate of tachyphylaxis

3. Clonidine (α2 & imidazoline receptors in CNS. Activation of these receptors leads to a reduction in sympathetic outflow from the vasomotor center in the medulla, and clonidine is used to treat hypertension

• Also used to facilitate abstinence from opioids in persons being treated for drug dependence

• The activation of α2-adrenoceptors in the central nervous system is also responsible for the sedative and analgesic effects of clonidine

Indirect-acting AdrenoceptorAgonists• Amphetamine high lipid solubility and ↑

synaptic conc. of NE in CNS & PNS (vc,card.+, ↑BP, and CNS +. Tyramine Bananas.

• Cocaine LA & + Sym. NS by blocking the neuronal reuptake of norepinephrine at both peripheral and central synapses (vc,card.+,↑BP)

• Cocaine abusers Severe HTN & cardiac damage, ischemia & necrosis of nasal mucosa

Mixed-acting AdrenoceptorAgonists• DA, ephedrine, and pseudoephedrine

• Ephedrine Ephedra; lipid solubility to enter CNS resistant to metabolism by MAO and COMT; its duration of action is several hours.

• Pseudoephedrine Isomer of ephedrine (nasal decongestant)

• α(α1) and β(β2) by direct and indirect mechanisms. also CNS + & insomnia.

α adrenoceptor antagonists

1. Nonselective α-Blockers Phenoxybenzamine(nc) phentolamine (compet. Antag.)

• Phenoxybenzamine forms a long-lasting covalent bond with α-receptors, resulting in noncompetitivereceptor blockade

• Indications hypertensive episodes in patients with pheochromocytoma until surgery can be performed to remove the tumor

• Phentolamine Imidazoline compound

Uses of Phentolamine

1. Acute HTN episodes caused by α agonists

2. Counteract localized ischemia caused by accidental injection or extravasation (leakage from an intravenous infusion) of epinephrine or other vasopressor amines.

3. Accidental injection of a finger with an epinephrine autoinjector may result in localized vasoconstriction, ischemia, and necrosis. This condition can be treated by injecting the finger with phentolamine.

• NOT useful in treating chronic HTN (reflex tachycardia and may cause dizziness, headache, and nasal congestion)

Selective α1-Antagonists

• Prazosin HTN & BPH

• The selective α1-blockers do not cause as much reflex tachycardia as do phentolamine and other agents that nonselectively block both α1- and α2-adrenoceptors. This is because blockade of α2-adrenoceptors on sympathetic neurons prevents feedback inhibition of norepinephrine release and thereby leads to increased activation of cardiac β1-adrenoceptors and tachycardia

• A/E hypotension, dizziness, and sedation

β adrenoceptor antagonists

• Nonselective β1, β2 (nadol,pindolol, Ppnl, Timo) some exhibit ISA & membrane stabilizing (LA)

• Uses

1. HTN

2. Glaucoma (β2 effects)

3. In the liver, β2-adrenoceptor blockade inhibits epinephrine stimulated glycogenolysis and can thereby reduce hepatic glucose output during hypoglycemia resulting from excessive insulin administration.

Hypertension

• Acute Not effective (baroreceptor reflexes)

• Chronic Effective (↓ renin release ↓ ang. II & ald. renal loss of Na+ and H2O↓ BP)

• Hypertension in some patients is caused by emotional stress, which causes enhanced sympathetic activity. Beta-blockers can be very effective in these patients.

• Preop. mx of hypertension caused by a pheochromocytoma, which results in elevated circulating catecholamines

Pindolol (only for HTN)

• Has intrinsic sympathomimetic activity, (partial agonist activity), which enables it to exert a weak agonist effect on β-adrenoceptors.

• Eff. Obs. when the patient is resting & sympathetic tone is low, and it can result in a smaller reduction in heart rate than that caused by β-blockers without intrinsic sympathomimetic activity.

• When sympathetic tone is high, pindolol acts as a competitive receptor antagonist to inhibit sympathetic stimulation of the heart in the same manner as other β-blockers.

• Pindolol & PpnlMemb. stabilizing activity/LA (block Na channels in nerves and heart tissue and thereby slow conduction velocity)

• Nadolol HTN, angina, prevent migraine headache

• Timolol HTN, ac. MI, prevent migraine headache, glaucoma

• Selective β1-Blockers acebut, aten, esm,meto. (caution in pts. with asthma) high dose (β2 block)

Propranolol (Uses THAPPAD)

1. Thyrotoxicosis & Tremors

2. HTN & Hypertrophic cardiomyopathy

3. Angina & Acute MI

4. Prophylaxis of migraine

5. Phaeochromocytoma (along with alpha blockers)

6. Anxiety & Arrhythmias

7. Dissecting aortic aneurysm

8. Digitalis toxicity

Adverse effects of beta blockers (BBC Loses Viewers in Rochedale)• Bradycardia

• Bronchoconstriction

• Claudication

• Lipids (profile altered)

• Vivid dreams & nightmares

• Negative ionotropic action

• Reduced sensitivity to hypoglycemia

Contraindications of Propranolol

• Don’t Prescribe Him Propranolol

1. Diabetes mellitus

2. Pulmonary diseases (Asthma, COPD)

3. Heart block, bradycardia

4. Prinzmetal’s angina

5. Peripheral vascular disease

Specific Properties

• Acebutolol HTN & cardiac arrhythmias (vent. premature beats)

• Atenolol Lower lipid solubility and ↓ CNS s/e (e.g., vivid dreams, tiredness, and depression) HTN, angina & acute MI

• Esmolol (shorter t1/2) i.v. (HTN & SVT during surg.)

• Metoprolol HTN, ang, AMI

• Betaxolol ↓ aqueous humor secretion (POAG)

α- and β-adrenoceptor antag.

• Carvedilol (β1,β2,α1) & has antioxidant activity:-1. inhibition of lipid peroxidation in myocardial

membranes

2. scavenging of free radicals

3. inhibition of neutrophil release of O2

• In addition, it has antiapoptotic properties that can prevent myocyte death and reduce infarct size in persons with myocardial ischemia. (MI)

• “third-generation β-blocker and neurohumoralantagonist,” (HTN, AMI, HF)