Se ha denunciado esta presentación.
Utilizamos tu perfil de LinkedIn y tus datos de actividad para personalizar los anuncios y mostrarte publicidad más relevante. Puedes cambiar tus preferencias de publicidad en cualquier momento.
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
par...
Neurotransmitters
Ach  All autonomic ganglia, at parasympathetic
neuroeffector junctions, and at somatic NMJ, few
sympath...
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 al...
Regulation of the heart
Dominant tone = parasympathetic
Sympathetic
Increases heart rate
and contractility via
beta-1 and ...
Regulation of the blood vessels
Veins
Dominant tone =
parasympathetic
Arterioles/arteries
Dominant tone =
sympathetic
Cont...
Regulation of the liver
• Sympathetic
• Increase gluconeogenesis and glycogenolysis
• Provide glucose to fuel “flight or f...
Control of stomach acid
Parasympathetic
• Increase histamine
release from ECL cell
via M3
• Increase H+
production from
pa...
Regulation of the bladder
Parasympathetic
• Bladder wall
• Constriction via M3
• Relaxation via beta-2
• Sphincter
• Relax...
Glandular secretion
Sweat
Salivary
Appocrine – increased via
alpha-1
Eccrine – increased via M
Increased via M3
Lacrimal g...
Predominant tones of major organ
systems
• Heart - parasympathetic
• Arterioles/arteries - sympathetic
• Veins - sympathet...
Physiological effects of autonomic innervation and
receptors that govern the effect
Parasympathetic Sympathetic
• Contract...
Ach receptor agonists
1. Direct acting agonists  Bind & activate Ach rec.
a) Choline esters  Ach, Bethanechol, Carbachol...
2. Indirect acting agonists (Anti-chE)
i) Reversible anti-chE
a) Natural alkaloid  Physostigmine
b) Others  Edrophonium,...
Direct acting AchR agonists
1. Choline esters  Quaternary ammonium
compds. (poorly abs. from GIT n BBB)
• Ach & Carbachol...
Urinary bladder
Loc. of receptors in bladder
• α1A  bladder neck, urethra and prostate to enhance
bladder outlet resistance, in BPH
• β3-...
Effects of pilocarpine and atropine on the eye.
A, The relationship between the iris sphincter and
ciliary muscle is shown...
When the ciliary muscle is relaxed, the choroid acts like a spring pulling on the lens via the
zonule fibers causing the l...
Acetylcholine
• Choline ester of acetic acid
• Uses
1. During cataract surgery (Miosis) NO topical
2. Diagnostic coronary ...
Clinical uses of direct acting AchR ag.
• Bethanechol
1. Urinary retention (Postoper. Or neurogenic bld.)
2. GIT atony (Ex...
• Nicotine  Smoking cessation programs (gum, t.d)
• Pilocarpine  Xerostomia, Glaucoma
• Cevimeline  Xerostomia (Sjogr.,...
Indirect acting AchR agonists
1. Drugs that inhibit AchE
1. Reversible chE inhibitors (shorter acting)
• Edro, neo, pyrido...
Reversible chE inhibitors
1. Edrophonium (+vely charged alc. that reversibly
binds to a –vely charged anionic site on AchE...
Neo, pyrido (Q. amine), physo 3oa
Clinical uses of reversible ChE
inhibitors
• Edrophonium  Diff. b/w myasthenic & c. crisis
• Donepezil, Galantamine & Riv...
• Neostigmine (NO CNS penetration – Quat. Amine)
Muscarinic
1. Postop. Paralytic ileus
2. Postop. urinary retention
Nicoti...
Poisoning
• Organophosphates (lipid soluble)
1. Insecticides  Malathion (lice-p.c.), Parathion,
Dyflos
2. Nerve gases  S...
OPs form a tight covalently bound intermediate with the catalytic site of chE
The phosphorylated intermediate is then hydr...
• OPs augment cholinergic neurotransmission at both
central and peripheral cholinergic synapses
• Excessive activation of ...
Anti-chE poisoning
M  Miosis
U  Urination
S  Sec. ↑ (Salivation, lacrimation & sweating)
C  Cardiac contraction & cond...
Treatment
1. Termination of further exposure to the poison
2. Maintain patent airway  PPV
3. Supportive measures
4. Speci...
Acetylcholine
• Choline ester of acetic acid
• Uses
1. During cataract surgery (Miosis) NO topical
2. Diagnostic coronary ...
Atropine & Scopolamine (t.a.)
• t1/2  2 hrs (oral route)
• After topical ocular administration, they have
longer-lasting ...
Effects
• Ocular eff.  Myd. + cycloplegia
• Cardiac eff.  ↑ HR & AV conduction velocity by
blocking the effects of the v...
Indications
• Ocular Indications  mydriasis (facilitate peripheral
retina), cycloplegia (refractive errors), iritis and
c...
• GIT Indications  Relieve intestinal spasms & pain
• UT indications  Relieve urinary bladder spasms in
persons with ove...
Atropine
Uses (ATROPA)
1. As mydriatic-cycloplegic in refraction error
testing, fundoscopy, iridocyclitis
2. Traveller’s d...
MUSCARINIC effects (OP poisoning)
M  Miosis
U  Urination
S  Secretions ↑ (salivation, lacrimation, sweating)
C  Cardia...
Adverse effects of Atropine
(DHATURA)
1. Dry mouth, difficulty in swallowing & speaking
2. Hot dry skin & hypotension
3. A...
Type 5 PDE inhibitors
1. Sildenafil & Tadalafil  ED, BPH, PAH
Ach activates M3 rec. in vascular endothelial cells
↓
↑ NO
...
BPH  cGMP-mediated vasodilation in prostate and
bladder tissue, as well as relaxation of prostate and
bladder smooth musc...
A/E of PDE 5 inh.
• headache, nasal congestion, dyspepsia, myalgia,
back pain, and visual disturbances
• Concurr. Admin. o...
AchR antagonists
• Drugs that selectively block either muscarinic or
nicotinic receptors.
• Muscarinic receptor blockers  Relax smooth
mus...
Musc. Rec. ant.,Anti-chol.,psymly.
• Belladonna Alkaloids  Extracted from Atropa
belladonna (the deadly nightshade), Datu...
Atropine & Scopolamine (t.a.)
• t1/2  2 hrs (oral route)
• After topical ocular administration, they have
longer-lasting ...
Effects
• Ocular eff.  Myd. + cycloplegia
• Cardiac eff.  ↑ HR & AV conduction velocity by
blocking the effects of the v...
• GIT eff.  Atropine ↓ lower esophageal muscle tone
(GERD), relaxed GI muscle (except sphincters), intestinal
motility, t...
Indications
• Ocular Indications  mydriasis (facilitate peripheral
retina), cycloplegia (refractive errors), iritis and
c...
• GIT Indications  Relieve intestinal spasms & pain
• UT indications  Relieve urinary bladder spasms in
persons with ove...
Hyoscyamine
• levorotatory isomer of racemic atropine is
responsible for the pharmacologic effects of
atropine
• Formulati...
Semisynthetic & Synthetic Muscarinic
Receptor Antagonists
• Ipratropium & Tiotropium (Q.a.)  OLD(Obstr. Lung
disease) not...
• Glycopyrrolate  Blocks musc. rec.
1. preop. inhibit excessive salivary and respiratory
tract secretions.
2. It is also ...
NICOTINIC RECEPTOR
ANTAGONISTS
1. Ganglionic blocking agents
• Their lack of selectivity for sympathetic or
parasympatheti...
N.m. Blocking Agents (Paralytics)
• Bind to NM & inhibit neurotransmission at skeletal
NMJ  muscle
weakness and paralysis...
Nondepolarizing Neuromuscular
Blocking Agents (Curariform drugs)
• atracurium, cisatracurium, pancuronium,
rocuronium, and...
Mechanisms & effects
• Competitive antagonists of Ach at NMJ
• Paralysis sequence - Small & rapidly moving
muscles of the ...
Interactions
• Potentiated  inhalational anesthetic agents (e.g.,
sevoflrane), aminoglycoside, tetracycline,CCBs, m.g.
• ...
Indications
1. Induce muscle relaxation during surgery &
facilitate surgical manipulations.
2. Adjunct to ECT to prevent i...
Drug Selection
• Atracurium, cisatracurium, rocuronium, and
vecuronium provide  duration of action (30 to 60
minutes).
• ...
Depolarizing Neuromuscular
Blocking Agents
• Succinylcholine  2 molecules of Ach
• Binds to NM  transient muscle contrac...
Adverse effects
• Succinylcholine can cause hyperkalemia (burns and,
paralysis caused by spinal cord injury (up-regulation...
Regulation of the heart
Dominant tone = parasympathetic
Sympathetic
Increases heart rate
and contractility via
beta-1 and ...
PREDOM
1. Ach Cardiac effects  ↓ impulse formation in
SAN by ↓ the rate of diastolic depolarization (↓
HR) & ↑ PR interval (Time...
CVS eff. Of NE, E, Isoprenaline
• NE  Activation of α1 receptors (V.c. & ↑ TPR)
Reflex bradycardia if blood pressure incr...
Baroreceptor reflex
Dopamine
• Low doses (< 2 μg/kg per min)  D1 dopaminergic
receptors in renal, mesenteric, and coronary
vascular beds. (va...
Adrenaline
Uses (ABCD)
1. Anaphylactic shock (DOC)  0.5 mg (0.5 ml of 1
in 1000 solution for adult) i.m.
2. Bronchial ast...
Adrenoceptor agonists
• Adrenoceptors  α or β (potency of agonists)
• E & NE > iso at (smooth muscle)  α
• Iso > E & NE ...
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 a...
Effects on CVS
1. NE  Activation of α1 (vasoconstr. & ↑ TPR
[↑SBP & DBP]). Reflex bradycardia
2. E  ↑ SBP (↑ HR & CO), ↑...
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. E...
Shock
• Shock  Circulation to vital organs is profoundly
reduced as a result of
1. inadequate blood volume (hypovolemic s...
• Catecholamines that ↑ BP  vasopressors
• Hypovolemia should always be corrected by i.v.
fluids coz vasopressors will no...
• Dopamine  septic or cardiogenic shock (2 mg/kg/
min) with i.v. fluids & vasopressors
• Norepinephrine  septic & cardio...
• Noncatecholamines  Do not contain a catechol
moiety, and they are not substrates for COMT.
Some of the noncatecholamine...
Phenylephrine (α1-receptors
(smooth muscle contraction)
• Indications
1. Nasal decongestant in patients with viral rhiniti...
Terbutaline
• Management of preterm (premature) labor, < 37
wks Delays delivery to enable corticosteroids to be
given to p...
Imidazoline Drugs
• Activate α and imidazoline receptors.
1. Oxymetazoline and similar drugs α1. never be
used for more th...
2. Apraclonidine and Brimonidine. (α2 receptors in
ciliary body); high rate of tachyphylaxis
3. Clonidine (α2 & imidazolin...
Indirect-acting Adrenoceptor
Agonists
• Amphetamine  high lipid solubility and ↑
synaptic conc. of NE in CNS & PNS (vc,ca...
Mixed-acting Adrenoceptor
Agonists
• DA, ephedrine, and pseudoephedrine
• Ephedrine  Ephedra; lipid solubility to enter C...
α adrenoceptor antagonists
1. Nonselective α-Blockers  Phenoxybenzamine
(nc) phentolamine (compet. Antag.)
• Phenoxybenza...
Uses of Phentolamine
1. Acute HTN episodes caused by α agonists
2. Counteract localized ischemia caused by
accidental inje...
Selective α1-Antagonists
• Prazosin  HTN & BPH
• The selective α1-blockers do not cause as much
reflex tachycardia as do ...
β adrenoceptor antagonists
• Nonselective  β1, β2 (nadol,pindolol, Ppnl, Timo)
some exhibit ISA & membrane stabilizing (L...
Hypertension
• Acute  Not effective (baroreceptor reflexes)
• Chronic  Effective (↓ renin release  ↓ ang. II &
ald.  r...
Pindolol (only for HTN)
• Has intrinsic sympathomimetic activity, (partial
agonist activity), which enables it to exert a ...
• Pindolol & Ppnl  Memb. stabilizing activity/LA
(block Na channels in nerves and heart tissue and
thereby slow conductio...
Propranolol (Uses  THAPPAD)
1. Thyrotoxicosis & Tremors
2. HTN & Hypertrophic cardiomyopathy
3. Angina & Acute MI
4. Prop...
Adverse effects of beta blockers
(BBC Loses Viewers in Rochedale)
• Bradycardia
• Bronchoconstriction
• Claudication
• Lip...
Contraindications of Propranolol
• Don’t Prescribe Him Propranolol
1. Diabetes mellitus
2. Pulmonary diseases (Asthma, COP...
Specific Properties
• Acebutolol  HTN & cardiac arrhythmias (vent.
premature beats)
• Atenolol  Lower lipid solubility a...
α- and β-adrenoceptor antag.
• Carvedilol  (β1,β2,α1) & has antioxidant activity:-
1. inhibition of lipid peroxidation in...
Autonomic nervous sytem
Autonomic nervous sytem
Autonomic nervous sytem
Autonomic nervous sytem
Autonomic nervous sytem
Autonomic nervous sytem
Autonomic nervous sytem
Autonomic nervous sytem
Autonomic nervous sytem
Autonomic nervous sytem
Autonomic nervous sytem
Autonomic nervous sytem
Autonomic nervous sytem
Autonomic nervous sytem
Autonomic nervous sytem
Autonomic nervous sytem
Autonomic nervous sytem
Autonomic nervous sytem
Autonomic nervous sytem
Autonomic nervous sytem
Autonomic nervous sytem
Autonomic nervous sytem
Autonomic nervous sytem
Autonomic nervous sytem
Autonomic nervous sytem
Autonomic nervous sytem
Autonomic nervous sytem
Autonomic nervous sytem
Autonomic nervous sytem
Autonomic nervous sytem
Autonomic nervous sytem
Autonomic nervous sytem
Autonomic nervous sytem
Autonomic nervous sytem
Autonomic nervous sytem
Autonomic nervous sytem
Autonomic nervous sytem
Próxima SlideShare
Cargando en…5
×

Autonomic nervous sytem

There is a great deal of confusion regarding autonomic nervous system. In order to make the concepts a bit more clear, I've uploaded a presentation regarding the same which is a bit more comprehensive & which deals with various cholinergic, anticholinergic, adrenergic & anti-adrenergic drugs

  • Inicia sesión para ver los comentarios

Autonomic nervous sytem

  1. 1. ANS Dr. Karun Kumar JR – II Dept. of Pharmacology
  2. 2. Nervous system hierarchy Enteric Nervous System
  3. 3. 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
  4. 4. Neurotransmitters Ach  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 neuroeffector junctions 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
  5. 5. M3  Smooth musc. Contraction (except sphincters) & gland secretion
  6. 6. Cholinergic neurotransmission • Ach synth. from choline and acetate in neuronal cytoplasm by chAT ↓
  7. 7. 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
  8. 8. 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
  9. 9. Regulation of the blood vessels Veins Dominant tone = parasympathetic Arterioles/arteries Dominant tone = sympathetic Contraction via alpha1 Relaxation via beta-2
  10. 10. Regulation of the liver • Sympathetic • Increase gluconeogenesis and glycogenolysis • Provide glucose to fuel “flight or fight” response • Primarily beta-2, possibly alpha-1
  11. 11. 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
  12. 12. Regulation of the bladder Parasympathetic • Bladder wall • Constriction via M3 • Relaxation via beta-2 • Sphincter • Relaxation via M3 • Constriction via alpha-1
  13. 13. Glandular secretion Sweat Salivary Appocrine – increased via alpha-1 Eccrine – increased via M Increased via M3 Lacrimal gland (tear production) – increased via M
  14. 14. 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
  15. 15. Physiological effects of autonomic innervation and receptors that govern the effect Parasympathetic Sympathetic • Contracts the ciliary muscle via M-3 • Decelerates the sinoatrial node 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 • 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
  16. 16. 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
  17. 17. 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
  18. 18. Direct acting AchR agonists 1. Choline esters  Quaternary ammonium compds. (poorly abs. from GIT n BBB) • Ach & Carbachol  M + N; Bethanechol  M 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).
  19. 19. Urinary bladder
  20. 20. 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.
  21. 21. 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, and the 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 pupillary dilatation (mydriasis) and increases the tension on the suspensory ligaments so that the lens becomes thinner and focuses on distant objects.
  22. 22. 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.
  23. 23. 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
  24. 24. 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) • Methacholine  MCT (bronchial asthma) • Carbachol  Miosis during ophthalmic surgery • Pilocarpine (Tertiary amine) sel. For Muscarinic R 1. Ophthalmic  Glaucoma, mydr., break adhesions 2. Sialagogue  Xerostomia (laryng. surg., radioth.)
  25. 25. • Nicotine  Smoking cessation programs (gum, t.d) • Pilocarpine  Xerostomia, Glaucoma • Cevimeline  Xerostomia (Sjogr., radiation ther.) • Varenicline  Smoking cessation (Nicotinic ag.)
  26. 26. Indirect acting AchR agonists 1. Drugs that inhibit AchE 1. 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
  27. 27. 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 edr  muscle weakness ↑  patient’s dose of chE inhibitor should be ↓
  28. 28. Neo, pyrido (Q. amine), physo 3oa
  29. 29. Clinical uses of reversible ChE inhibitors • Edrophonium  Diff. b/w myasthenic & c. crisis • Donepezil, Galantamine & Rivastigmine (t.a.)  AD • Neost., Pyridostigmine  Myasthenia gravis • Neo, pyrido, and edro  Reverse eff. of curariform drugs when muscle relaxation is no longer required
  30. 30. • 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)
  31. 31. 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
  32. 32. OPs form a tight covalently bound intermediate with the catalytic site of chE The 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
  33. 33. • 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.
  34. 34. 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
  35. 35. 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
  36. 36. 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
  37. 37. 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
  38. 38. 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.
  39. 39. Indications • Ocular Indications  mydriasis (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
  40. 40. • 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 chE inhibitors are given to patients with myasthenia gravis. 2. Reverse the muscarinic effects of cholinesterase inhibitor overdose.
  41. 41. 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)
  42. 42. 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
  43. 43. 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
  44. 44. Type 5 PDE inhibitors 1. 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
  45. 45. 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
  46. 46. 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
  47. 47. AchR antagonists
  48. 48. • 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.
  49. 49. Musc. Rec. ant.,Anti-chol.,psymly. • Belladonna Alkaloids  Extracted from Atropa belladonna (the deadly nightshade), Datura stramonium (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.
  50. 50. 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
  51. 51. 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.
  52. 52. • 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.
  53. 53. Indications • Ocular Indications  mydriasis (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
  54. 54. • 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 chE inhibitors are given to patients with myasthenia gravis. 2. Reverse the muscarinic effects of cholinesterase inhibitor overdose.
  55. 55. 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
  56. 56. Semisynthetic & Synthetic Muscarinic Receptor 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.
  57. 57. • 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. • Tropicamide  Mydriatic (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.
  58. 58. NICOTINIC RECEPTOR ANTAGONISTS 1. Ganglionic blocking agents • Their lack of selectivity for sympathetic or parasympathetic ganglia & A/E  Stopped 2. Neuromuscular blocking agents
  59. 59. 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 “anesthesia awareness” during surgery, because they render a patient immobile without affecting mental status
  60. 60. Nondepolarizing Neuromuscular Blocking 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).
  61. 61. 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
  62. 62. Interactions • Potentiated  inhalational anesthetic agents (e.g., sevoflrane), aminoglycoside, tetracycline,CCBs, m.g. • Reversed  neostigmine • Sugammadex  Reversing rocuronium.
  63. 63. 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
  64. 64. 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
  65. 65. 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)..
  66. 66. 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
  67. 67. 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
  68. 68. PREDOM
  69. 69. 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 ↑
  70. 70. 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
  71. 71. Baroreceptor reflex
  72. 72. 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
  73. 73. 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)
  74. 74. 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 neuroeffector junctions) 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.
  75. 75. Direct acting agonists • Catecholamines  Naturally occurring (E, NE, DA) & Synthetic (isoproterenol and dobutamine)
  76. 76. 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)
  77. 77. 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)
  78. 78. Respiratory Tract Effects • E & Iso  potent bronchodilators. • Nowadays  more selective β2 agonists
  79. 79. 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
  80. 80. 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
  81. 81. • 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.
  82. 82. • 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.
  83. 83. • 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
  84. 84. 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)
  85. 85. 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.
  86. 86. 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)
  87. 87. 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
  88. 88. Indirect-acting Adrenoceptor Agonists • 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
  89. 89. Mixed-acting Adrenoceptor Agonists • 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.
  90. 90. α adrenoceptor antagonists 1. Nonselective α-Blockers  Phenoxybenzamine (nc) phentolamine (compet. Antag.) • Phenoxybenzamine  forms a long-lasting covalent bond with α-receptors, resulting in noncompetitive receptor blockade • Indications  hypertensive episodes in patients with pheochromocytoma until surgery can be performed to remove the tumor • Phentolamine  Imidazoline compound
  91. 91. 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)
  92. 92. 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
  93. 93. 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.
  94. 94. 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
  95. 95. 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.
  96. 96. • Pindolol & Ppnl  Memb. 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)
  97. 97. 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
  98. 98. 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
  99. 99. 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
  100. 100. 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)
  101. 101. 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 neurohumoral antagonist,” (HTN, AMI, HF)

×