DRUGS ACTING ON PERIPHERAL NERVOUS SYSTEM

Based on BPharm syllabus.
It includes :
Cholinergic agonist and antagonist, adrenergic agonist and antagonist, skeletal muscle relaxants, local anaesthetic classification

1. DRUGS ACTING ON PERIPHERAL NERVOUS SYSTEM Ms. FATHIMATH RAIHANA ASSISTANT PROFESSOR P A COLLEGE OF PHARMACY

2. NERVOUS SYSTEM Central Nervous System (CNS) Brain Spinal cord Peripheral Nervous System (PNS) Motor Neurons Sensory Neurons Somatic Nervous System Autonomic Nervous System Sympathetic System Parasympathetic System Flight or Fight Rest or Digest Receives and processes sensory information. Initiate responses, memories, generate thoughts and emotions. Conducts signals to and from the brain, controls reflex action. Controls Voluntary actions Controls Involuntary actions CNS to muscles and glands . Sensory organs to CNS.

3. The Autonomic Nervous System (ANS) functions below the level of consciousness and control visceral functions. The ANS consist of : Autonomic afferents Central autonomic connections Autonomic efferents Autonomic efferents : Most visceral nerves are mixed nerves and carry non-myelinated visceral fibres. The cell bodies of afferent fibres are located in : dorsal ganglion of spinal nerves and the sensory ganglia of cranial nerves. They mediate visceral pain. CVS, respiratory and other visceral reflexes are regulated. ORGANISATION AND FUNCTION :

4. ii. Central autonomic connections : There is no autonomic areas in the CNS. Intermixing and integration of somatic and autonomic innervation occurs. The highest regulating autonomic function is in the hypothalamus : Posterior and lateral nuclei- sympathetic Anterior and medial nuclei – parasympathetic Many autonomic nerves are located in the mid-brain and medulla in the cranial nerves.

5. iii. Autonomic efferents : They are divided into parasympathetic and sympathetic . Many organs receive both innervation and the two subdivisions are functionally antagonistic . Most blood vessels, spleen, sweat glands and hair follicles receive sympathetic. Ciliary muscle, bronchial smooth muscle, gastric and pancreatic glands receive parasympathetic innervation.

6. ANS

7. NEUROHUMORAL TRANSMISSIONS : Neuro – nerves Humoral – Chemical messengers It refers to the transmission of message across synapses and neuroeffector junctions by the release of chemical messengers. ( Transfer of signal from one neuron to another ) Steps : Impulse conduction Transmitter release Transmitter action or postjunctional membrane Post-junctional activity Termination of transmitter action

8. Impulse conductance : In this step, impulse is generated by the process of action potential or electrical impulses. When there is no impulse, the neurons will be in the resting state. i.e , -70mV. Na + ion conc. is high at outside the cell and more + ve charge at outside the plasma membrane. K + ion conc. is high at inside the cell and more negative charge inside the plasma membrane.

9. ii. Transmitter release : Nerve impulse promotes fusion of vascular and axonal membrane through calcium entry. This promotes exocytosis in synaptic cleft. iii. Transmitter action or postjunctional membrane : The transmitter release and gets attached to the receptor on post-junctional membrane.

10. Depending on the nature, it induce 2 types of action . Action Excitatory post-synaptic potential Inhibitory post-synaptic potential Increase in permeability to all cations – Na + or Ca + influx. Influx cause depolarization by K +. Inhibitory neurotransmitter increase the permeability of small ions. K + moves out Cl + moves in.

11. iv. Post-junctional activity : Propagated action potential results in nerve impulse, contraction in muscles or secretions in gland. v. Termination of transmitter action : The action of transmitter is terminated by : D egradation of neurotransmitter – Eg : Aceytl choline Reuptake back to the pre-synaptic neuron. Eg : Noradrenaline Specific carrier proteins mediate this reuptake. Eg : NET - Norepinephrine Transporter DT - Dopamine Transporter SERT – Serotonin Transporter

12. Co-transmission : It is the release of several types of neurotransmitters from a single nerve terminal alongwith the primary neurotransmitters. These includes : Dopamine Nitric oxide ATP Serotonin Vasoactive intestinal peptide Cholecystokinin GABA

13. For eg : Primary neurotransmitter : Acetyl choline Co- transmitters are : Purines – ATP Peptides – Vaso Intestinal Peptide (VIP) Nitric oxide Prostaglandins On release of acetyl choline, glutamate, VIP cotransmitters release. Different sets of neurons contain different neurotransmitters. Eg : Excitatory neurons of gut - Vaso Intestinal Peptide, Cholecystokinin, and GABA. Inhibitory neurons of gut – ATP , Nitric oxide.

14. NEUROTRANSMITTERS

15. Neurotransmitters are chemical messengers that transmit signal from a neuron to target cell across the synapses. They are stored in synaptic vesicles inside the pre-synaptic neuron. Neurotransmitter release from the pre-synaptic neurons Bind to the receptor present in the post-synaptic neurons Action is produced

16. CLASSIFICATION EXCITATORY INHIBITORY BOTH Adrenaline Aspartate Nitric oxide Glycine GABA Serotonin Acetyl choline Norepinephrine Dopamine

17. Excitatory neurotransmitters : It is the chemical substance responsible for the conduction of impulses from presynaptic neurons to post-synaptic neurons. Signal enters the neuron and passes through the terminal, where it triggers the neurotransmitter stored in vesicles. The Ca 2+ enters inside the neuron and neurotransmitter is released from the vesicles. The released transmitter will proceed the signal towards post-synaptic neuron and will generate the action potential. They will bind to the excitatory receptor and produce action. This opens Na + channel and causes depolarization. Na +

18. Inhibitory neurotransmitters : It is a chemical substance which inhibits the conduction of impulses from the presynaptic neuron to the post-synaptic neuron. When it is released due to the arrival of action potential, it causes opening of potassium channels in post-synaptic membrane. It causes efflux of potassium ions and influx of Cl - ions. This leads to hyperpolarization called Inhibitory post-synaptic potentials.

19. PARASYMPATHOMIMETICS/ CHOLINERGIC AGONIST

20. Parasympathomimetics / Cholinergic Agents / Cholinomimetics : These are the chemicals that act at the same site as that of acetyl choline and thereby mimic their actions. Hence the name.

21. CHOLINERGIC TRANSMISSION : Acetylcholine (Ach) is the neurotransmitter of the parasympathetic system. The nerves that synthesize, store or release Ach are called cholinergic. Neurotransmission in cholinergic neuron involves 6 steps : Synthesis Storage Release Binding of Ach to a receptor Degradation of the neurotransmitter in the synaptic cleft. Recycling of choline and acetate

22. Synthesis : Choline is transported from the extracellular fluid into the cytoplasm of the cholinergic neuron by an energy-dependent carrier system. The uptake of choline is the rate limiting step in the Ach synthesis. Choline acetyl transferase catalyse the reaction of choline with acetyl coA to form Acetyl choline. ii. Storage : ACh is packaged and stored into presynaptic vesicles by active transport process and protect it from degradation.

23. iii. Release : When an action poten tial arrives at the nerve ending V oltage-gated calcium channel open, influx of calcium leads to increase in the concentration of intracellular calcium. Elevated calcium promotes the fusion of vesicles and release the neurotransmitters into the synaptic cleft . iv. Binding of ACh to a receptor : ACh released from the vesicles diffuses across the synaptic cleft and binds to the receptor present on the post-synaptic neuron to produce biological response.

24. v. Degradation of ACh : Acetylcholinesterase enzyme degrades acetyl choline to choline and acet ate in the synaptic cleft. vi. Recycling of choline and acetate : Choline may be recycled by sodium coupled high affinity reuptake system that transports the molecule back into the neuron. It is acetylated to acetyl choline that is stored until released by action potential.

25. Ca 2+

26. Cholinergic receptors Nicotinic receptors (N) Muscarinic receptors (M) M 1 Gastric ganglia CNS M 2 Heart CNS M 3 Eye GIT Bladder Bronchus Glands CNS M 4 CNS M 5 CNS N N Ganglia Adrenal medulla N M Neuromuscular junction

27. Cholinergic Receptors : Two types : Muscarinic receptors Nicotinic receptors i . Muscarinic receptors : They are G-Protein coupled receptors. These receptors are selectively stimulated by muscarine and blocked by atropine. Types : M1, M2, M3, M4, M5. M1, M3 and M5 – coupled with Gq mediated G-protein M2 and M4 – Gi mediated G-protein

28. ii . Nicotinic receptors : It is a ligand-gated ion channel receptor having pentameric structure. Their activation causes opening of the channels and rapid flow of ions. This results in depolarization and action potential. Two types : N M : Present at skeletal muscle end plate. N N : Present on ganglionic cells and adrenal medulla.

29. CLASSIFICATION : Cholinergic agonist Directly acting Indirectly acting / Anticholinesterases Choline esters Acetyl choline Methacholine Carbachol Bethenacol Alkaloids Pilocarpine Muscarine Arecoline Reversible Irreversible Carbamates Physostigmine Neostigmine Pyridostigmine Rivastigmine Alcohol Edrophonium Others Donepezil Galantamine Tacrine Organophosphorous compound Parathion Malathion Sarin Soman Echothiophate Carbamates Propoxur Carbaryl

30. Directly acting : Choline esters : Acetyl choline : It produce muscarinic and nicotinic effects by binding to certain receptors. Muscarinic actions : CVS : Heart : Ach + M 2 Opens K + channel and hyperpolarization. H eart rate ( Negative chronotropic effect ) F orce of contraction ( Negative inotropic ) AV conduction ( Negative dromotropic ) The acetyl choline binds to the M2 receptor in the heart, which is Gi mediated G-protein coupled receptor . It reduces the heart rate, force of contraction. In large doses may produce AV conduction and may leads to partial or total AV block.

31. b. Blood vessels : Ach Release of Nitric oxide Vasodilation BP M3 + Acetyl choline binds to the M3 receptor, which is Gq mediated protein receptor produce action through phospholipase C/IP3-DAG pathway. It relaxes the vascular smooth muscles and causes vasodilation by the stimulation of nitric oxide production. This causes decrease in BP.

32. ii. SMOOTH MUSCLES : a. GIT : Ach M3 Tone of gut Peristaltic movements GI secretions Relaxes the sphincter – may lead to defecation + b. Urinary bladder : Ach + M3 Contracts detrusor muscle Relaxes trigone and sphincter – causes urination. Tone and peristalsis is enhanced, sphincters are relaxed resulting in rapid propulsion of intestinal contents. It leads to the contraction of detrusor and relaxation of trigonal sphincters, thereby promotes the voiding of urine.

33. c. Bronchi : Ach + Bronchoconstriction or bronchospasm Increases tracheobronchial secretions ‘Cholinergic drugs are contraindicated in asthmatics’ EXOCRINE GLANDS : Saliva Lacrimal secretions Sweat Bronchial Gastric GI secretions Enhanced bronchial secretions and bronchospasm results in dyspnoea. Secretions are increased through M3 receptors and some M2 receptors. Secretion of milk and bile is not affected.

34. ACh stimulates the M3 muscarinic receptor causing constriction of pupil by contracting the circular muscles of iris.( Miosis ) Ciliary muscle contraction results in spasm of accommodation, increased outflow thereby reduction in intraocular pressure. iv. EYE : Ach No effect on topical administration because of poor penetration to the tissues. I.V M 3 Miosis – constriction of pupil

35. II. NICOTINIC ACTION : To elicit nicotinic action, larger doses of Ach are required. Autonomic ganglia : Higher doses of Ach produce dangerous muscarinic effects. Hence, atropine must be given prior to the administration. Higher doses activate both sympathetic and parasympathetic ganglia by N N receptors. Tachycardia Increased BP

36. ii. Skeletal muscles contraction – N M receptors : At high conc . P roduces twitching / contraction Prolonged depolarization Paralysis iii. CNS : I.V Ach does not cause central effects because of poor penetration to Blood Brain Barrier.

37. 2. Bethanecol : Selective muscarinic action on GIT and urinary bladder. Used in : Post-operative urine retention Paralytic ileus

38. ii. Alkaloids : Pilocarpine : It is obtained from the leaves of Pilocarpus plant and other species. It produces muscarinic and nicotinic effects by directly interacting with the receptors. Actions : Applied to the eye, pilocarpine produces rapid miosis and contraction of ciliary muscles. When the eye undergoes this miosis , it experiences a spasm of accommodation. The vision becomes fixed at some particular distance making it impossible to focus. The drug promotes salivation, tears and sweating.

39. Muscarine : It is an alkaloid present in several species of Amanita and Inocybe species. It is responsible for the symptoms of mushroom poisoning. Arecoline : Found in areca nut (Areca catechu) - has both muscarinic and nicotinic actions but is of no therapeutic value.

40. 2. Indirectly acting: Anticholinesterases : Theses are the drugs which inhibit the enzyme cholinesterase. Acetyl choline Choline + Acetic acid Cholinesterase - Mechanism of action : Anticholinesterase resembles ACh , they binds to Acetylcholinesterase enzyme and inactivate them. Thus acetyl choline is not hydrolysed and accumulated.

41. The structure of AChE have an anionic site and esteratic site.

42. Physostigmine : Better penetration to tissues. Crosses BBB. Uses : In glaucoma Used in atropine and tricyclic antidepressant poisoning. Neostigmine : Poorly absorbed from gut. Does not cross BBB Uses : To treat myasthenia gravis Post-operative paralytic ileus Atony of urinary bladder. Pyridostigmine : Similar to neostigmine. Longer acting Used in myasthenia gravis.

43. Edrophonium : Diagnosis of myasthenia gravis. Rivastigmine Donepezil Tacrine Galantamine Alzheimer’s disease

44. Uses of reversible anticholinesterases : 1. As miotic : Physostigmin e causes miosis . It is used in : In glaucoma – physostigmine , pilocarpine Alternatively with mydriatic ( to break adhesions between the iris and lens ) To reverse the effect of mydriatics 2. Myasthenia gravis 3. Poisoning due to anticholinergic drugs. Physostigmine – in atropine poisoning.

45. 4. Post-operative paralytic ileus and urinary retention – Neostigmine 5. Cobra bite – IV edrophonium prevents respiratory paralysis . 6. Alzheimer’s disease - Donepezil, galantamine , rivastigmine , tacrine . 7. Curare poisoning – Neostigmine, pyridostigmine

46. Irreversible Anticholinesterases : Organophosphorous compounds are powerful inhibitors, binds to the enzyme by covalent bonds. They bind only to the esteratic sit e and enzyme is phosphorylated. All organophosphates except echothiophate are highly lipid soluble and hence are absorbed even through intact skin. Uses : Echothiophate eye drops – glaucoma.

47. ORGANOPHOSPHOROUS POISONING : Organophosphate s are used as agricultural and domestic insecticides. Poisoning may be occupational- while spraying insecticides, accidental or suicidal. Symptoms result from muscarinic, nicotinic and central effects. Vomiting A bdominal cramps Diarrhoea Miosis Sweating Weakness Coma Death is due to respiratory paralysis. Tracheobronchial and gastric secretions Bronchospasm Hypotension Muscular twitchings Convulsions Weakness

48. TREATMENT : Atropine Blocks muscarinic receptors Reverses muscarinic effects Life saving Hence drug of choice in OP poisoning. Nicotinic symptoms not reversed. Pralidoxime Binds to cholinesterase organophosphate complex Cholinesterase degrades to Ach Reverses all symptoms

49. i . If poisoning is through skin, remove clothing and wash the skin with soap and water. If consumed orally - gastric lavage. ii. Maintain BP and patent airway. iii. Patient should be in prone position to avoid secretions. iv. Drug of choice – atropine IV 2mg every 10 minutes till pupil dilates. v. Cholinesterase reactivators.

50. ANTICHOLINERGIC DRUGS / PARASYMPATHO LYTICS

51. These are the agents which blocks the effect of acetyl choline on cholinergic receptors. Conventionally, a ntimuscarinic drugs are referred to as anticholinergic drugs. Drugs that block the nicotinic receptors are ganglion blockers or neuromuscular blockers. Anticholinergic drugs N icotinic blockers Ganglion blockers (N N blockers ) Neuromuscular blockers (N M blockers ) M uscarinic blockers

52. CLASSIFICATION I. ANTI-MUSCARINIC AGENTS Natural Alkaloids Atropine Hysocine ( Scopolamine) Semisynthetic derivatives Homatropine Ipratropium bromide Tiotropium bromide Synthetic substitutes Mydriatics Cyclopentolate Tropicamide Antispasmodic- antisecretory Oxyphenonium Dicyclomine Antiparkinsonian Benzhexol Benztropine Vasicoselective Oxybutynin Flavoxate Solifenacin

53. ATROPINE Secretions of exocrine glands Tone Motility Relieves spasm Sphincter tone increases Controls tremor and rigidity of parkinsonism Initial bradycardia with low doses Tachycardia Tone of detrusor muscle decreases. Tone of trigone sphincter increases- urinary retention. Mydriasis Cyclopegia Loss of light reflex Relaxes bronchial smooth muscle but dries up all secretions. CNS GIT CVS Urinary Tract Respiratory system EYE

54. PHARMACOLOGICAL ACTIONS : CVS : Heart : Atropine increases the heart rate by blockade of M2 receptors. Large doses may cause vasodilation and hypotension may occur. BP : Therapeutic dose: no significant reduction in BP. 2. Secretions: It reduced all the secretions except milk. Lacrimal, salivary, nasopharyngeal and tracheobronchial secretions are decreased. Decreased salivation may leads to dry mouth and swallowing. In higher doses, increases the body temperature. Atropine reduces gastric secretions as well.

55. 3. Smooth muscle : GIT: Atropine blocks the effect of Ach on gut reduces the tone, motility and relives spasm. These effects together with decreased secretions may cause constipation. It reduces the tone of intestine- antispasmodic. ii. Biliary tract : Smooth muscles are relaxed, biliary spasm is relieved. iii. Bronchi : Causes bronchodilations. Atropine is used as symptomatic relief in bronchial asthma and COPD patients. iv. Genitourinary tract : Atropine relaxes ureters and the urinary bladder which may cause urinary retention in men having prostatic hypertrophy.

56. 4. Eye : On local application, atropine produces mydriasis by blocking the muscarinic receptors. The ciliary muscle is paralysed resulting in cyclopegia or paralysis of accommodation. 5. CNS : In higher doses, stimulates the CNS resulting in restlessness, disorientation, hallucinations and delirium.

57. PHARMACOKINETICS : Atropine and hyoscine are well-absorbed, cross the BBB and are metabolized in liver. Has t 1/2 of 3-4 hours. Hysocine is absorbed through intact skin hence used as transdermal patch. ADVERSE EFFECT: Blurring of vision Dry mouth Dysphagia Dry skin Fever Constipation Urinary retention Skin rashes.

58. BELLADONA POISONING : Overdose of atropine or belladonna alkaloids. High doses cause : Hyperthermia Palpitations Flushing Psychosis Restlessness Delirium Hallucinations, etc … In toxic doses, CNS stimulation followed by depression with circulatory collapse and respiratory failure.

59. Treatment : If taken orally , gastric lavage. Hyperthermia – controlled by cold water sponging. Respiratory supp ort is needed. Physostigmine ( 1-3mg ) slow IV (repeated after 1-2 hours) can reverse the effect. Diazepam is given to control seizures.

60. USES OF BELLADONA ALKALOIDS : (Atropine ) As antispasmodics : Atropine relieves colic and abdominal pain in diarrhoea and dysentery. ii. As mydriatic and cyclopegic : Diagnostic examination of eye. Therapeutic : To provide rest to the iris . Mydriatics used with miotics to break the adhesion between iris and lens. Eg : homatropine iii. As preanesthetic medication : Atropine is given 30 minutes before to reduce the salivary and respiratory secretions during surgery. Glycopyrrolate is also used.

61. iv. In poisoning : Organophosphorous poisoning Mushroom poisoning v. Bronchial asthma vi. Peptic ulcer vii. Parkinsonsim viii. In CVS : Atropine may be used in bradycardia or partial heart block. Atropine derivatives are given

62. ix : Motion sickness : Hyoscine is given 30 minutes before the journey to prevent travelling sickness. x . Urinary disorders : It is used in urinary disorders like: Overactive bladder Urinary incontinence Nocturnal eneuresis -reduces urinary frequency. xi. Labour : Hyoscine can be given during labour to produce sedation and amnesia.

63. II. NICOTINIC BLOCKERS : i . GANGLION BLOCKERS : Trimethaphan : Short acting drug. Used intravenously to produce hypotension during surgeries. Reduces bleeding Dissecting aneurysm of the aorta. Mecamylamine : Used alongwith ransdermal nicotine in smokers trying to quit smoking. Blocks nicotinic receptors and reduce nicotine craving.

64. NEUROMUSCULAR BLOCKERS SKELETAL MUSCLE RELAXANTS ( PERIPHERAL ) ii.

65. Skeletal muscle relaxants are drugs that reduce the muscle tone either by acting peripherally at the neuromuscular junction or centrally. They reduce the spasticity (abnormal muscle contractions) in variety of neurological conditions and are useful in surgeries.

66. Skeletal muscle relaxants : Drugs acting peripherally At NMJ Directly acting on the muscle Competitive blockers (Non-depolarizing blockers) Depolarizing blockers Others d- Tubocurarine Pancuranium Atracurium Vecuronium Mivacurium – short acting Succinyl choline Decamethonium Dantrolene Botulinum toxin Long-acting Intermediate-acting

67. Directly acting : Competitive blockers / Non-depolarizing blockers : Tubocurarine Binds and blocks N M receptors Competitively blocks the action of acetylcholine Skeletal muscle relaxation N M

68. ACTIONS : Skeletal muscle : On parenteral administration, it cause muscular weakness followed by flaccid paralysis. Recovery occurs in the reverse order. Effect lasts for 30-60 minutes. ii. Autonomic ganglia : In higher doses, block the ganglia and adrenal medulla leading to hypotension. iii. Histamine release : Cause histamine release from mast cells Bronchospasm, increased bronchial and gastric secretions . Also leads to hypotension.

69. P/K : Not absorbed orally. They are given either IM or IV. ADR : Respiratory paralysis and apnoea Hypotension Flushing and bronchospasm

70. Treatment of toxicity : ( Curare poisoning ) Neostigmine and edrophonium reverse the skeletal muscle paralysis. Antihistamines should also be given to counter the effects of histamine. Neostigmine or edrophonium may be used to reverse the N M blockade after surgeries. Antidote- sugammadex – given for overdosage of rocuronium and vecuronium . It chelates and reverses the effects. The complex is excreted in urine.

71. Synthetic competitive blockers : Pancuronium Atracurium Vecuronium Less histamine release. Do not block autonomic ganglia, hence cause less hypotension. Spontaneous recovery. Some are more potent than tubocurarine . Pipecuronium Rapacuronium Rocuronium

72. Cistracurium : It cause less histamine release than that of atracurium . Hence it is preferred now. Mivacurium : Short-acting neuromuscular blocker. Rapidly metabolised by cholinesterases . Causes significant histamine release. Gantacurium : New non-depolarizing NM blocker. Short action.

73. Rapacuronium : Rapid onset of action. Cause severe bronchospasm Rocuronium : Does not cause hypotension, tachycardia. Fast acting . Atracurium : Used in patients with renal impairment as it is degraded by non-enzymatic hydrolysis by Hofmann elimination.

74. DEPOLARISING BLOCKERS : SUCCINYLCHOLINE : Also known as suxamethonium . It is a quaternary ammonium compound with 2 molecules of acetyl choline together. Mechanism of action : Succinylcholine Binds to the nicotinic receptor at motor end plate Leads to membrane depolarization Persistent depolarization Flaccid paralysis

75. Higher doses causes dual block. Phase I block : (Depolarising, rapid onset and potentiated by anticholinesterases) Phase II block : (Non-depolarising, slow onset and reversed by anticholinesterases)

76. Pharmacological actions : Skeletal muscles : On IV, onset of action is rapid . Initially, transient muscular twitchings occur in the chest and abdominal regions, followed by paralysis due to the stimulation of muscle fibres. It is short acting and to be given continuously as an infusion. 2. CVS : Hypotension and bradycardia results from the stimulation of vagal ganglia. Also followed by hypertension and tachycardia due to stimulation of sympathetic ganglia. Higher doses cause- cardiac arrhythmias. Also cause histamine release.

77. Pharmacokinetics : Succinylcholine is rapidly hydrolysed by pseudocholinesterase . Hence are short-acting. Some have abnormal pseudocholinesterase enzyme. In such cases, SCh will not get metabolise and even the usual dose may cause : Apnoea Paralysis Hence artificial ventilation and fresh blood transfusion are needed to supply pseudocholinesterase .

78. Adverse reactions : 1. Post operative muscle pain : Due to the muscle damage to muscle fibres. 2. Hyperkalemia : Due to sudden release of K + . It may result in cardiac arrest. 3. Cardiac arrhythmias : Stimulates the nicotinic receptors in the ganglia and cardiac muscarinic receptors. 4. Malignant hyperthermia : Due to release of intracellular calcium from the sarcoplasmic reticulum. 5. Muscle rigidity or soreness

79. Drug interactions : General anaesthetics increase the action of skeletal muscle relaxants. Anticholinesterases like neostigmine reverse the action of competitive blockers. Aminoglycosides and calcium channel blockers potentiate the action. Succinylcholine and halothane increase hyperthermia.

80. Other drugs : Botulinum toxin : Produced by anaerobic bacteria Clostridium botulinum. It inhibits the release of acetyl choline resulting in flaccid paralysis of skeletal muscles. Useful in the treatment of : Dystonias Sports or writer’s cramps Muscle spasms Tremors Cerebral palsy Rigidity Used to relieve blepharospasm ( abnormal blinking or eyelid movement ) Also used in cosmetic therapy for the removal of facial lines and wrinkles.

81. USES OF PERIPHERALLY ACTING SKELETAL MUSCLE RELAXANTS : Adjuvant to anaesthesia 2. In minor procedures : Used during laryngoscopy, bronchoscopy and in orthopaedic procedures like fractures, dislocations. 3. In electroconvulsive therapy (ECT) : Protect convulsions and trauma during ECT. 4. In spastic disorders Used to overcome the spasm of tetanus and athetosis . 5. In status epilepticus : When convulsion cannot be controlled by anticonvulsants, NMBs are used. 6. In patients on ventilator : To facilitate artificial ventilation. To reduce the resistance on chest wall.

82. II. Directly acting on muscles : Eg : Dantrolene Binds to the ryanodine receptors (RyR1) channel Blocks the opening of channel Inhibits Ca + release from sarcoplasmic reticulum Inhibits muscle contraction Skeletal muscle relaxation

83. ADRENERGIC DRUGS / SYMPATHOMIMETIC DRUGS

84. Adrenergic transmission involves release of 3 catecholamines : Noradrenaline Adrenaline Dopamine

85. 1. Synthesis of catecholamines : They are synthesized from the amino acids phenylanine . 2. Storage of catecholamines : They are stored in synaptic vesicles. 3. Release of catecholamines : The nerve impulse leads to the release of catecholamines and all vesicular contents. 4. Reuptake : The noradrenaline released from the nerve terminal is recaptured. Axonal uptake : By Norepinephrine Transporter (NET) transporter. Vesicular uptake : The membrane of vesicles have Vesicular Monoamine Transporter (VMAT-2). Neurotransmission in adrenergic system involves :

86. 5. Metabolism or degradation : It is metabolised by MAO and COMT enzyme. 6. Binding to the receptors : Adrenergic receptors are : G-protein coupled receptors act by by increasing or decreasing the intracellular production of secondary messengers cAMP or IP3/DAG. In some cases the activated G-protein itself operates K+ or Ca2+ channels, or increases prostaglandin production.

87. Tyrosine DOPA Dopamine Noradrenaline NA NA Tyrosine NET NA Metabolite MAO COMT Metabolite Receptor α β

88. i . Adrenergic receptors α -adrenergic receptors β -adrenergic receptors ii. Dopamine receptors α 1 α 2 β 1 β 2 β 3 Stimulation of α receptors – produce excitatory effects ( except GIT ) Stimulation of β receptors – produce inhibitory effects ( except heart )

89. Adrenergic drugs or sympathomimetic drugs are those drugs which mimic the action of symapathetic agonist.

90. Adrenergic drugs 1. Chemical classification : Based on presence / absence of catechol nucleus 2. Depending on the mode of action 3. Therapeutic or clinical classification Catecholamines Noradrenaline Adrenaline Dopamine Isoprenaline Non- Catecholamines Ephedrine Amphetamine

91. 2. Depending on the mode of action : i . Directly acting : Noradrenaline Adrenaline Dopamine Phenylephrine Salbutamol Xylometazoline ii. Indirectly acting : Amphetamine Tyramine iii. Mixed acting : Ephedrine Pseudoephedrine iv. Catecholamine reuptake inhibitors : Atomoxetine Duloxetine Sibutramine

92. 3. Therapeutic or Clinical i . Vasopressors: Noradrenaline Dopamine Phenylephrine ii. Cardiac stimulants : Adrenaline Dopamine Ephedrine Dopexamine iii. CNS stimulants : Amphetamine Ephedrine iv. Bronchodilators: Adrenaline Isoprenaline Salbutamol Terbutaline Salmeterol v. Nasal decongestants : Ephedrine Pseudoephedrine Phenylephrine vi. Appetite suppressants : Fenfluramine Sibutramine vii. Uterine relaxants : Isoxsuprine Ritodrine Salbutamol Terbutaline

93. Adrenaline : 1. CVS : Heart : Adrenaline β 1 + + Heart rate Force of contraction Cardiac output Conduction velocity ii. Blood vessel : Adrenaline α 1 β 2 Vasoconstriction Vasodilation iii. Other vascular beds : Adrenaline causes renal vasoconstriction Fall in renal blood flow DIRECT ACING :

94. + 2 . Smooth muscles : Bronchi : β 2 Bronchodilator α Pulmonary vasoconstriction ii. Uterus : Non-pregnant – contracts Last month - relaxes iii. Gut : Smooth muscle is relaxed. iv. Bladder : β 3 + + Detrusor is relaxed Trigone is contracted increasing the holding capacity of the bladder. Ad Ad

95. 3 . Eye : Ad + + Mydriasis 4. Metabolic effects : Ad Increases blood sugar level Inhibits insulin release Enhancing breakdown of triglycerides in the adipose tissue 5. Skeletal muscles : Ad NM transmission by action of both α and β receptors, they enhance the amount of Ach released.

96. USES OF ADRENALINE : Anaphylactic shock : The drug of choice. Reverses Hypotension. Laryngeal edema Bronchspasm . Life saving in angioneurotic edema of the larynx. IM route is preferred.

97. 2. Cardiac arrest : Sudden cardiac arrest due to drowning, electrocution are treated with CPR. IV or intracardiac adrenaline is given. Before injecting, ensure that the tip of the needle is in the heart. If the piston is removed, blood should enter the syringe. 3. Control of haemorrhage : Used as topical haemostatic to control bleeding . Bleeding stops due to vasoconstriction. Adrenaline packs are used for bleeding with tooth extractions and epitaxis . (nose bleed )

98. 4. With local anaesthetics : Adrenaline produces vasoconstriction and reduces the rate of absorption of Local anaesthetics. Thus prolongs the duration of action and reduces systemic toxicity. 5. Acute bronchial asthma : Adrenaline produces vasodilation and not preferred as more selective drugs are available. 6. Glaucoma : It decreases intraocular pressure (IOP). But are poorly absorbed and short acting. Dipivefrin - prodrug which gets converted into adrenaline after corneal penetration.

99. Pharmcokinetics : They are rapidly inactivated in the gut and liver, they are not given orally. Adrenaline Adrenaline COMT Metanephrine MAO Vanilyl mandelic acid Excreted in urine COMT Normetanephrine MAO

100. Adverse reactions : Anxiety Palpitations Weakness Tremor Restlessness Throbbing headache Contraindications : In angina pectoris hypertension in patients with β -blockers

101. Noradrenaline : Used in shock to increase BP. Isoprenaline : Cardiac stimulant Smooth muscle relaxant Potent bronchodilator. Used in heart block and shock – cardiac stimulant actions. Used in bronchial asthma

102. Dopamine : Precursor of Noradrenaline. It acts on dopaminergic and adrenergic receptors. Dopamine receptors are of 5 types : D 1 , D 2 , D 3 , D 4 and D 5 . Dopamine Low doses High doses D 1 , D 2 Renal, mesenteric, coronary vasodilation. Increase renal blood flow. Increase GFR. β 1 in heart Force of contraction. Heart rate . α 1 in vascular Vasoconstriction Increase in BP

103. Dopamine does not cross BBB. Hence has no CNS effects. It is given IV. It is metabolized by COMT and MAO. Uses : Treatment of shock. Useful in renal dysfunction.

104. Salbutamol, Terbutaline, Salmeterol, Formoterol : They are selective beta-2 agonist. Uses : Bronchial asthma Premature labour – salbutamol, terbutaline Hyperkalemia – promote uptake of potassium into skeletal muscles.

105. Phenyephrine Methoxamine Mephentermine – Directly acting on alpha1 agonist + releases NA Cause vasoconstriction Increase peripheral vascular resistance Increase in BP Directly acting on alpha1 agonist Phenylephrine : Nasal decomgestant Mydriatic

106. INDIRECT ACTING : Amphetamine : CNS stimulant : Therapeutic doses : Insomnia, alertness, euphoria confusion, headache, etc.. Chronic use : fatigue, depression, suppresses appetite b. Cardiac stimulant : Tachycardia Palpitations Rise in BP Cardiac arrythmias

107. Uses of amphetamine : Narcolepsy : Sleep disorder characterised by uncontrollable desire for sleep. b. Anorexiant : reduce body weight. c. Attention-deficit hyperactivity disorder : children with hyperactivity disorder.

108. MIXED-ACTING : Ephedrine : It is a CNS stimulant Vasoconstrictor Cardiac stimulant Nasal decongestant Bronchodilator Mydriatic Urinary retention

109. Uses : To treat hypotension due to spinal anaesthesia . Used in heart block. Narcolepsy Bronchial asthma ADR : Insomnia Hypertension Tachycardia Difficulty in urination Palpitation Tachyphylaxis occurs on repeated administration.

110. SYMPATHOLYTICS / ADRENERGIC ANTAGONISTS

111. Adrenergic blockers are the drug that binds to the adrenergic receptors and prevent the action of adrenergic drugs. They may block α or β receptors or both.

112. Adrenergic blockers bind to the adrenergic receptors and prevent the action of adrenergic neurotransmitters. They may block α or β receptors or both. α -blockers – B lock the adrenergic responses mediated through α -adrenergic receptors. β -blockers – B lock the adrenergic responses mediated though β -receptors. Sympatholytics α -blockers β - blockers

113. α -blockers Non-selective Selective α 1 Blocks α 1 Vasodilation Decrease BP Reflex Tachycardia Decrease BP, Increase heart rate ( tachycardia ) Blocks α 2 Increase NA release Increase heart rate, cardiac output Blocks α 1 Vasodilation Decrease BP , mild tachycardia α 2 not blocked Decreased NA release No tachycardia

114. ADR of α blockers : Postural hypotension Palpitations Nasal stuffiness Miosis Impaired ejaculation and impotence

115. α -blockers Non-selective ( α 1 and α 2 ) Non-competitive Phenoxybenzamine Competitive Ergot alkaloids Phentolamine Tolazoline Chlorpromazine Selective α 1 blockers Selective α 2 blockers Prazosin Tamsulosin Terazosin Trimazosin Doxazosin Alfuzosin Yohimbine Idazoxan

116. Phenoxybenzamine : Given IV. BP falls within 1-2 hours. The action lasts for 3-4 days. It blocks histamine, 5-HT and cholinergic receptors. Phenoxybenzamine can be given orally but absorption is less. Cannot be IM or SC as it can be painful. Adverse effects : Postural hypotension Palpitation Nasal stuffiness Inhibition of ejaculation NON-SELECTIVE α BLOCKERS:

117. Ergot alkaloids : Competitive antagonist. Short duration Some have direct stimulant effect on smooth muscles cause : C ontraction of uterus Increase BP due to vasoconstriction Phentolamine and Tolazoline : They also block 5-HT receptors. They stimulate gut motility and increase gastric secretion. Hence cause vomiting and diarrhoea.

118. SELECTIVE α 1 BLOCKERS : Prazosin : It is highly potent , highly selective. It is given orally. Well absorbed from GI tract and undergoes first pass metabolism. No significant tachycardia. It inhibits the enzyme phosphodiesterase, the enzyme that degrades cAMP . This results in increase in cAMP and causes vasodilation. ADR : Postural hypotension occurs one hour after the initial dose, hence should be started at low dose at bedtime. Headache Dizziness

119. Terazosin, Doxazosin : Benign Prostatic Hyperplasia -BPH Hypertension Tamsulosin : It relieves the symptoms of BPH without fall in BP. Hence is preferred in BPH. It reduces the resistance to urine flow and in blood vessel no action. It can cause abnormal ejaculation.

120. SELECTIVE α 2 BLOCKERS : Yohimbine : It increases noradrenaline release thereby increasing BP and heart rate. It was used to treat impotence but now sildenafil is preferred.

121. USES OF α BLOCKERS : Hypertension : Prazosin Phenoxybenzamine Pheochromocytoma : It is an adrenal medullary tumour – secretes large amount of catecholamines – results in hypertension. The tumour has to be removed surgically. Phenoxybenzamine and phentolamine are used. iii. Peripheral vascular disease : Raynaud’s phenomenon.

122. iv. Congestive cardiac failure : Prazosin has vasodilator action, hence is preferred. But ACE inhibitors are preferred. v . Benign Prostatic hypertrophy : Enlargement of prostate gland results in straining to pass urine, incomplete voiding, hesitancy, nocturia , etc.. Blockade of alpha receptors decreases the tone of smooth muscles and reduces the resistance to urine outflow. Prazosin, terazosin, alfuzosin are useful in patients who cannot be operated. Tamsulosin is preferred because of its selectivity on α 1A receptors ( only relieve symptoms of BPH and no hypotension ) vi. Erectile dysfunction : A combination of phentolamine with papaverine is a good alternative to sildenafil.

123. β -blockers First generation Non-selective Second generation Cardioselective - β 1 Third generation Non-selective Carvedilol Labetalol Carteolol Bucindalol β 1 selective Celiprolol Nebivolol Propranolol Nadolol Timolol Sotalol Pindolol Penbutalol Oxprenolol Metoprolol Atenolol Bisoprolol Esmolol Acebutolol Betaxolol

124. Pharmacological actions of beta blockers : i . CVS : Heart : Decreases heart rate, force of contraction and cardiac outpu t. Also improve exercise tolerance in angina patients. High doses – cause depression of heart. b. Blood vessels : Reduce BP. On long term use, reduce Total Peripheral Resistance, reduce renin release, reduce cardiac output and thus BP.

125. ii. Respiratory tract : Blockade of beta-2 receptors in bronchial smooth muscle Increase in airway resistance Acute attack in asthmatics iii . Eye : Reduce intraocular pressure (IOP) Decreased secretion of aqueous humour iv. Metabolic : Block lipolysis and glycogenolysis induced by sympathetic stimulation . Hence non-selective beta blockers helps in recovery from hypoglycaemia in diabetics.

126. v. Other effects : Many in higher doses block sodium channels and have local anaesthetic effect. This is not used as this requires higher doses and has irritant property. Eg : Propranolol

127. Pharmacokinetics : They are well-absorbed on oral administration. Some may undergo first pass metabolism. Food improves the bioavailability of propranolol. ADR : Bradycardia : Patients with AV conduction defects may develop arrhythmias and heart block with beta-blockers. 2. CCF : In CCF, sympathetic activity supports the heart. Beta blockers eliminate this effect and may precipitate CCF and acute pulmonary edema .

128. 3. Cold extremities : Seen in patients with peripheral vascular resistance. 4. Acute asthmatic attack : They are contraindicated in asthmatic patients. 5. Fatigue : Decreased blood flow to the muscles during exercise and reduced cardiac output. 6. CNS : Insomnia, depression, hallucination, dizziness. 7. Topical : Timolol eye drops may cause burning and dryness of the eyes. 8. Sudden withdrawal after prololnged use may leads to rebound hypertension. This is due to upregulation of β - receptors.

129. 9. Metabolic effects : Weakness, reduced exercise capacity. Carbohydrate tolerance may be impaired in diabetics. DRUG INTERACTIONS : Propranolol + Insulin : When diabetics receive propranolol, it masks tachycardia caused by hypoglycaemia. ii. Propranolol + Verapamil : Both cause myocardial depression, profound depression may result. iii. β-blockers + catecholamines : Intense vasoconstriction – receptor upregulation.

130. iv. β-blockers + digitalis, verapamil : Depression of AV conduction. May cause cardiac arrest. v. Enzyme inducers : Rifamipicin increase the metabolism and reduce the plasma levels of propranolol. vi. NSAIDs : Oppose the antihypertensive effect of β-blockers.

131. Propranolol : Highly lipid soluble- crosses BBB . Nadolol : Long acting β-blockers. Used in: Hypertension Angina Migraine Oesophageal varices Timolol : Non- selectiv , short-acting. Used in glaucoma- eye drops. Used orally in : Hypertension Angina Myocardial infarction

132. Pindolol , Oxprenolol and penbutalol : Non-selective Has weak intrinsic sympathomimetic activity. Advantages : Milder bradycardia Milder myocardiac depression Better tolerated in asthmatics Disadvantages : Not suitable for prophylaxis of migraine and myocardial infarction.

133. Second generation- cardioselective blockers : Atenolol: Selective β 1 blocker. Longer acting- given once daily. Less lipid soluble- does not cross BBB. Commonly used in hypertension and angina. Metoprolol : Selective β 1 blocker . Given twice daily. Undergoes first pass metabolism. Used in hypertension and angina pectoris.

134. Esmolol : Selective β 1 blocker. Rapid acting Used IV Safe in critically ill patients Useful in emergencies when immediate action is required. Used in arrhythmias, perioperative hypertension. Acebutalol : Used in hypertension and arrhythmias.

135. Betaxolol : Used in Glaucoma Hypertension Angina pectoris

136. Third generation β blockers : These have additional vasodilatory properties. Nebivolol : Selective β -1 blocker. Causes vasodilation through nitric oxide production. No myocardial depression. Reduce BP by reducing vascular resistance. Labetalol: Useful in pheochromocytoma hypertension in elderly gestational hypertension

137. USES OF β -BLOCKERS : Hypertension : Useful in the treatment of mild to moderate hypertension. They are suitable for combination with drugs that produce tachycardia. ii. Angina pectoris: Useful in prophylaxis of angina. They reduce both cardiac work and oxygen demand. iii. Cardiac arrhythmia : Useful in both ventricular and supraventricular arrhythmias. iv. Myocardial infarction : IV beta-blockers in acute MI may limit the size of the infarct, also prevent ventricular arrhythmias. In patients, who have recovered from MI need long term treatment which prolongs survival.

138. v . Congestive cardiac failure : Recent studies shows that they reduce the risk of sudden death and prolong survival on long term use. vi. Obstructive cardiomyopathy vii. Pheochromocytoma : Propranolol is given before surgery to control hypertension. viii. Dissecting aneurysm of the aorta : Eg : Propranolol

139. ix. Thyrotoxicosis : Propranolol controls symptoms like palpitations, tremors. x. Glaucoma : Timolol used topically as the first line treatment in glaucoma. xi. Prophylaxis of migraine : Reduces the frequency and severity of migraine . xii. Anxiety : Propranolol prevents acute panic symptoms seen in public speaking, examination and other anxiety provoking situations. xiii. Cirrhosis : Reduce portal vein pressure.

140. xiv. Esophageal varices : In patients who have bleeding varices, a combination of nadolol and isosorbide mononitrate has been given. xv. Alcohol withdrawal : By reducing central sympathetic overactivity .

141. CONTRAINDICATIONS: Beta blockers prevent the increase in heart rate and cardiac output. These may be dangerous in patients with CCF. Should be avoided in patients with tachycardia. Contraindicated in patients with heart block because they depress AV conduction. Must be avoided in patients with asthma and COPD. Should be avoided in diabetic patient because they mask the initial symptoms of hypoglycaemia.

142. LOCAL ANAESTHETICS

143. Local anaesthetics are drugs that blocks the nerve conduction and cause reversible loss of all sensation in the part supplied by the nerve. It is the loss of sensation without the loss of consciousness.

144. Local anaesthetics diffuse through the cell membrane B ind to the voltage-sensitive sodium channels from the inner side of the cell membrane. They prevent the increase in permeability of sodium and gradually raise the threshold for excitation. Prevent entry of sodium into the neuron thereby decreasing the rate of depolarization. Prevent generation of action potential No generation and conduction of impulses to CNS Local anaesthesia

145. CLASSIFICATION : LOCAL ANAESTHETICS 1. According to clinical use 2. According to structure Esters : Cocaine Procaine Chlorprocaine Benzocaine Tetracaine b. Amides : Lignocaine Mepivacaine Bupivacaine Prilocaine Ropivacaine Surface anaesthetics Cocaine Lignocaine Tetracaine Benzocaine Oxethazaine Injectable anaesthetics Short acting Procaine Chlorprocaine Intermediate acting Lignocaine Mepivacaine Prilocaine Long acting Tetracaine Dibucaine Bupivacaine

146. Pharmacological actions : Depending on the concentration, any Local anaesthetics can produce systemic effects. 1. CNS : It depress the cortical inhibitory pathway. This loss of inhibition may leads to restlessness, tremors and may produce convulsions. This may also lead to generalised CNS depression and death may result from respiratory failure. 2. CVS : The primary site of action is myocardium. Lignocaine decreases excitability, conduction rate and force of contraction. 3. Smooth muscles : They depress contractions in the bowel. They also relax vascular and bronchial smooth muscles.

147. 4. Blood vessels : Cause hypotension which is due to sympathetic blockade. They also cause arteriolar dilatation. Cocaine – rise in BP due to sympathetic stimulation. Procaine – short acting Hence procainamide is used as antiarrhythmic . Bupivacaine is more cardiotoxic than other LAs. 5. Local actions : It bring reversible loss of sensation depending on the site of administration.

148. PHARMACOKINETICS : Local anaesthetics are rapidly absorbed from the mucous membranes and abraded skin. Rate of absorption is dependent on the vascularity of area. Vasoconstriction decreases the absorption. Toxicity depends upon the balance between absorption and metabolism. If it gets metabolised as it gets absorbed, then toxicity is less. Ester-linked LA – hydrolysed by pseudocholinesterase Amide-linked LA – metabolised by microsomal enzymes, hence are not effective orally. They undergo first pass metabolism.

149. ADVERSE EFFECTS : Hypersensitivity reactions : Include skin rashes, dermatitis, asthma. 2. CNS : Dizziness Sedation A uditory and visual disturbances M ental confusions Disorientation Higher doses induce anxiety, convulsions and respiratory failure. 3. CVS: Blockade of sodium channels in the myocardium results in myocardial depression with decrease in force of contraction, bradycardia. Rarely, cardiac arrest may occur.

150. Lignocaine is used in arrhythmias. LA s also cause vasodilation resulting in hypotension. But cocaine causes vasoconstriction as it blocks the reuptake of noradrenaline in the adrenergic nerve endings. Bupivacaine – most cardiotoxic . Lipid rescue : IV infusion of lipid is given to overcome this. Mechanism is not clear. But may be because the lipophilic compound extracts the lipophilic drug from the tissues and could restore energy to the myocardium. 4. Local irritation : E g :Bupivacaine. Wound healing may be delayed.

151. Lignocaine : Widely used. Fast and long acting. Maximum effect is seen 2-5minutes and lasts for 30-45 minutes. Side effect : Drowsiness, mental clouding. It is a good corneal anaesthetic but not generally preferred because it causes local irritation. Bupivacaine : More potent and longer acting than lignocaine. Cause more cardiotoxicity than others with or without adrenaline. Levobupivacaine : Less cardiotoxic and neurotoxic than bupivacaine.

152. Ropivacaine : Less cardiotoxic than bupivacaine . Chlorprocaine : Potency is twice as that of procaine. Toxicity is lower because of rapid metabolism. Etidocaine : Analgesic action lasts 2-3 times longer. Used for epidural and all types of infiltration&regional anaesthesia. Mepivacaine : Action is more rapid and more prolonged action than lignocaine.

153. Prilocaine : Intermediate onset of action. Duration of action is longer and less toxic to CNS due to large volume of distribution. Cocaine : It produces euphoria. It is a drug of dependence and abuse. It was used for ocular anaesthesia. But it causes constriction of conjunctival vessels, clouding and corneal sloughing, it is not used. It is used topically for anaesthesia of upper respiratory tract. It act as vasoconstrictor and local anaesthetic simultaneously .

154. Procaine : Was used widely once. It is hydrolysed to PABA which interferes with action of sulphonamides. Rapidly absorbed by parenteral administration. Ineffective when applied topically . Tetracaine : It is a PABA derivative. It is 10 times more toxic and more active than procaine. Used as eye drops, ointments, creams. Injection is used for spinal anaesthesia.

155. Local anaesthetics used on eye : Benoxinate : Produce corneal anaesthesia within 60 seconds –tonometry. Less irritation. No mydriasis. Used as eye drops. Proparacaine : Surface anaesthetic on eye. Tetracaine : Eye drops.

156. Local anaesthetics used on the skin and mucous membrane : Dibucaine Dyclonine Pramoxine These drugs are effective when used topically in anal, genital pruritus, poison ivy rashes, dermatitis. Dibucaine is the most potent, most toxic and longest acting. Available as cream and ointment. Eg : Lignocaine gel – anal fissures.

157. Poorly soluble anaesthetics : Slowly absorbed. They can be applied to wound directly and ulcerated surfaces as they produce sustained anaesthetic effect. Eg : Benzocaine Butamben

158. TECHNIQUES OF LOCAL ANAESTHESIA : Surface anaesthesia : Local anaesthetic is applied on abraded skin and mucous membrane of the nose, mouth, eyes, throat, upper respiratory tract, ulcers, urethra, oesophagus, burns, fissures. Eg : Tetracaine 2% Lignocaine 2%-10% Surface anaesthetics are available as solution, ointment, gel, cream, spray, lozenges, etc.. Addition of adrenaline does not prolong the duration of action because of poor penetration. Topical anaesthetics are used in many diagnostic procedures like tonometry in eye and during endoscopies.

159. 2. Infiltration anaesthesia : It is directly into the tissues to be operated, it blocks sensory nerve endings. Addition of adrenaline prolongs the duration of anaesthesia. Suitable only for small areas. It can be used for : Drainage of an abscess Excision of small swelling Suturing of cut wounds Episiotomy. Disadvantage : Requirement of large amounts of drugs to anaesthetize small area.

160. 3. Conduction block : Field block anaesthesia : It is achieved by injecting LA subcutaneously which anaesthetizes the area distal to the injection. It is used in case of minor procedures of scalp, abdominal wall, upper and lower extremities in which small dose produces larger area of anaesthesia. ii. Nerve block anaesthesia : It is injected very close to or around the peripheral nerve or nerve plexuses. It produces larger areas of anaesthesia than field block.

161. 4. Spinal anaesthesia : It is the most popular form. It is injected into the subarachnoid space to anaesthetize spinal roots. The level of anaesthesia is influenced by : Site of injection Amount of fluid injected Force of injection Specific gravity of the drug solution Position of the patient LAs used for spinal anaesthesia are : Lignocaine, tetracaine , bupivacaine, etc … Addition of adrenaline increases the duration of action.

162. Uses of spinal anaesthesia : Used for surgical procedures below umbilicus. That is : Lower limb surgery Caesarean section O bstetric procedures Prostatectomy Appendicectomy , etc … Advantages : No loss of consciousness Good muscle relaxation Good analgesia Patients with cardiac, pulmonary and renal disease tolerate spinal anaesthesia better than general anaesthesia.

163. Complications : Headache due to leakage of CSF. Hypotension Respiratory paralysis Septic meningitis Postoperative urinary retention Contraindications : Should not be used in young children Vertebral abnormalities Hypotension Shock

164. 5. Epidural anaesthesia : It is injected into the epidural space ( thoracic/lumbar canal). Eg : Lignocaine Bupivacaine It is safer, but technique is more difficult. It requires larger amount of drug. It is used in obstetrics during labour. It acts by injecting the anaesthetic into epidural space Stop pain signals from travelling from your spine to your brain.

165. Uses : To provide pain relief during labor or child birth. To manage certain causes of back pain and chronic pain. Delivery of epidural anaesthesia may be as : Single injection Epidural with catheter Epidural with patient controlled analgesia Advantages : Pain relief either short-term or long-term Reduced need of general anaesthesia Reduced opioid use Improved breathing Control movements of body. Disadvantages : Sedating Low blood pressure Headache Temporary nerve damage Inadequate pain relief Decrease in respiration

166. 6. Intravenous regional anaesthesia /Bier’s block : It is used to anaesthetize the upper limb. Eg : Lignocaine Prilocaine Drug interactions : Lignocaine * Propranolol : Propranolol reduce hepatic blood flow , impairs the clearance of lignocai ne which result in toxicity. Procaine * Sulphonamides : Procaine is hydrolysed to PABA – reduces the effect of sulphonamides.