Overview “muscarinic receptor agonists” cholinergic agonists are drugs that act on acetylcholine receptors, thus causing excitation of the parasympathetic autonomic nervous system there are 2 types of acetylcholine receptors 1) NICOTINIC RECEPTORS – are receptor-mediated ion channels – 3 types RECEPTOR TYPE MUSCLE TYPE GANGLION TYPE LOCATION – neuromuscular junction – sympathetic autonomic ganglia – parasympathetic autonomic ganglia – CNS.
CNS TYPE – agonists of nicotinic receptors are discussed later (“depolarizing neuromuscular blocking agents”, see 16) 2) MUSCARINIC RECEPTORS – are g-protein coupled receptors – 3 types RECEPTOR TYPE M1 LOCATION – CNS – exocrine glands (gastric. bronchial-, salivary-, lacrimal-, and sweat glands) – CNS – GI tract smooth muscle – atria of the heart – exocrine glands – GI tract smooth muscle – 37 – M2 M3
– genito-urinary tract smooth muscle – bronchial smooth muscle – smooth muscle of the eye – endothelium of blood vessels General Effects 8 types ORGAN CNS EFFECT – increased skeletal muscle tension – tremor – hypothermia – improved cognition (improved learning) – decreased heart rate (“bradycardia”) – decreased force of contraction – decreased blood pressure (due to vasodilation) – myosis (due to contraction of the pupilary sphincter) – accomodation to near vision (due to contraction of the ciliary muscle) – decreased intraoccular pressure (due to opening of the schlemm canal).
– GI tract emptying (due to increased peristalsis) – urinary bladder emptying (due to contraction of the detrusor muscle) – bronchoconstriction (due to contraction of bronchial smooth muscle) – increased gastric secretion – increased bronchial secretion – increased salivation – increased lacrimation – increased sweating HEART BLOOD VESSELS EYE GI TRACT GENITO-URINARY TRACT BRONCHI EXOCRINE GLANDS Relevant Drugs 3 types – 38 – DRUG NAME ACETYLCHOLINE.
DESCRIPTION General information – acetylcholine itself – non-selective acetylcholine receptor agonist (acts on both nicotinic- and muscarinic receptors) – not used clinically General information – selective muscarinic receptor agonist (acts only on muscarinic receptors) – selective to the eye and exocrine glands Clinical uses – treatment of glaucoma (by reduction of intraoccular pressure) PILOCARPINE MUSCARINE General information – same as pilocarpine (see above) – found naturally in toadstool – the causative agent of mushroom poisoning – not used clinically CHOLINESTERASE INHIBITORS.
Overview there are 2 types of cholinesterase enzymes ENZYME NAME PLASMACHOLINESTERASE DESCRIPTION – “butyrylcholinesterase” – located in the blood – responsible for the breakdown of acetylcholine in the blood stream – not discussed further here – located in the cholinergic synapses – responsible for the breakdown of acetylcholine in the cholinergic synapses ACETYLCHOLINESTERASE – cholinesterase inhibitors (“anticholinesterases”).
Inhibit the degradation of acetylcholine by acetylcholinesterase at the nicotinic cholinergic synapses, thus prolonging it’s effect – 39 – General Effects 2 types ORGAN PARASYMPATHETIC POSTGANGLIONIC SYNAPSES EFFECT – increased parasympathetic effects (see above) – large doses may lead to decreased parasympathetic effects (due to depolarization block in autonomic ganglia caused by continuous acetylcholine action) – increased skeletal muscle tension – large doses may lead to paralysis (depolarization block).
NEUROMUSCULAR JUNCTION Relevant Drugs 2 categories 1) REVERSIBLE – 3 types DRUG NAME NEOSTIGMINE DESCRIPTION Clinical uses – treatment of myasthenia gravis Clinical uses – same as neostigmine (see above) General information – may cross the blood-brain barrier Clinical uses – treatment of glaucoma Side effects – coma and respiratory failure (due to initial CNS excitation followed by CNS depression)
PYRIDOSTIGMINE PHYSIOSTIGMINE 2) IRREVERSIBLE – 2 types DRUG NAME DESCRIPTION – 40 – ECOTHIOPATE Clinical uses – treatment of glaucoma Side effects – peripheral nerve neurotoxicity (due to demyelination and following slowly developing weakness and sensory loss) PARATHION General information – an insecticide – causes poisoning – not used clinically Side effects – same as ecothopiate (see above)
– 41 – 15. MUSCARINIC RECEPTOR ANTAGONISTS Overview muscarinic receptor antagonists are competitive antagonists to acetylcholine on cholinergic receptors, thus blocking the effect of the parasympathetic nervous system they elicit effects opposite to those of muscarinic agonists (see 14, except no vasoconstriction due to no parsympathetic innervation of vascular smooth muscle (vaodilation is due to circulating acetylcholine)) Relevant Drugs 2 categories 1).
TERTIARY AMINES – are lipophilic – , thus may cross the blood-brain barrier – 3 types DRUG NAME ATROPINE DESCRIPTION General information – found naturally in nightshade (“atropa belladonna”) Clinical uses – treatment of irreversible cholinesterase inhibitor poisoning (see 14) – treatment of bradycardia – treatment of spasms of the GI tract – treatment of parkinson’s disease (see 46) – supplement to anaesthesia (by reduced exocrine gland secretions).
Side effects – midriasis (due to relaxation of the pupillary sphincter) – cycloplegia (due to relaxation of the ciliary muscle leading to inhibition of accomodation) – urine retention (due to relaxation of the detrusor muscle) – dry mouth (due to inhibition of salivation) – dry skin (due to inhibition of sweating) – 42 – – restlessness, anxiety and/or disorientation (due to CNS stimulation) SCOPOLAMINE General information – “hyosciene” – found naturally in thorn apple (“datura stramonium”).
Clinical uses – same as atrophine (see above) – treatment of motion sickness (“antiemetic effect”, see 37) Side effects – sedation (due to CNS depression) PIRENZEPINE General information – selective to GI tract smooth muscle Clinical uses – treatment of peptic ulcer (by decreased gastric secretion, see 37).
2) QUARTERNARY AMINES – are hydrophilic – , thus may not cross the blood-brain barrier – 2 types DRUG NAME ATROPINE METHONITRATE DESCRIPTION Clinical uses – treatment of spasms of the GI tract Clinical uses – treatment of asthma and bronchitis (by bronchodilation and reduced bronchial secretions) IPRATROPIUM – 43 – 16. NEUROMUSCULAR BLOCKING AGENTS.
DRUGS ACTING ON AUTONOMIC GANGLIA NEUROMUSCULAR BLOCKING AGENTS Overview neuromuscular blocking agents are drugs that competitively inhibit nicotinic receptors at the neuromuscular junction, thus causing flaccid muscle paralysis (however, they do not block the awareness of pain (! )) Relevant Drugs.
2 categories 1) NON-DEPOLARIZING – are nicotinic receptor antagonists – 4 types (listed from slowest onset and longest duration to fastest onset and shortest duration) DRUG NAME TUBOCURARINE DESCRIPTION General information – onset: 5-10 minutes, duration: 1-2 hours – found naturally in curare (“south american indian arrow poison”).
Medical uses – supplement to anaesthesia (by skeletal muscle paralysis) Side effects – hypotension (due to inhibition of ganglion type nicotinic receptors) – bronchoconstriction (due to histamine release from mast cells due to its strongly basic character) GALLAMINE Medical uses – same as tubocurarine (see above) Side effects – tachycardia (inhibition of M2 muscarinic receptors due to muscarinic antagonist activity).
ATRACURIUM Medical uses – same as tubocurarine (see above) – 44 – MIVACURIUM General information – onset: 2 minutes, duration: 10 minutes Medical uses – same as tubocurarine (see above) 2) DEPOLARIZING – are nicotinic receptor agonists (!) – mechanism of action A) bind to the active site, thus triggering an initial depolarization leading to initiation of an action potential and following muscle twitches B) however, they remain bound to the receptor due to inability of acetylcholinesterase to degrade them, thus causing inability of the striated muscle fibers to repolarize and trigger a new action potential 1 type DRUG NAME SUXAMETHONIUM DESCRIPTION.
General information – onset: immediately, duration: 10 minutes Medical uses – supplement to anaesthesia (by skeletal muscle paralysis) Side effects – bradycardia (muscarinic agonist effect) – cardiac dysrythmias (due to muscle denervation leading to nicotinic receptor spread outside the neuromuscular junction, continuous depolarization, continously opened k+ channels, and continuous leakage of k+ out of the skeletal muscle fibers) – increased intraoccular pressure (due to simultaneous contraction of extraoccular muscles) DRUGS ACTING ON AUTONOMIC GANGLIA Overview – 45 – –
drugs acting on autonomic ganglia act both on the sympathetic- and parasympathetic autonomic nervous system, thus giving very complex effects in the body (not discussed further here) Relevant Drugs 2 categories 1) GANGLION STIMULANTS – are ganglion-type nicotinic receptor agonists – 2 types DRUG NAME NICOTINE DESCRIPTION General information – causes initial ganglial stimulation, followed by ganglial block due to continuous depolarization (“depolarization block”) – also stimulates sensory- and noradrenergic nerve terminals of the CNS (not discussed here) – not used clinically – see 48 General information – causes ganglial stimulation – not used clinically LOBELINE.
2) GANGLION BLOCKERS – are ganglion-type nicotinic receptor antagonists – 1 type DRUG NAME TRIMETAPHAN DESCRIPTION Clinical uses – emergency treatment of malignant hypertension (by vasodilation) – supplement to anaesthesia (minimizes bleeding due to vasodilation) – 46 – 17. AGENTS ACTING ON THE BIOSYNTHESIS, STORAGE, RELEASE AND ELIMINATION OF CATECHOLAMINES Overview see 18 there are 2 types of catecholamines.
NEURONTRANSMITTER NAME NORADRENALINE DESCRIPTION – “norepinephrine” – secreted by autonomic sympathetic nerve terminals (and to a smaller extent by the n-cells of the adrenal medulla) – “epinephrine” – secreted by the a-cells of the adrenal medulla ADRENALINE BIOSYNTHESIS Overview biosynthesis of catecholamines is done in 3 (4) steps TYROSINE tyrosine hydroxylase DOPA DOPA decarboxylase.
DOPAMINE dopamine beta-hydroxylase NORADRENALINE phenylethanolamide N-methyltransferase (“PNMT”) ADRENALINE , thus there are 3 (4) enzymes involved in catecholamine biosynthesis ENZYME NAME TYROSINE HYDROXYLASE DESCRIPTION – the rate-limiting step – located in the cytoplasm of sympathetic postsynaptic neurons – 47 – DOPA DECARBOXYLASE – general enzyme located in the cytoplasm of most cells – catalyses decarboxylation of aromatic amino acids – located in the synaptic vesicles of postsynaptic sympathetic nerve terminals – located in the a-cells of the adrenal medulla DOPAMINE BETA-HYDROXYLASE PNMT Relevant Drugs.
3 types DRUG NAME ALPHA-METHYLTYROSINE DESCRIPTION General information – a tyrosine hydroxylase inhibitor – inhibits tyrosine hydroxylase, thus causing inhibition of catecholamine synthesis Clinical use – treatment of pheochromocytoma (a catecholamineproducing adrenal medullary tumor) Side effects – hypotension (due to vasodilation) – drowsiness.
METHYLDOPA General information – a central DOPA decarboxylase inhibitor (may cross the blood-brain barrier) – alternate substrate for DOPA decarboxylase , thus displacing DOPA from the active site of DOPA decarboxylase and following inhibition of catecholamine synthesis – is converted by DOPA decarboxylase to methylnoradrenalin (a selective alpha-2 agonist, see 19) Clinical use – treatment of hypertension during pregnancy (by inhibition of the sympathetic nuclei of the brainstem)
Side effects – same as alpha-methyltyrosine (see above) – 48 — impotency – hypersensitivity reactions CARBIDOPA General information – a peripheral DOPA decarboxylase inhibitor (may not pass the blood-brain barrier) Clinical use – treatment of parkinson’s disease (by inhibition of the use of DOPA for catecholamine synthesis in peripheral neurons, thus freeing it for restorement of the dopaminergic pathways of the brain, see 46)
STORAGE Overview noradrenaline is stored in synaptic vesicles of noradrenergic nerve terminals as a complex with 4 ATP molecules both initial uptake of dopamine for synthesis of noradrenaline and re-uptake of noradrenaline for re-use is done by a vesicular monoamine transporter (“VMAT”) located in the synaptic vesicular membrane Relevant Drugs
1 type DRUG NAME RESERPINE DESCRIPTION General information – found naturally in rauwolfia – blocks VMAT, thus depleting noradrenaline stores – may cross the blood-brain barrier RELEASE Overview noradrenaline is released into the synaptic cleft by fusion of the synaptic vesicles with the neuron cell membrane upon arrival of a nerve impulse Relevant Drugs 3 categories – 49 – 1).
PRESYNAPTIC NORADRENERGIC NEURON-BLOCKING DRUGS – blocks noradrenaline release upon arrival of a nerve impulse by interaction with presynaptic receptors in the noradrenergic nerve terminals – 7 types DRUG NAME ADRENALINE/NORADRENALINE ACETYLCHOLINE HISTAMINE ENKEPHALIN DOPAMINE SEROTONIN PROSTAGLANDIN E – “5-Hydroxytryptamine, “5-HT” – “PGE” DESCRIPTION.
2) NORADRENERGIC NEURON-BLOCKING DRUGS – blocks noradrenaline release upon the arrival of a nerve impulse by local anaesthetic action (see 22) – 1 type DRUG NAME GUANETHIDINE DESCRIPTION 3).
INDIRECTLY-ACTING SYMPATHOMIMETIC DRUGS – evokes noradrenaline release independently from the arrival of a nerve impulse – mechanism A) enters the postsynaptic sympathetic nerve terminal by the way of uptake 1 (see below) located in the neuron cell membrane in exchange for cytoplasmic noradrenaline into the synaptic cleft B) enters the synaptic vesicles by the way of VMAT in exchange for vesicular noradrenaline into the cytoplasm 3 types DRUG NAME AMPHETAMINE – 50 DESCRIPTION General information – may cross the blood-brain barrier – also causes release of dopamine and serotonin in the CNS – not used clinically – see 48 EPHEDRINE General information – an amphetamine analogue (see above).
Clinical uses – treatment of nasal congestion (by vasoconstriction) Side effects – same as amphetamine, though less pronounced (see above) TYRAMINE General information – found naturally in mature cheese and wine – usually metabolized by monoamine oxidase (“MAO”, see below) in the enterocytes – may reach the blood stream upon MAO inhibition ELIMINATION Overview elimination of catecholamines may be done by 2 mechanisms MECHANISM REUPTAKE DEGRADATION DESCRIPTION REUPTAKE Overview most important form of ELIMINATION.
– 51 – – reuptake of catecholamines is done by 2 types of membrane transporters TRANSPORTER NAME UPTAKE 1 DESCRIPTION – located in the neuronal cell membrane – has a high affinity to catecholamines – transports only noradrenaline – located in the cell membrane of the target tissues – has a low affinity to catecholamines – transports both adrenaline and noradrenaline UPTAKE 2 Relevant Drugs 2 types DRUG NAME TRICYCLIC ANTIDEPRESSANTS DESCRIPTION General information – blocks uptake 1 – also has an atropine-like effect (see 15) – see 42 General information – blocks uptake 1 – may cross the blood-brain barrier – see 48 COCAINE DEGRADATION.
Overview degradation of catecholamines is done by enzymes located in the cytoplasm of most cells degradation differs in the periphery and in the CNS 1) PERIPHERY – 3 steps NORADRENALINE alimentary monoamine oxidase (“MAO-A”) NORADRENALINE ALDEHYDE aldehyde dehydrogenase DIHYDROXYMANDELIC ACID (“DOMA”) – 52 – cathecol-O-methyl transferase (“COMT”) VANYLYLMANDELIC ACID (“VMA”) 2) CNS – 3 steps NORADRENALINE brain monoamine oxidase (“MAO-B”) NORADRENALINE ALDEHYDE aldehyde reductase.
DIHYDROXYPHENYLGLYCOL (“DOPEG”) cathecol-O-methyl transferase (“COMT”) METOXY-HYDROXYPHENYLGLYCOL (“MOPEG”) , thus there are 2 (3) important enzymes involved in catecholamine degradation ENZYME NAME MAO-A MAO-B COMT DESCRIPTION – located in the periphery – located in the CNS – see 42 – 53 – 18. PHARMACOLOGICAL EFFECTS OF CATECHOLAMINES 19.
ADRENERGIC RECEPTOR AGONISTS Overview catecholamines are neurotransmitters that work on adrenergic receptors, thus causing excitation of the sympathetic autonomic nervous system activation of adrenergic receptors usually elicits effects opposite to those of parasympathetic muscarinic receptor activation (see 14) there are 2 types of adrenergic receptors 1) ALPHA RECEPTORS – 2 types.
RECEPTOR TYPE ALPHA-1 EFFECT – increased blood pressure (due to vasoconstriction) – midriasis (due to contraction of the radial fibers of the pupilary sphincter) – loss of accommodation (due to contraction of the radial fibers of the ciliary muscle) – decreased GI tract emptying (due to decreased peristalsis) – decreased urinary bladder emptying (due to contraction of the urinary bladder sphincter) – ejaculation (due to contraction of the seminal tract) – cardiac- and prostate hypertrophy (due to increased smooth muscle proliferation) – hyperglycemia (due to increased glycogenolysis in the liver).
ALPHA-2 – decreased blood pressure (due to inhibition of the sympathetic vasomotor center in the brain stem and of the sympathetic- and parasympathetic ganglia, and following vasodilation) – decreased GI tract emptying – thrombosis (due to increased platelet aggregation) – hyperglycemia (due to decreased insulin secretion by the pancreas).
2) BETA RECEPTORS – 3 types RECEPTOR TYPE BETA-1 EFFECT – increased heart rate (“tachycardia”) – increased force of heart contraction – 54 – BETA-2 – decreased blood pressure (due to vasodilation) – decreased GI tract emptying – decreased urinary bladder emptying (due to relaxation of the urinary bladder detrusor muscle) – distension of the uterus during pregnancy (due to relaxation of uterine smooth muscle) – bronchodilation (due to relaxation of bronchial smooth muscle ) – bronchodilation (due to decreased histamine release from mast cells in the lungs) – increased skeletal muscle contraction strength.
(due to skeletal muscle hypertrophy) – increased skeletal muscle contraction speed (due to increased tension of fast-twitch skeletal muscle fibers) – hyperglycemia (due to increased glycogenolysis in the liver) – decreased proliferation, activity, and cytokine release of lymphocytes (decreased immune defense system) BETA-3 – increased thermogenesis from skeletal muscle and adipose tissue (due to uncoupling of oxidative phosphorylation) – decreased fat stores (due to increased beta-oxidation).
General Effects see above Relevant Drugs “directly acting sympathomimmetic drugs” 5 categories 1) NON-SELECTIVE AGONISTS – act on both alpha- and beta receptors – 2 types DRUG NAME NORADRENALINE DESCRIPTION General information – not used clinically Clinical uses – supplement to local anaesthesia (by vasoconstriction and following increased – 55 – ADRENALINE duration of action) – treatment of anaphylactic shock (due to vasoconstriction) – treatment of cardiac arrest (by increased heart rate and increased force of contraction) – treatment of asthma (by bronchodilation).
Side effects – hypertension (due to vasoconstriction) – reflex bradycardia (due to activation of vascular baroreceptors as a response to hypertension) – tachycardia (due to increased heart rate) – ventricular dysrythmias (due to increased heart rate) 2) ALPHA-1 AGONISTS – 2 types DRUG NAME PHENYLEPHRINE DESCRIPTION Clinical uses – treatment of hypotension (by vasoconstriction) – treatment of rhinitis (by vasoconstriction and following decreased nasal congestion) Side effects – hypertension – reflex bradycardia METHOXAMINE General information – same as phenylephrine (see above).
3) ALPHA-2 AGONISTS – 2 types DRUG NAME CLONIDINE DESCRIPTION Clinical uses – treatment of hypertension (by vasodilation) – treatment of diarrhea (by decreased peristalsis) – treatment of migraine (by cerebral blood vessel vasodiation) – 56 – Side effects – orthostatic hypotension (due to vasodilation) – rebound hypertension (due to abrupt seizure of administration and following vasoconstriction) – oedema (due to vasodilation) – drowsiness METHYLNORADRENALINE.
General information – see 17 – same as clonidine (see above) 4) BETA-1 AGONISTS – 2 types DRUG NAME ISOPRENALINE DESCRIPTION Clinical uses – treatment of cardiogenic shock (by increased heart rate and increased force of heart contraction) Side effects – ventricular dysryhmias (due to increased heart rate) DOBUTAMINE General information – same as isoprenaline (see above).
5) BETA-2 AGONISTS – 2 types DRUG NAME SALBUTAMOL DESCRIPTION General information – also has a weak beta-1 agonist activity Clinical uses – treatment of asthma (by bronchodilation) – prevention of premature labor (by relaxation of the uterine smooth muscle).
Side effects – tachycardia (beta-1 agonist activity) – 57 – – ventricular dysrythmias (beta-1 agonist activity) – hypotension (by vasodilation) – tremor (by increased tension of fast-twitch skeletal muscle fibers) CLENBUTEROL General information – same as salbutamol (see above) – abused as a performance enhancer (increased muscle mass and contraction speed) – 58 – 20. ALPHA ADRENERGIC RECEPTOR ANTAGONISTS General Effects alpha adrenergic receptor antagonists generally elicit effects opposite to those of alpha adrenergic receptor agonists (see 18/19) Relevant Drugs.
3 categories 1) NON-SELECTIVE ALPHA ANTAGONISTS – 2 types DRUG NAME PHENOXYBENZAMINE DESCRIPTION General information – long-acting, irreversible (binds covalently) Clinical uses – treatment of phaeochromocytoma (catecholaminesecreting tumor of the adrenal medulla) Side effects – orthostatic hypotension (due to vasodilation) – nasal congestion (due to vasodilation) – reflex tachycardia (due to vasodilation and following hypotension) – diarrhea (due to increased peristalsis) – failure of ejaculation (due to relaxation of the seminal tract) PHENTOLAMINE General information – short-acting, reversible – not used clinically 2)
ALPHA-1 ANTAGONISTS – 2 types DRUG NAME PRAZOSIN DESCRIPTION Clinical uses – treatment of hypertension (by vasodilation) Side effects – same as phenoxybenzamine, but less reflex – 59 -tachycardia (see above) TAMSOLUSIN General information – selective for the genito-urinary tract Clinical uses – treatment of urinary retention due to prostatic hypertrophy (by relaxation of the urinary bladder sphincter) Side effects – failure of ejaculation (due to relaxation of the seminal tract) 3)
ALPHA-2 ANTAGONISTS – 1 type DRUG NAME YOHIMBE DESCRIPTION General information – an aphrodisiac (vasodilation) – 60 – 21. BETA ADRENERGIC RECEPTOR ANTAGONISTS General Effects beta adrenergic receptor antagonists (“beta-blockers”) generally elicit effects opposite to those of beta adrenergic receptor agonists (see 18/19) the effects of beta adrenergic receptor antagonists depend on the degree of sympathetic activity (weak during rest (low sympathetic activity), stronger during exercise (high sympathetic activity)) Relevant Drugs.
3 categories 1) NON-SELECTIVE BETA ANTAGONISTS – 2 types DRUG NAME PROPANOLOL DESCRIPTION General information – may cross the blood-brain barrier Clinical uses – treatment of hypertension (by vasodilation, decreased heart rate and decreased force of contraction) – treatment of cardiac dysrythmias (by decreased heart rate) – treatment of myocardial infarction (by prevention of cardiac dysrythmias) – treatment of angina pectoris (by decreased heart rate and decreased force of heart contraction, and following decreased myocardial oxygen consumption and increased cardiac blood supply) – treatment of tremor (by decreased skeletal muscle twitch tension) – treatment of glaucoma (by contraction of the radial fibers of the ciliary muscle and following opening of the schlemm canal).
Side effects – depression (due to CNS stimulation) – fatigue (due to decreased heart rate and decreased force of heart contraction, and following decreased oxygenation of the CNS and skeletal muscle) – cardiac failure (due to decreased heart rate and decreased force of heart contraction) – cold extremities (due to vasoconstriction in cutaneous thermoregulatory vessels) – bronchoconstriction (due to constriction of bronchial smooth – 61 -muscle) – hypoglycemia (due to decreased glycogenolysis).
ALPRENOLOL General information – also has a weak beta agonist activity (, thus increasing heart rate during rest and decreasing heart rate during exercise) Clinical uses – same as propanolol (see above) Side effects – same as propanolol (see above) – increased heart rate during rest and decreased heart rate during exercise (due to beta agonist activity) 2).
BETA-1 ANTAGONISTS – 1 type DRUG NAME METOPROLOL DESCRIPTION Clinical uses – treatment of hypertension – treatment of caridac dysrythmias – treatment of angina pectoris Side effects – same as propanolol, though less pronounced bronchoconstriction (see above) 3) BETA-2 ANTAGONISTS – 1 type DRUG NAME BUTOXAMINE DESCRIPTION General information – not used clinically – 62 – 22.
LOCAL ANAESTHETICS Overview local anaesthetics block the propagation of nerve impulses by blocking the sodium channels responsible for initiation and propagation of the nocioceptive action potential they are ampiphilic molecules composed of a hydrophilic aromatic group and a basic amine group joined by an ester- or an amide bond the basic amine group is partly ionized at physiological ph, some thing which is important since only the non-ionized form can penetrate the myelin sheet of the axonal membrane while only the ionized form can bind to and block the sodium channels the importance of partial ionization may provide problems when anaesthetizing inflamed tissues.
(acidic pH, thus completely ionizing the basic amine group) the sodium channels are more susceptible to blockage in their activated- and in their inactivated states, and less susceptible in their resting state (“use-dependence”) mechanism of action 1) penetration of the myelin sheet and axonal membrane in it’s non-ionized form 2) binding to activated- or inactivated sodium channels in it’s ionized form local anaesthetics block propagation of different nerve fibers in the following order SMALL MYELINATED AXONS UNMYELINATED AXONS LARGE MYELINATED AXONS , thus nocioception and sympathetic transmission are the first to be blocked there are 6 types of local anaesthesia LOCAL ANAESTHESIA TYPE SURFACE ANAESTHESIA.
DESCRIPTION – spray onto the surface of mucous membranes (not skin) – used for surgery of the nose, mouth, bronchi, cornea and urinary tract – euretic mixture of local anaesthetics (“EMLA”), a mixture of lidocaine and prilocaine (see below), may be applied on the skin – direct injection into tissues to reach nerve branches and -terminals INFILTRATION ANAESTHESIA – 63 – – used in minor surgery – adrenaline may be co-administered to reduce side effects (see 19).
INTRAVENOUS REGIONAL ANAESTHESIA – intravenous injection distally to a pressure cuff (arrests blood flow thus preventing systemic effects) – used for limb surgery – injection close to a nerve trunk (eg.brachial plexus, intercostal- and/or dental nerves), thus causing distal anaesthesia – used for surgery, dentistry and analgesia (relief of pain) – injection into the CSF of the subarachnoidal space – used for surgery of the abdomen, pelvis and/or leg when general anaesthesia can not be used – often cause severe side effects – injection into the epidural space, thus causing anaesthesia of the spinal roots – used for painless labor – may cause severe side effects.
NERVE-BLOCK ANAESTHESIA SPINAL ANAESTHESIA EPIDURAL ANAESTHESIA General Side effects due to escape of local anaesthetics into the SYSTEMIC CIRCULATION 3 types ORGAN CNS SIDE-EFFECT – confusion (may lead to extreme anxiety) – tremor (may lead to convulsions) – depression of the respiratory center (may lead to cessation of breathing) – reduced force of contraction (inhibition of sodium-potassium ATPase, thus depleting intracellular potassium required for contraction) – hypotension (due to vasodilation) HEART BLOOD VESSELS – 64 – Relevant Drugs.
5 types (listed from rapid onset, short duration, and good tissue penetration to slow onset, long duration and poor tissue penetration) DRUG NAME LIDOCAINE DESCRIPTION Clinical uses – all types of local anaesthesia Clinical uses – surface anaesthesia Side effects – different side effects than the others due to it’s action of blocking uptake 1 (see 17).
PRILOCAINE Clinical uses – infiltration-, intravenous regional-, and nerve-block anaesthesia Side effects – does not cause vasodilation – may cause methemoglobinemia (heamoglobin unable to release oxygen due to covalent binding of prilocaine) TETRACAINE Clinical uses – infiltration-, and nerve-block anaesthesia Clinical uses – infiltration-, nerve-block-, and epidural anaesthesia COCAINE BUPIVACAINE – 65 – A1. DRUGS, 1ST SEMESTER 14.
CHOLINERGIC AGONISTS AND CHOLINESTERASE INHIBITORS 1) CHOLINERGIC (MUSCARINIC RECEPTOR) AGONISTS – Acetylcholine – Pilocarpine – Muscarine 2) CHOLINESTERASE INHIBITORS A) REVERSIBLE – Neostogmine – Pyridostogmine – Physiostigmine B) IRREVERSIBLE – Ecothiopate – Parathion 15. MUSCARINIC RECEPTOR ANTAGONISTS 1) TERTIARY AMINES – Atropine – Scopolamine – Pirenzepine 2) QUARTERNARY AMINES – Atropine Methonitrate – Ipratropium 16.
NEUROMUSCULAR BLOCKING AGENTS. DRUGS ACTING ON AUTONOMIC GANGLIA 1) NEUROMUSCULAR BLOCKING AGENTS A) NON-DEPOLARIZING – Tubocurarine – Gallamine – Atracurium – Mivacurium B) DEPOLARIZING – Suxamethonium 2) DRUGS ACTING ON AUTONOMIC GANGLIA A) GANGLION STIMULANTS – Nicotine – 66 – – Lobeline B) GANGLION BLOCKERS – Trimetaphan 17.
AGENTS ACTING ON THE BIOSYNTHESIS, STORAGE, RELEASE AND ELIMINATION OF CATECHOLAMINES 1) BIOSYNTHESIS – Alpha-Methyltyrosine – Methyldopa – Carbidopa 2) STORAGE – Reserpine 3) RELEASE A) PRESYNAPTIC NORADRENERGIC NEURON-BLOCKING DRUGS – Adrenaline/Noradrenaline – Acetylcholine – Histamine – Enkephalin – Dopamine – Serotonin – PGE B) NORADRENERGIC NEURON-BLOCKING DRUGS – Guanethidine C) INDIRECTLY-ACTING SYMPATOMIMETIC DRUGS – Amphetamine – Ephedrine – Tyramine 4) ELIMINATION A) REUPTAKE – Tricyclic Antidepressants – Cocaine B) DEGRADATION – MAO-A – MAO-B – COMT 18. /19. PHARMACOLOGICAL EFFECTS OF CATECHOLAMINES. ADRENERGIC RECEPTOR AGONISTS 1) NON-SELECTIVE AGONISTS – 67 -.
– Noradrenaline – Adrenaline 2) ALPHA-1 AGONISTS – Phenylephrine – Methoxamine 3) ALPHA-2 AGONISTS – Clonidine – Methylnoradrenaline 4) BETA-1 AGONISTS – Isoprenaline – Dobutamine 5) BETA-2 AGONISTS – Salbutamol – Clenbuterol 6) BETA-3 AGONISTS 20. ALPHA ADRENERGIC RECEPTOR ANTAGONISTS 1) NON-SELECTIVE ALPHA ANTAGONISTS – Phenoxybenzamine – Phentolamine 2) ALPHA-1 ANTAGONISTS – Prazosin – Tamsulosin 3) ALPHA-2 ANTAGONISTS – Yohimbe 21. BETA ADRENERGIC RECEPTOR ANTAGONISTS 1) NON-SELECTIVE BETA ANTAGONISTS – Propanolol – Alprenolol 2) BETA-1 ANTAGONISTS – Metoprolol 3) BETA-2 ANTAGONISTS – Butoxamine 22. LOCAL ANAESTHETICS – Lidocaine – Cocaine – Prilocaine – 68 – – Tetracaine – Bupivacaine – 69 -.