Definition of synapse:

Transcription

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2 Definition of synapse: A junctional connection between two neurons, across which a signal can pass Pre-synaptic neuron: Where a neurotransmitter is synthesized, stored and released upon cell activation. Post-synaptic neuron or effector cell: Where neurotransmitter is detected and its action translated into cellular activities.

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4 The Race Horse and the Cow Sympathetic Nervous System Fight or Flight Rest and Digest

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7 Autonomic Receptor Classification:

8 Muscarinic receptors 1. M1 Receptors. are found mainly in the central nervous system and peripheral neurons as well as gastric parietal cells (responsible for gastric acid secretion). 2. M2 Receptors. The major location of these receptors is on the myocardium (cardiac muscle) although they can also occur on peripheral neurons. They exert mainly inhibitory effects. 3. M3 receptors: miosis, bronochospasm increase GI motility decrease sphincter tone

9 Adrenergic receptors A. adrenergic receptor : the agonist being epiniphrine and norephinephrine Adrenergic receptors, on smooth muscle, all blood vessels (causing constriction) and causes dilation of pupil of eye on stimulation Adrenergic receptors, presynaptic are found at adrenergic and cholinergic nerve terminals.

10 Adrenergic receptors adrenergic receptors: the agonist being epiniphrine, and norephinephrine, Antagonist is propranolol. Divided into: 1. 1 adrenergic receptors on heart (some 2 also) increases rate and force of contraction adrenergic receptors dilation effect on smooth muscle (some blood vessels), bronchial muscle.

11 Autonomic drugs Cholinergic agonists Cholinergic antagonists Adrenergic agonists Adrenergic antagonists

12 Cholinergic agonist A. Decrease in the heart rate and cardiac output. B. Decrease in blood pressure (vasodilation). C. Increase the salivary secretion and stimulate intestinal secretion and motility. D. Decrease the Bladder sphincter tone. E. Contraction of the eye papillary muscles

13 Bethanecol Therapeutic uses, in urologic treatment, Bethanecol is used to stimulate the atonic bladder, particularly in or postpartum or postoperative, nonobstructive urinary retention. Diabetic autonomic neuropathy Neurogenic bladder Paralytic ileus or abdominal distension

14 Bethanecol Adverse effect, effect of generalized cholinergic stimulation: sweating, salivation, decreased blood pressure, bronchospasm. Alert- Never give IM or IV circulatory collapse, hypotension, cardiac arrest poss.

15 Pilocarbine Pilocarbine exhibits muscurinic activity and is used primarily is ophthalmology. Its major therapeutic indication is the treatment of glaucoma. It is one of the most potent stimulators of secretions such as sweat, tears, and saliva, but the use is limiting due to its lack of selectivity. Xerostomia Head and neck radiation Sjögren's syndrome. Adverse effect: it can enter the brain and cause disturbances.

16 Contraindications of cholinomimetics 1. Asthma. 2. Hypotension. 3. Peptic ulcer.

17 Anticholinesterases prolonging the lifetime of ACH. provoke a response at all cholinoceptors mascurinic and nicotinic receptors.

18 Physostigmine 1. This drug is lipophilic enough to cross the blood brain barrier. It is thus useful in treating atropine poisoning. 2. antimuscarinic side effects overdoses, Tricyclic antidepressants Antihistamines (H1) 3. Physostigmine, instilled as drops into the eye, and is commonly used in the treatment of glaucoma, but Pilocarbine is more effective. Remember: cholinergic drugs decrease the visual acuity on the long run.

19 Neostigmine It also produces some what more nicotinic effects than physostigmine, and has a greater effect on skeletal muscles. The main use of neostigmine is to reverse the effect of neuromuscular blocking drugs which are used to induce muscle paralysis during surgical procedures. Symptomatic treatment of the mysthenia gravis (an autoimmune disease) Usually given with atropine to avoid muscarinic adverse effect

20 Assessment: Myasthenia Gravis Signs and symptoms: muscle weakness, ptosis (droopy eye lid), diplopia (double vision), difficulty chewing and swallowing, decreased activity intolerance. How do you know medication is working? Increased muscle tone, no droopy eye lid or double vision, increased activity tolerance.

21 Alzheimer s disease Donepezil was approved for clinical use. Improved cognition and global clinical function were seen in the week intervals studied (Dooley and Lamb, 2000). In long-term studies, the drug delayed symptomatic progression of the disease for periods up to 55 weeks. Side effects are largely attributable to excessive cholinergic stimulation, with nausea, diarrhea, and vomiting being most frequently reported. The drug is well tolerated in single daily doses. Usually, 5-mg doses are administered at night; if this dose is well tolerated, the dose can be increased to 10 mg daily.

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23 Cholinergic Antagonists (Muscarinic receptor) Drugs which bind to cholinergic receptor but do not activate it Prevent acetylcholine from binding Opposite clinical effect to agonists lower activity of acetylcholine In addition to the inhibition of the muscarinic function, these agents block the few sympathetic neurons that are cholinergic, such as those innerving sweat glands.

24 Antimuscarinic agents Cholinergic antagonist Atropine (A) was isolated in Atropine is a quite highly specific antagonist, with a persistent effect and is still a useful drug today. main effects 1. increase heart rate, as acetylcholine slows the heart. 2. decreases tone and motility in the gastrointestinal tract, making it useful in diarrhea treatment. 3. markedly diminish salivary secretion (dry mouth), 4. cause pupil dilation. 5. Atropine relaxes the urinary tract and the airway smooth muscle

25 Atropine uses Dentistry: used to diminish salivation, to produce a dry field Bradycardia < 60 administer Atropine.5mg IV 1mg IM every 5 minutes until max dose of 3 mg

26 Scopolamine (B) Produce peripheral effect similar to atropine. However, it has a greater action on the CNS and longer duration of action, and it is less potent in its effect on the heart, bronchial muscles, and intestine. Actions: a. One of the most effective anti-motion sickness drug available. b. Also has the unusual effect of blocking short-term memory.

27 Atropine overdose tachycardia, blurred vision, photophobia, dry mouth. Can cause marked CNS excitation, with irritation, confusion, and convulsions. red as a beet (flushing), dry as a bone (dry skin), mad as a hatter (delirium, hallucinations), hot as Hades (hyperthermia), blind as a bat (mydriasis).

28 Classification of Neuromuscular Blocking Agents AGENT CHEMICAL CLASS PHARMACOLOGIC TIME OF ONSET AL PROPERTIES (MIN) a Succinyl Dicholine ester Ultrashort choline duration; (ANECTINE, depolarizing others) D- Tubocurarin e b Natural alkaloid (cyclic benzylisoquinoline) Metocurine b Benzylisoquinolin e Atracurium Benzylisoquinolin (TRACRIUM, e others) Cisatracuriu m (NIMBEX) Benzylisoquinolin e Long duration; competitive Long duration; competitive Intermediate duration; competitive Intermediate duration; competitive Long duration; competitive Short duration; competitive CLINICAL MODE OF DURATION (MIN) a ELIMINATION Hydrolysis by plasma cholinesterases 6 80 Renal and hepatic elimination Renal elimination 3 45 Hofmann elimination; hydrolysis by plasma Esterases Hofmann and renal elimination Doxacurium b Benzylisoquinolin e Renal elimination Mivacurium Benzylisoquinolin Hydrolysis plasma e by cholinesterases Pancuroniu Ammonio steroid Long duration; Renal and hepatic m (generic) competitive elimination Pipecuroniu Ammonio steroid Long duration; Renal elimination;

29 Neuromuscular blocking drugs These drugs block the cholinergic transmission between motor nerve ending and the nicitonic receptors on the neuromascular end plate of skeletal muscle. They are structural analogue of acetylcholine and act either antagonist (non-depolarizing type) or agonist (depolarizing type). Some of them are useful during surgery for producing complete muscle relaxation, without having to employ higher anesthetic doses. Others are useful to control spastic muscle tone.

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31 non-depolarizing blockers Tubocurarine (B) Tubocurarine is given by i.v. injection. Mechanism of action It binds to the endplate nicotinic cholinoceptors without exciting them, acting as a competitive antagonist towards ACh. Muscular paralysis develops within about 4 min. d- Tubocurarine does not penetrate into the CNS. The patient would thus experience motor paralysis and inability to breathe, while remaining fully conscious but incapable of expressing anything

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33 Succinylcholine (B) Mechanism of action, Depolarizing agents - attaches to the nicotinic receptors and act like ACH to depolarize the junction. Unlike ACH these agents persist at high concentration in the synaptic cleft remaining attached for a relatively longer time and providing constant stimulation of the receptors. - The continue binding of theses agents renders the receptor incapable of transmitting further impulses and the end result is flaccid paralysis (phase II).

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35 Depolarizing agents Therapeutic uses Depolarizing agents are used a. as surgical adjuvant to anesthesia for facilitating endotracheal intubations. b. with electroconvulsant shock.

36 Adrenergic agonist

37 What do these receptors do? Alpha 1 Vasoconstriction, BP, tonus sphincter muscles Alpha 2 Inhibit norepinephrine, insulin release Beta 1 Tachycardia, lipolysis, myocardial contractility Beta 2 Vasodilation, bronchodilation, insulin release

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39 Epinephrine (A) (Adrenalin) can stimulate both alpha and beta receptors i. skin has primarily an alpha response --vasoconstriction ii. heart primarily beta response an increased beta response increases (a) rate POSITIVE CHRONOTROPIC (b) force of contraction POSITIVE INOTROPIC (c) cardiac output (d) oxygen utilization --oxygen utilization is increased tremendously????

40 uses 1. agent of choice in allergic reactions and asthmatic reactions --counteracts effect of histamine in such reactions, dose is ml of a l:l,000 solution, either SQ or IV Adrenaline provides rapid relief of hypersensitivity reactions to drugs and allergens through physiological antagonism of the hypotensive effects of these mediators, and relieving bronchoconstriction which may occur in anaphylactic shock.

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42 2. local anesthetics uses Adrenaline is also combined with local anesthetics to prolong their action by virtue of the alpha mediated constrictor effect on blood vessels of the skin and subdermis. concentration 1:50,000 to 1:250,000 most common: 1:100,000 also reduce the toxicity of the local anesthetic by limiting its systemic absorption. local anesthetic such as Lidocaine in toxic doses can produce cardiac arrthythmias and convulsions.

43 (cardiopulmonary resuscitation) IV would be 0.1 to 0.25 mg 3. It is also used to restore cardiac activity in cardiac arrest. Epinephrine is the best studied and most widely administered adrenergic agonist used for the treatment of cardiac arrest. Used to jump start the heart.

44 Adverse effect adrenaline may lead to symptoms of fear, anxiety, tenseness, restlessness, headache, tremor, weakness, dizziness or palpitation. As a result of significant blood pressure elevation, cerebral haemorrhages may occur. It may trigger cardiac arrhythmia, particularly if patient is receiving digitalis.

45 Contraindications and cautions i. cardiovascular disease increases workload on the heart in a very inefficient manner; oxygen is rapidly consumed and patients with cardiovascular disease already have compromised access to adequate oxygen in the heart. ii. hypertension vasoconstriction can be throughout the body, including the muscles of the blood vessels. iii. hyperthyroidism epinephrine can further stimulate the release of thyroid hormone AND cause an increase in side effects of the hyperthyroid condition!

46 Phenylephrine (A) ( 1&2). Therapeutic uses: It is a component of a number of cold medication, where it acts as a nasal decongestant by virtue of its vasoconstrictor ability. Rebound nasal congestion can occur with chronic use nasal decongestant. as a Mixed with local anaesthetics for the same reason as adrenaline. Phenylephrine is used in ophthalmology to produce pupillary dilation (mydriasis) without paralysis of accommodation (cycloplegia). Of course, atropine would produce both phenomena.

47 TAC-4 Alternate Dental Gel Dental Gel (Prilocaine / Lidocaine / Tetracaine / Phenylephrine) Phenylephrine helps shrink blood vessels, which in turn may help with the prevention of bleeding.

48 Dopamine (B) Dopamine is a naturally occurring catecholamine and neurotransmitter within the CNS. Most of the cardiovascular effects of dopamine are produced by its weak effects on 1 receptors and receptors. Its effects on renal and mesenteric vasculatures are mediated through stimulation of specific dopaminergic receptors. Dopamine has become favoured as a pressor agent to maintain blood pressure in shock.

49 Dopamine (B) Dopamine has the following advantages over other sympathomimetics a. It causes cardiac stimulation with little increase in myocardial oxygen consumption. b. It is less likely to cause cardiac arrhythmias than other sympathomimetics. c. The increase in renal blood flow which it produces helps to maintain glomerular filtration, urine production and sodium excretion whereas adrenaline and noradrenaline decrease renal blood flow to the point where renal necrosis is possible.

50 1 Receptors. Dobutamine (B) This is a synthetic and relatively new substance. It increases cardiac contractility and cardiac output by selectively stimulating cardiac 1 receptors. Dobutamine appears to have advantages over other catecholamines forimprovement of myocardial function in heart failure associated with myocardial infarction. Since the the effects of dobutamine on heart rate and systolic pressure are less than the other catecholamines, there is less oxygen demand by the myocardium compared to other sympathomimetic drugs. Dobutamine should be used with caution in atrial fibrillation, as the drug increase atrioventricular conductivity.

51 Ephedrine (A) Is a mix acting sympathomimetic agent, which has both direct and indirect action: Its primary action is indirect: it cause the release of norepinephrine from storage in nerve terminals. It also produce direct stimulation of adrenergic receptors. Ephedrine increase the blood pressure by vasoconstruction and cardiac stimulation. It produces bronchodilation, but it is less potent than epinephrine and produces its action more slowly. Its main therapeutic uses are in the treatment of bronchial asthma, and as a nasal decongestant.

52 Selective 2 stimulants Salbutamol (A) These drugs are very widely used in the treatment of asthma. Have a relaxant effect on the bronchial smooth muscle and show little effect on cardiac 1 receptors. They are used therapeutically for treatments of bronchial asthma, they chiefly as aerosol inhalants, oral and injection, are available

53 Salbutamol (A) nearly devoid of cardiac effects in the usual human doses, It is as potent as Isoproterenol in its ability to cause bronchodilation but has only about 1/50th of the cardiac stimulant properties. Other examples include mtaproterenol, albuterol, turbutaline, and bitolterol. These agents differ in their onset of action and the duration of their effects.

54 Sales of Supplements Containing Ephedrine Alkaloids (Ephedra) Prohibited On April 12, 2004, a final rule went into effect prohibiting the sale of dietary supplements containing ephedrine alkaloids (ephedra). Ephedra, also called Ma huang, is a naturally occurring substance derived from plants. Its principal active ingredient is ephedrine, which when chemically synthesized is regulated as a drug. In recent years ephedra products have been extensively promoted to aid weight loss, enhance sports performance, and increase energy. But FDA has determined that ephedra presents an unreasonable risk of illness or injury. It has been linked to significant adverse health effects, including heart attack and stroke. From 54

55 2 agonists eg, clonidine and Methyldopa (antihypertensive drugs) when given orally, reduce sympathetic outflow from CNS and consequently decrease BP Central 2 agonists hypertension menopausal hot flushes narcotics, alcohol, smoking withdrawal

56 2-Adrenergic Agonists Reduce Blood Pressure by Reducing Sympathetic Output from the Brain Brain Brain Stem (Cardiovascular Control Center) 2 Receptors Sympathetic ganglion 1 Receptors Heart 1 Receptors Kidney 1 Receptors

57 2-Adrenergic Agonists Reduce Blood Pressure by Reducing Sympathetic Output from the Brain Brain Brain Stem (Cardiovascular Control Center) 2 Receptors Sympathetic ganglion Decreased sympathetic tone Decr. HR Decr. Contractility Decr. Renin release Decr. Vasoconstriction 1 Receptors Heart Kidney 1 Receptors 1 Receptors

58 Adrenoreceptor Antagonists 58

59 - Adrenoreceptor Blockade non-selective Non-selective -antagonists have limited beneficial effects on blood pressure reduction, due to associated 2 block which increases nor adrenaline effects (remember, block of the negative feedback 2 receptor will increase noradrenaline release). This may cause increased 1 stimulation with tachycardia etc - an unwanted additional effect.

60 Phenetolamine (A) Produce a Competitive block of both 1 and 2 receptors. Decrease peripheral resistance and increase venous capacity. Used to control acute hypertension episodes caused by sympathomimetics. Phenetolamine induce reflex cardiac stimulation and tachycardia through the baroreceptor reflex and by blocking the 2 receptors of cardiac sympathetic nerve.

61 Phenoxybenzamine Binds covalently to the receptors, produce an irreversible blockade. The only mechanism to overcome this blockade is to synthesis new adreno-receptors, which require a day or so. phenoxybenzamine induce hypotension due to lack of the sympathetic vasoconstruction. It is used to reverse vasoconstruaction in shock, and also in acute hypertension episodes. Pheochromocytoma

62 Selective 1 -blockers Selectively block 1 receptors Ie. Alfuzosin, doxazosin, prazosin, terazosin.. Used in the treatment of chronic hypertension Also used to treat urinary retention in men with benign prostatic hyperplasia

63 Prazosin Prazosin, is a selective 1 antagonist, still used in some cases of hypertension, as 1 vasoconstriction effect is blocked without an increase in adrenergic effects at -receptor sites. Lower blood pressure by causing relaxation of both arterial and venous smooth muscle. Importantly, it produce what called first dose syncope, by exaggerated hypotensive response that can result fainting. First dose effect can be minimize by adjusting the dose to one third or one fourth, and by giving the drug at bedtime.

64 Prazosin 1 antagonist may cause dizziness, lack of energy, nasal congestion, headache, and drowsiness. Significant orthostatic hypotension is a possibility; monitor patient when getting out of dental chair.

65 -adrenoreceptor blockade The drugs which block -receptors are very widely used in therapeutics, mostly for their antihypertensive effect, and efficacy in the treatment of angina and some arrhythmias. In the 1960's -blockers were developed, and the earliest prototype -blocker was Propanolol, a non-specific receptors antagonist, which is still widely used. While -blockers are still widely used for the treatment of hypertension, exactly how they lower blood pressure has never been clarified.

66 -adrenergic receptor antagonists Both non-selective and selective -blockers Non-selective ie nadolol, pindolol, propranolol, tomilol Block both 1 receptors in cardiac tissue and 2 in smooth muscle, liver and other tissues Blockade of 1 reduces sympathetic stimulation of heart Therefore, negative chronotrope inotrope Blockade of 2 may cause bronchoconstriction and limit glycogenolysis Adverse effects

67 1 -antagonist 1 -antagonists

68 Selective 1 -blockers Have greater affinity for 1 than for 2 receptors Ie Acebutolol, atenolol, esmolol, metoprolol CARDIOSELECTIVE BLOCKERS Produce fewer adverse effects than non-selective, but their selectivity is not absolute

69 Clinical uses -blockers have a number of clinical applications including treatment of: migraines Hypertension angina pectoris cardiac arrhythmia glaucoma

70 Propanolol Adverse effects -Propanolol can induce heart failure, especially in patients with compromised myocardial function. -Rash, fever and prolonged use may cause fatigue, depression, sexual dysfunction. -Rapid withdrawal can lead to supersensitivity of receptors, which can provoke anginal attack, arrhythmia, or myocardial infraction.

71 Propanolol Contraindications: a. Propanolol must never given to any individual with chronic obstruction pulmonary disease because it causes an immediate contraction of the bronchiolar smooth muscles, which may result in a serious and potential lethal side effect. b. Propanolol effect the carbohydrate metabolism, and may increase the action of insulin, so diabetics treated with insulin should use it with caution.

72 Selective 1 blockers These include Atenolol, Acebutolol, Esmolol, and Metopropolol. These agents enjoy wide use as antihypertensive, although less so today than 10 years ago. Relatively little effect on the pulmonary function, peripheral resistance, and carbohydrate metabolism. They are also useful in diabetic hypertensive patient who are receiving insulin.

73 Pindolol and Acebutolol Are not pure antagonists, instead, they have the ability to weakly stimulate both 1 and 2 receptors (agonist effect), and produce what is called intrinsic sympathomemitic activity. These partial agonist stimulate the receptors and also inhibit the stimulation by the endogenous neurotransmitters adrenaline and noradrenalin. The intrinsic sympathomemitic activity decreased metabolic effects that are seen with other blockers, such as carbohydrate metabolism (make them valuable in treatment hypertension in diabetics). They used therapeutically to treat hypertension with moderate bradycardia, because a further decrease in the heart rate is less pronounced with these agents.

74 Labetolol is also used to treat hypertensive emergencies because it can rapidly lower blood pressure. Labetalol and carvedilol Antagonist of both and adrenoreceptors These two agents are reversible blockers and 1 blocker (producing peripheral vasodilatation). So they contrast -blockers in producing peripheral vasodilation, and therefore useful in treating hypertensive patient whom increased peripheral vascular resistance is undesired, such as elderly and blacks. Labetolol may employed as an alternative to hydralazine in the treatment of pregnancy-induced hypertension.