Osteoporosis & Gout Lecture Notes PDF

Assisst.prof. Hassan Khuder Rajab 2nd class theory lect in pharmacology of undergraduate stage Osteoporosis Assisst.prof. HASSAN KHUDER RAJAB 2ND CLASS LECT. GOUTE ARTHRITIS Objective :►Defenition of gout. ►treatment of acute attack. ►prophylaxis of gout therapy ►how we evaluate our treatment of gou...

Assisst.prof. Hassan Khuder Rajab 2nd class theory lect in pharmacology of undergraduate stage Osteoporosis Assisst.prof. HASSAN KHUDER RAJAB 2ND CLASS LECT. GOUTE ARTHRITIS Objective :►Defenition of gout. ►treatment of acute attack. ►prophylaxis of gout therapy ►how we evaluate our treatment of gout. ACUTE GOUTY ARTHRITIS Nonpharmacologic Therapy Patients may be advised to reduce their intake of foods high in purines (e.g., organ meats), avoid alcohol, increase fluid intake, and lose weight if obese. Joint rest for 1 to 2 days should be encouraged, and local application of ice may be beneficial. Nonsteroidal Antiinflammatory Drugs Colchicine Colchicine is an antimitotic drug that is highly effective in relieving acute gout attacks but has a low benefit-toxicity ratio. When colchicine is started within the first 24 hours of an acute attack, about two-thirds of patients respond within several hours. The likelihood of success decreases substantially if treatment is delayed longer than 48 hours after symptom onset. Oral colchicine causes dose-dependent GI adverse effects (nausea, vomiting, and diarrhea) in 50% to 80% of patients before relief of the attack. Non-GI adverse effects include neutropenia and axonal neuromyopathy, which may be worsened in patients taking other myopathic drugs (e.g., statins) or in those with renal insufficiency. Colchicine should not be used concurrently with macrolide antibiotics (especially clarithromycin) because reduced biliary excretion may lead to increased plasma colchicine levels and agranulocytosis. Colchicine should be reserved for patients with insufficient relief, intolerance, or contraindications to NSAIDs. The usual oral colchicine dose is 1 mg initially, followed by 0.5 mg every 1 hour until the joint symptoms subside, the patient develops abdominal discomfort or diarrhea, or a total dose of 8 mg has been given. IV colchicine should be avoided because it is associated with serious adverse effects (e.g., bone marrow suppression, tissue necrosis from local extravasation, disseminated intravascular coagulation, hepatocellular toxicity, and renal failure). If considered necessary, the recommended initial IV dose is 2 mg (if renal function is normal) diluted in 10 to 20 mL of normal saline administered slowly over 10 to 20 minutes in a secure, free- flowing IV line to avoid extravasation. This may be followed by two additional doses of 1 mg each at 6-hour intervals, with the total dose not exceeding 4 mg. After a full IV course, patients should not receive colchicine by any route for at least 7 days. Corticosteroids Corticosteroids may be used to treat acute attacks of gouty arthritis, but they are reserved primarily for patients with a contraindication or who are unresponsive to NSAID or colchicine therapy. Patients with multiple-joint involvement may also benefit. The recommended dose is prednisone 30 to 60 mg (or an equivalent dose of another corticosteroid) orally once daily for 3 to 5 days. Because rebound attacks may occur upon steroid withdrawal, the dose should be gradually tapered in 5-mg over 10 to 14 days and discontinued. A single intramuscular injection of a long-acting corticosteroid (e.g., methylprednisolone acetate) can be used as an alternative to the oral route if patients are unable to take oral therapy. If not contraindicated, low-dose colchicine can be used as adjunctive therapy to injectable corticosteroids to prevent rebound flare-ups. Intraarticular administration of triamcinolone hexacetonide 20 to 40 mg may be useful for acute gout limited to one or two joints. Adrenocorticotropic hormone (ACTH) gel, 40 to 80 USP units, may be given intramuscularly every 6 to 8 hours for 2 to 3 days and then discontinued and it should be reserved for patients with contraindications to first-line therapies (e.g., heart failure, chronic renal failure, history of GI bleeding). PROPHYLACTIC THERAPY OF GOUT General Approach Prophylactic treatment can be withheld if the first episode of acute gouty arthritis was mild and responded promptly to treatment, the patient’s serum urate concentration was only minimally elevated, and the 24-hour urinary uric acid excretion was not excessive (less than 1,000 mg/24 hours on a regular diet). If the patient had a severe attack of gouty arthritis, a complicated course of uric acid lithiasis, a substantially elevated serum uric acid (greater than 10 mg/dL), or a 24-hour urinary excretion of uric acid of more than 1,000 mg, then prophylactic treatment should be instituted immediately after resolution of the acute episode. Prophylactic therapy is cost-effective for patients with frequent attacks of gouty arthritis Colchicine given in low oral doses (0.5 to 0.6 mg twice daily) may be effective in preventing recurrent arthritis in patients with no evidence of visible tophi and a normal or slightly elevated serum urate concentration. The oral dose should be reduced to no more than 0.6 mg daily or every other day in patients with renal or hepatic dysfunction. Treated patients who sense the onset of an acute attack should increase the dose to 1 mg every 2 hours; in most instances, the attack aborts after 1 or 2 mg. Discontinuation of prophylaxis may be attempted if the serum urate concentration remains normal and the patient is symptom-free for 1 year. Uricosuric Drugs Probenecid and sulfinpyrazone increase the renal clearance of uric acid by inhibiting the renal tubular reabsorption of uric acid. They should only be used in patients with documented underexcretion of uric acid. Therapy with uricosuric drugs should be started at a low dose to avoid marked uricosuria and possible stone formation. Maintenance of adequate urine flow and alkalinization of the urine with sodium bicarbonate or Shohl’s solution during the first several days of uricosuric therapy further diminish the possibility of uric acid stone formation. Probenecid is given initially at a dose of 250 mg twice daily for 1 to 2 weeks, then 500 mg twice daily for 2 weeks. Thereafter, the daily dose is increased by 500-mg increments every 1 to 2 weeks until satisfactory control is achieved or a maximum dose of 2 g/day is reached. The initial dose of sulfinpyrazone is 50 mg twice daily for 3 to 4 days, then 100 mg twice daily, increasing the daily dose by 100-mg increments each week up to 800 mg/day. The major side effects associated with uricosuric therapy are GI irritation, rash and hypersensitivity, precipitation of acute gouty arthritis, and stone formation. These drugs are contraindicated in patients who are allergic to them and in patients with impaired renal function (CLcr 300 mg. ►ANABOLIC THERAPY Teriparatide is a recombinant product representing the first 34 amino acids in human parathyroid hormone. Teriparatide increases bone forma- tion, the bone remodeling rate, and osteoblast number and activity. Both bone mass and architecture are improved. Teriparatide is FDA approved for postmenopausal women and men who are at high risk for fracture. Candidates for therapy include patients with a history of osteoporotic fracture, multiple risk factors for fracture, very low bone density (e.g., T-score isoproterenol ), its G protein on avtivation α 1(postsynaptic memberane of effector organ) intiate secondry massenger IP3 &DAG , α 2 (locate in presynaptic , b cell of pancrease , vascular smooth muscle ) , NE release into synaptic interact with α1 & part interact with α2 that cause feedback inhibition of release more NE , α2 present in presynaptic parasympathethic neurons also inhibit release of acetylcholine by same mechanism , α2 response mediated via inhibition of adenylyl cyclase that fall intacellular cAMP level , α 1α2 sub-sub divided into α1A , α1B, α1C ,α1D & α2A ,α2B , α2C , α2D for more selective action. β receptor show more responsivness to isoproterenol than NE (isoproterenol>E>NE) , β1(affinity for E& NE =) while β2(E>NE) , activation ob β receptor activate adenylyl cyclase that increase cAMP level in cell desensitization of receptor on prolong exposuer to neurotransmitter that reduce responsiveness(3 mechansim explain this phenomena Asequestration of receptor so unavailable to interact with ligand , B-ddown regulation ↓ receptor by destruction or ↓ synthesis ,C- inability to couple G protein due to phosphorylated on cytoplasmic site by protein kinase A or adregergic receptor kinase ). 1α 2α 1β 2β -Vasoconstriction -↑peripheral resistance -↑BP -Mydriasis -↑closure of internal sphinctor of bladder -Inhibit release of NE & acetylcholine -inhibit insulin release -Tachycardia -↑lipolysis -↑Renin release -↑myocardial contractility -Vasodilatation -Bronchodilator -Slightly ↓BP -Relax uterine smooth muscle -↑Glucagon release -↑Muscle&liver glycogenolysis Adregergic agonist Adregergic agonist can catecholamine or noncatecholamines , catecholamine(dopamine ,NE,E, Isoproterenol ) of high potency to interact with β &α rectptor but rapidly metabolite via COMT (in postsynaptic &gut wall )& MAO(in intraneuronal ,gut wall & liver) , so of short action parentrally & inactive orally , poorly enter CNS(polar) nevertheles cause anxiety ,tremor & headache. Noncatecholamines(phenylphrine ,ephedrine, amphetamine ) lack catechol hydroxyl group of long t1/2 (not inactivated viaCOMT) & poor substrate for MAO , lack hyroxyl group make it more lipid soluble & more entery into CNS. Mechanism of action of adrenergic agonist agent A-direct acting agonist(dirrect oction on α, β receptor like(NE,E,isoproterenol , phenylphrine) ,B-indirect acting agonist(tyramine ,cocaine ,amphetamine)block uptake of NE(cocaine) or taken into presynaptic neuron & release NE(amphetamine) , C- mixed agonist action(ephedrine, pseudoephedrine , metaraminol ), stimulate receptor directly & cause release of NE. Direct acting adrenergic agonist A-Epinephrine :-one of the four catecholamine that used as therapy , synthesized in adrenal medula & secret into blood tream. at low dose β predominant to cause vasodilation & at high dose α strongest to cause vasoconstriction , Action 1-onCVS :-+inotropic β1 action(↑contractil strength)& +chronotropic action(↑rate of contraction) →cardiac output &↑O2 demand , constrict arterioles of skin,cutaneous membrane & viscera(↓renal blood flow) & dilate vesseles going to liver →end results ↑systolicBP &↓diastolic BP.2- onRESP. system :-powerful bronchodilator(in allergic induce BC) via β2 action , via such action its lifesaving in anaphylactic shock & in asthma(releive dyspnea, ↑tidal volume& inhibit release of allergy mediators). 3-Hyperglycemia ↑glycogenolysis in liver(β2 action→↑glucagon& α2 action→↓insulinrelease).4-lipolysis via β action. Uses :-bronchospasm(asSC repeat after hours), glaucoma (2%solution to ↓IOP by ↓aqueous humor roduction via ciliary boddy blood vessel constriction ), anbaphylactic shock (type 1 hypersensitivity) , cardiac arrest , anesthesia(local one→vasocostriction &↑persist of anesthesia at site of injection). Can be use as IV, SC, topical, inhalation , & via endotracheal tube , of rapid onset action & brief. Metabolism by COMT &MAO final product in urine(metanephrine&vanillylmandelic acid). Advers effects :1- on CNS anxiety ,headache tremor ,2-hemorrahgic(↑ICP → cerebral hemorrahge) ,3-arrhythemias (use with digitalis ) , 4-pulmonary edema. Drug interaction :-1-in diabetus insulin should increase , in βblocker only α action persist →↑BP, in ihal nesthes →tachycardia , in hyperthyroidism its dose to reduce(reduce CV action) , in cocaine exaggerate CV action(inhibit its reuptake). B-Norepinephrine :-mostly affecteing α receptort therapeutic doe , Action :-1-on CVS via α1 effects rise PR of most vascular beds including kidney→ ↑BP(systolic&diastolic) , it weak effect on β receptor make it (more vasoconstriction & usefulless in asthma tha epinephrine) , 2- if atropine use before it cause tachycardia , 3- on baroreceptor on ↑BP→ reflex↑in vagal activity via barorecptor →reflex bradycardia. therapeutic uses of NE :shock , may cause extravasation of blood from vessels as it potent vasoconstriction , available clinical form called(levarterenol). use as IV(rapid onset of action & duration1-2 minutes ), on SC poorly absorbed , not use orally, their metabolite (normetanephrine) excret in urine. side effects like epinephrine + blanching & sloughing of skin along injected veins. C-Isoproterenol:-its synthetic catecholamine predominantly stimulate β1& β2 , rarely use since its nonselective. its action :-1- on CVS ↑both rate & force of contraction to ↑COP(its=epinephrine) , by effect on β2 cause skeletal muscle arterioles dilatation. 2-pulmonary:rapid& profound bronchodilation (β2 action) use in asthma as inhalor its effct for 1 hour.3-other effect like via β action ↑blood sugar& lipolysis. Uses :-asthma & stimulate heart in emergency situation. side effects like epinephrine , use parenterally or sublingual or inhalor, stable for MAO & marginal substrate to COMT D-Dopamine :- immediate metabolic precursor of NE naturally in CNS in basal ganglia & adrenal medula , stimulate both α & β receptor , on high dose act on α1 cause vasoconstriction , at low dose act on cardiacβ1. Also act on Dopaminergic receptor(D1& D2) , present in mesentric & renal vascular beds activation cause vasodilator , D2 in presynaptic neuron activation interfer with NE release.Action 1-on CVS: of +inotropic & chronotropic effects(β1 action) , at very high dose via α1 cause vasoconstriction , 2- renal & visceral : via D receptor dilate renal & splanchnic arterioles make it use in shock. Uses like :-1-shock(↑BP by act on cardiac β1to ↑COP , via α→↑PR , ↑blood perfusion to kidney & splanchnic areas ,) , metabolite by COMT&MAO to homovanillic acide , side effects like hypertension , nausea &arrhythemias. E-Dobutamine :- its synthetic B1 direct acting agonist it↑ HR &COP(no significant ↑ in O2 demands of myocardium ) , used in CHF to ↑cop as well as for inotropic support after cardiac surgery, side effects its ↑AV conduction(use cautionally in AF), tolerance on prolong uses. F-Oxymetazoline :-synthetic direct acting agonist act on both α1 & α2 , primary used locally in eye or nose as vasoconstrictor , in nasal spray as well as eye drop to relief redness of eyes(by cold ,swimming or contact lens) , cause on stimulate receptor reduce blood supply for nose & eye & ↓congestion. if reach systemic circulation regardless of adminstration route cause headache , nervousness, trouble sleeping , nasally apply cause burning of nasal mucosa 7 sneezing. G-Phenylephrine :-dirct acting synthetic agonist agent favors α1 over α 2 , its not catechol derivative sop not substrate COMT , is rise both systolic & diastolic blood pressure , its cause relux bradycardia if use parentrally , use locally for eye for mydriasis & for nasal membrans as nasal decongestant & produce prolong vasoconstriction(VC) , use to raise blood pressure & termnate episode of SVT. large dose cause cardiac irregularities & hypertensive headache. H-Methoxamine :- dirct acting synthetic agonist agent favors α1 over α 2 , raise blood pressure by action on arterioles receptor causing VC , use for paroxysmal SVT & to over come hypotension induce by halothene anesthesia , side effects like vomiting & hypertensive headache. I-Clonidine :-α2 agonist used to lower BP & minimize withdrawal symptoms of opiate or benzodiazepine , its centrally acting to inhibit sympathatic vasomotor center (↓sympathatic outflow to periphery). J-Metaproterenol :-chemincally similar to isoproterenol but not catechol so not substrate for COMT ,act on B2 cause dilation so use in asthma to induce bronchodilator with little effect on heart , used orally or as inhalor. K-Albuterol , Pirbuterol , Terbutaline :- B2 agonist of short acting(3 hours ) agents as inhalor to induce bronchodilator with less cardiac stimulation unlike nonselective like metaproterenol. L-Salmeterol & Formoterol :- both are selective long acting B2 agonist as bronchodilator , as inhalor once daily dose give sustain effect over 12 hours ,more effecacy obtain if combine with steroid , used for nocturnal asthma. In-Direct Acting Adrenergic Agents they potentiate endogenous NE effects of no direct effects on postsynaptic receptors , cause NE release of inhibit their re-up-take. A-Amphetamine :- its of central stimulatory action make its to be abuse for this action. its able to ↑BP by affecting α receptor of vesseles & β stimulation on heart, while peripherally its inhibit reuptake or cause NE release , limited of uses like physiological & psychological dependence with tolerance development , uses like 1-child hyperactivity disorders ,2-narcolepsy (sleep disorder) ,3- appetite control , not use in pregnancy. B-Tyramine:- of no clinical importance but found in fermented food ,as it normal product of tyrosine metabolism its metabolite via GIT –MAO , its precipitate vasopressor effect in used with MAO inhibitor. C-Cocaine:-its local anesthetic agents act by1- blocking Na/K activated ATPase that requierd for NE re-up-take , so ↑NE& E in synaptic space & potentiate their action ,2- ↑the duration of action f both NE & E , its able to raise BP by their action as α agonist & β stimulating effects. Mixed Action Adrenergic Agonist :-this group cause release of NE & activate adrenergic receptor on the post-synaptic membranse. Ephedrine & Pseudoephedrine are the example of this group , both plant alkaloid but nowaday chemical synthetic available , of action on both α & β in post synaptic membrane & also stimulate the release of NE from the nerve ending terminle storage , like epinephrine of wide variaty of adrenergic action , both not a catechole so poorly substrate by both MAO & COMT which increase thir duration of action , both well orally absorbed to be eliminate in urine as unchange as for ephedrine while pseudoephedrine undergo incomplete hepatic metabolism then excrete , both penetrate into CNS but pseudoephedrine of fewer CNS effects ,. Ephedrine cause 1-raising of both systolic & diastolic BP like epinephrine aslso in induce 2- bronchodilation make its uses in asthmatic patient but it less potent than isoproterenol & epinephrine , also it induce its effects slowly make it to be use prophylactically to inhibit attack than use in acute attack , 3-get a role in treating mysthenia gravis (better to be use with anticholinesterase) to improve motor function& the contractility , 4- asCNS stimulation that cause increase alertness , decrease fatigue & prevent sleep. 5improve atheletic performance , 6- may be use as nasal decongestant , Adrenergic antagoinst agents :Alpha adrenergic blocking agents :- by blocking these receptor decrease sympathetic tone of blood vessels result in decreaseing PR & frflux tachycardia as response to lower BP. A-Phenoxybenzamine :- non-competitive nonselective agent bind both α1 post & α2 pre-synaptically irreversibly that mean body can not over come it only if new receptor synthesis , so its effect last for 24 hours , before action need biotransformation to be active. used as injection. their action 1- on CVS ↓response to endogenous catecholamine so ↓PR & cause reflux tachycardia , by blocking α2 presynaptic cause ↑NE & ↑COP. 2reverse action of E but not NE or isoproterenol (as result cause ↓BP block its α action but not its β 1 action that cause vasodilation). Their uses:- 1-in phaeochromocytoma (adrenal medulla tumor ) , either prior to surgery or chronic management 2-Raynauds disease 3- autonomic hyperreflexia. side effects [postural hyoptension , nausea , vomiting , reflux tachycardia , nasal stuffiness ] not use in patient with decrease coronary perfusion. B-Phentolamine :-α1α2 receptors as competitively , action last 4 hours , also produce postural hypotension & reverse E- action , arrhythemias & angina pain , used as short term treatment of pheochromocytoma C-Prazosin , Terazosin , Doxazosin, Alfuzosin, Tamsulosin :all are competitive selective α1 blocker , 1st 3 used in treat HT while last 2 use in prostatic hyperplasia , metabolism produce inactive agent excrete in urine except for doxazosin in feces & its of longest action one. their action :cause relaxation of both arterial & venous smooth mucsle that ↓PR & ↓BP , tamsulozosin of least action on blood vessels , with minimal change in COP , renal blood flow , & GFR. their uses :-1- HT(1st dose effect= fainting or syncopal attack on 1st dose only to avoid it give the dose at bettime or in reduce dose 1/3 or 1/4 of normal dose) 2- BPH as alternative to suegery (↓smooth muscle tone of bladder neck & prostate to improve urine flow) , tamsulosin selective α1A agent {agent like finasteride &dutasteride inhibit 5α-reductase so reduce volium of prostate (inhibit conversion of dihydrotestisterone. →testisterone.)} side effects:-[dizziness , lack of energy , nasal congestion , orthoststic hypotension ,drowsiness ,headache ]. D-Yohimbine :- competitive selective α2 receptor blocker , found in bark of yohimbe tree used as sexual stimulant , act by increase sympathetic outflow to peripheral , improve vasoconstriction of rayaunds disease , so not used in CNS & CVS condition. Beta Adrenergic Blockers Agents :All as copetitive blockers , slective one act on β1 cardiac receptors while nonselective , no β2 antagonist that useful clinically , all lower BP but no cause postural hypotension(not block α receptor action) ,use also for AP , arrhythemias(SVT but not V arrhythemia except that induce by exercise) , MI , CHF, hyperthyroidism , gloucoma & migraine prophylaxis. A-Propranolol :- non selective beta antagonist drug , once daily dose of sustain release available , their action 1-on CVS ↓COP, -ve inotroic& choronotropic , supress SA& AV activity all→bradycardia also ↓O2consumpon.2-peripheral vasoconstriction :-beta blocker inhibit β2 mediated vasodilation , & on lowering BP→reflex peripheral vasoconstriction.3-bronchoconstriction worse asthma & COPD so it contrindicated.4-↑Na+retenson by ↓ renal perfusion , some time ↑BP so combine with diuretics.5disturbance in glucose metabolism →hypoglycemia due to ↓glucagon secretion & ↓glycogenolysis. 5- blocked action of isoproterenol , not affecting vasoconstriction of E(mediated by αction ) while ction o E not afectedt all.their uses :-[HT(↓renin release , ↓COP, ↓sympathetic outflow), glaucoma(timolol ↓IOP on topical application in chronic state able to ↓aqueeous humor secretion in acute attack pilocarpine drug of choice ) , migraine(↓severity 7 incidence of attack ) , hyperthyroidism(acute attack lifesaving aganist cardiac arrhythemias) , AP(↓O2 requierd by cardiac muscle) , MI(prevent next attack as prophylactic , ↓sudden death after attack by arrhythemia , reduce infarct size & haster recovery) ]. Side effects :-[bronchoconstriction , arrhythemia on sudden stop therapy , sexual impairment , hypoglycemia ]. drug interaction potentiate its antihypertensive effects byinterfer with metabolism (cimetidine , fluoxetine ,paroxetine & ritonavir) while other decrease its effects like(phenytoin , barbiturate , rifampin ). B-Timolol & Nadolol :-both nonselective more potent than propranolol β blocker , nadolol of longest duration of action agent among(14-24 h ) , used fo HT treatment. C-Acebutolol , Atenolol , Esmelol(of short t1/2 about 10 minutes) ,Metoprolol :-all selective β1 agent , requierd a dose 50-100 fold to block β1 less than need to block β2 , used in treatment of HT with pulmoary impairment, of least cold extermities(ommon side effect of BB) , & save in diabetus patients insulin or OHA. D-Pindolol & Acebutolol :- both antagonist with partial agonist activity(both β1, β2 partially activated but unable to respond to more potent catecholamine so ↓ cellular effects than induce by agonist ) ,used in treatment of HT. E-Labetalol & Carvedilol :- both antagonist α β receptor ,they only agent that produce peripheral vasodilation while other induce vasoconstriction , labetalol used in1- treatment of HT in elderly & black HT in whom increased peripheral resistance is undesirable , 2- alternative to methydopa in treat pregenacy induce HT , 3- use as IV in emergency HT. side effects like orthostatic hypotension & dizziness due to α1 blockade. Drugs affecting neurotransmitter release or uptake(indirect antagonist) :A-Reserpine:- its plant alkaloid block Mg+2/ATP dependent transport of biogenic amine , NE,E, D & serotonine from cytoplasm into storage vesicles thus deplet neurotransmitters ,its of long duration of action for many days after stop it , of slow onset of action. B -Guanethidine :-block release of storage NE & displace NE from storage vesicles →trnasient increase of BP ie deplet NE in nerve ending , it cause orthostatic hypotension & interfer with male sexual function Cholinergic & its antagonist agents Objectives By end of this lecturewe must know following 1-types of receptor on which cholinergic agents act. 2-Whats are cholinergic &its mimic drugs , their clinical effects ,uses. 3-anticholinesterase agents both reversible & irreversible. 4-cholinergic antagonist agents like a- anti-mucarinic agents b-ganglionic blocker agents c-neuro-muscular blocker agents Cholinergic drugs two type of receptor on which acetylcholine or its mimic agents acts , muscarinic & nicotinic receptors. A-Muscarinic receptor : of high affinity for acetylecholine & muscarine(poisnous in mushroom) & low affinity for nicotine. 5 sub- types of muscarinic receptor found on both autonomic effector organ like heart ,smooth muscle , exocrine gland brain or ganglia of peripheral nervous system M1 M2 M3 M4 M5. all found on neorons , but M1 in addition on parietal cells of stomach , M2 on the heart & smooth muscle , M3 on exocrine gland and smooth muscle. Drug on high conc. its effects extent to involve nicotic receptor. when the MI or M3 receptors are activated, the receptor undergoes a conformational change and interacts with a G protein, which in turn activates phospholipase C.,TI- is leads to the hydrolysis of phoshatidylinositol-(4,5)-bisphosphate (PIP2) to yield diacylglycerol (DAG) and inositol (I,4 ,5)-trisphosphate (IPS), which cause an increase in intracellular Ca++. This cation can then interact to stimulate or inhibit enzymes, or cause hyperpolarization, secretion or contraction , In contrast, activation of the M2 subtype on cardiac muscle stimulates a G protein that inhibits adenylyl cyclase increase K+ conduction that decrease heart rate & contraction force. Pirenzepine (tricyclic anticholinergic drug), selectively inhibits MI in the gastric mucosa , useful in the treatment of gastric and duodenalulcers (there are no clinically important agents that interact with the M4 and M5 receptors). B-Nicotinic receptors: bind acetylcholine & nicotine but show only a weak affinity for muscarine , located in the CNS ,adrenal medulla, autonomic ganglia (block by hexamethonium), and the neuromuscular junction(block by tubocurarine). Direct Acting Cholinergic Agonist Cholinergic agonists mimic the effects of acetylcholine by binding directly to cholinoceptors. These agents are synthetic esters of choline, such as carbachol and bethanechol, or naturally occurring alkaloids such as pilocarpine. All of the direct-acting cholinergic drugs have longer durations of action acetylcholine. A-Acetylcholine : It is a quarternary ammonium compound that cannot penetrate membranes , of no importance because of its multiplicity of actions and its rapid inactivation by acetylcholinesterase. Acetylcholine has both muscarinic and nicotinic activity. Its actions include: 1-decrease in heart rate & cardiac output (like vagal stimulation that regulate heart by releasing of acetylcholine at SN node). 2-decrease in blood pressure (via vasodilation effects insite of no parasympathetic innervation but cholinergic receptors found) , by increase intracellular Ca++(atropine block this receptors). 3-other effects like GIT(↑salivery secretion , intestinal secretion & motility ) , on Rsstimulate bronchial secretion , GUT (↑tone of detrusor urinae muscle) , on eye ↑ciliary muscle contraction for near vision & constriction of pupillae sphincter muscle →miosis. B-Bethanechol :Its srtucturally related to Acetylcholine , but acetate replace by carbamate & choline is methylated , not hydrolyzed by acetylcholinestrase but by other esterases. of strong muscarnic effect & little or no nicotinic action , duration of action 1 hour , act on smooth muscle of GIT & bladder. Their action increase GIT motility & tone , & stimulate the detrusor muscle of bladder while triggone & sphincter relax →urine expulsion. So use to treat atonic bladder(postpartum & postoperative non-obstructive retension).Side effects :sweating , salivation, flushing , decrease blood pressure , nausea , abdominal pain , diarrhea , bronchospasm. C-Carbachol (carbamylcholine) :Its of both muscarinic & nicotinic action , its ester of carbamic acid & a poor substrate fo acetylcholinesterase , of 1 hour action. Its effects on both CIT& CVS because its of ganglion-stimulating activity (1st stimulat then depress these system ), on local eye application cause miosis like acetylcholine , its release epinephrine from adrenal nedulla by its nicotinic action.Its use rarely(long duration&high potency) so used in eye only cause constriction of pupil& ↓intraocullar pressure(IOP). D-Pilocarpine :- Its a tertiary amine & stable to hydrolyze by acetylecholinesterase , less potent than acetylcholine , used for eye application only(muscarinic action) cause rapid miosis & not able to focus(spasm of accommodation).its potent stimulant of sexcretion of sweat, tears, saliva but not use for this purpose(nonselective agents ). uses 1-Drug of choice for emergency lowering IOP in both open & close angel glaucoma its effect last for 1 day, 2-to promot salivation in xerostomia(result from head-neck irradiation) & sjogren,s syndrome(lack of tear& dry mouth) treated by oral tablet of pilocarpine.its side effect it enter CNS cause disturbance , its cause sever sweating & salivation. E-Cevimeline other non-specific cholinergic agent like pilocarpine Anticholinesterase(reversible) :Acetylcholinesterase enzyme that cleaves acteylcholine to acetate & choline , locat in pre& post synaptic in terminal nerve. by ithibition of acteylcholinesterase →prolong lifetime of acetylcholine & accumulate in synaptic space troduce a respone at muscarinic & nicotinic receptors(NMJ& Autonomic NS). Alzheimer is treated by acetylcholinesterase inhibitors. A-Physostigmine :- Is an alkaloid (a nitrogenous compound found in plants) and a tertiary amine. It is a substrate for acetylcholinesterase, and forms a relatively stable enzymesubstrate intermediate that reversibly inactivates acetylcholinesterase , result in potentiation of cholinergic activity through-out the body.its duration of action 2-4 hours , enter & stimulate CNS , its of wide range of action ( stimulate muscarinic & nicotinic receptors(NMJ& Autonomic NS ). Uses: 1-its increases intestinal and bladder motility, which serve as its therapeutic action in atony of either organ. 2-Placed topically in the eye, it produces miosis and spasmof accommodation and a lowering IOP. It is used to treat glaucoma, but pilocarpine is more effective.3-also used in the treatment of overdoses of drugs with anticholinergic action like atropine, phenothiazine & tricyclic antidepressant. side effects ;-1- convulsion in eye using on high dose ,2-bradycardia ,3- paralysis of skeletal muscle (all rare at therapeutic dose ). B- Neostigmine its a synthetic compound that reversibly inhibits acetylcholinesterasea as does physostigmine, not enter CNS sice it more polar , their effect on skeletal muscle more than of physostigmine(stimulate contraction before paralysis) ,2-4 hours their duration of action , 1-used to stimulate the bladder& GIT plus as antidote for tubocurarine & other NM blocking agents(competitive) , 2- treatment of myasthenia gravis (autoimmune disease caused by antibodt to nicotinic receptor that bind to the acetylcholine receptors of neuromuscular junctions. This causes their degradation, and thus makes fewer receptors available for interaction with the neurotransmitter. Adverse effects (salivation,flushing,↓BP,abdominal pain,nausea,diarrhea bronchos-pasm). C. Pyridostigmine & ambenomium : used as chronic management of myasthenia gravis. Its duration of action (3-6 hours) & (4-8 hours) respectively. D-Edrophonium Its action like neostigmine , but of rapid absorbed& short duration of action (10-20 minutes). Edrophonium is a quarternary amine and is used in the diagnosis of myasthenia gravis. Intravenous injection of edrophonium leads to a rapid increase in muscle strength. Care must be taken since excess drug may provoke a cholinergic crisis. Atropine is the antidote, E-Demecarium ;Its a quaternary amine structuraly related to neostigmine like its action& side effects , used for 1-trea open angle gluacoma(referactory to other drugs) , 2-in closed angel glaucoma after irredectomy , 3- diagnosis & treatment of accommodative esotropia. F-(Tacrine , Donepezil , Rivastigmine , Galantamine) :In alzeheimers disaese ( deficiency of cholinergic neorons in CNS) , tacrine is the 1st one available but replace by other due to its hepatotoxicity , all able to delay the progression of disease but not stop it. GIT distress its side effects. Anticholinesterase (irreversible) A number of synthetic organophosphate compounds have the capacity to bind covalently to acetylcholinesterase(→ long lasting increase in acetylcholine at all sites ). Many of these drugs are extremely toxic and were developed by the military as nerve agents. Related compounds(parathion)are employed as insecticides. Echothiophate 1. Mechanism of action: is an organophosphate covalently binds by its phosphate group to a serine -OH at the active site of acetylcholinesterase.Once this occurs, the enzyme is permanentlv inactivated, and restoration of acetylcholinesterase activity requires the synthesis of new enzyme molecules., their action include generalize cholinergic stimulation , paralysis of motor function(→breathing difficulties), convulsion , intense miosis , high atropine dose reverse most of its effects. their uses 1- chronic treatment of open angle glaucoma as solution(effects last for 1 week after single use) its side effects& causing catracts limit its uses. Reactivation of acetylcholinesterase(pralidoxime) :- Its able to reactivate the enzyme if used at time before aging of acetylcholinesterase(before loss its alkyl group) , not cross intoCNS , act by displace phosphate group from organophosphate & regenerate the enzyme. side effects like acetylcholinesterase inhibitors as high dose. Cholinergic antagonist agents :- Also called parasympatholytic or anticholinergic or cholinergic blockers or cholinergic antagonist.Anti-muscarinis agents :- selectively bind muscarinic receptor&block it. Ganglionic blockers show prefernce for nicotinic receptors in both sympathatic & parasympathatic ganglia (least important of anticholinergic agents). Neuromuscular blocker agents interfere with impulse transmission to skeletal muscle ,used in anesthesia during surgery. l-Anti-muscarinic agents :Like atropine & scopolamine block muscarinic receptors causing inhibition of all muscarinic function plus block few of sympathatic neuron that innervate salivary & sweat glands with little or no action on Nmjunction or ganglia. A-Atropine :- Its tertiary amine belladonna alkaloid , compete with acetylcholine for muscarinic receptors acts centrally & peripherally , its duration of action 4 hours on local eye application may last for 1 day. Orally absorbed , t1/2 4 hours , eliminate via urine. Action :-1- on eye :-persistance mydriasis(dilate pupil), unresponsiveness to light & cycloplegia(inable to focus for near vision ) , dangerous elevation of IOP , so short acting agent like tropicamide or alpha adrenergic like phenylphrine used for ophthalmic examination. 2-GIT:-as antispasmolytic to reduce GIT activity , not affecting HcL production.3-GUT :-reduce hypermotility of urinary bladder (rare use in enuresis instate). 4-CVS:-at low dose cause bradycardia(central activation of vagal efferent outflow block M1), atr high dose cause tachycardia(block M2 in SA node ).5-Secretion:-decrease salivation sweat & lacrima glands. Uses :- for eye to measure refractive errors(induce mydriasis& cycloplegia). relax both GIT & bladder , antidote for cholinergic agonist poisening , as antisecretary to reduce block secretion fromupper & lower RS prior surgery. Side effects (dry mouth ,blurred vision ,tachycardia ,constipation , on CNS delirium, hallucination that end with depression , collapse respiratory system & death , increase body temperature especially in childern) , its over dose treated by physostigmine. B-Scopolamine Its a tertiary amine belladonna derived , of peripheral effects like atropine , of high action on CNS than atropine. Action :-most effective antimotion sickness agent sedation but at high dose excitment , induce euphoria(subject for abuse). Uses : motion sickness ,& amnesic action so use in anesthesia. C-Ipratropium :Inhaled ipratropium its a quaternary derivative of atropine use to treat asthma & chronic obstructive pulmonary disease , its +ve charge prevent its entery to circulation & CNS. D-Tropicamide & Cyclopentolate :Use as eye solution to induce mydriasis & cyclopegia as atropine , its duration 6 & 24 hours respectively while atropine 7-14 days. ll-Ganglionic blocker :A-Nicotine : its a compenent of cigarette , of no therapeutic benefit , it deleteriuos for health, available as patches, lozenges, gums & other form , patches absorbed via skin & reduce the craving for nicotine (for person wish stop cigarette).Its cause depolarize autonomic ganglia (1st stimulate then paralyse all ganglia) stimulation by effect on both para & sympathatic causing increase blood pressure , heart rate , secretion & persistalsis , on high dose BP fall(ganglionic blockade) & activity on GIT & bladder cease. B-Mecaylamine :-its a competitive nicotine recepto blockade , its duration of action 10 hours after single dose , good orally absorbed , used in treatment of emergency hypertension. lll-Neuro-Muscular Blocker agents: its block trasmission of cholinergic between motor nerve ending & the nicotinic receptor on the neuromuscular end plate of skeletal muscle ,they are structurally analogs of acetylcholine , its divided into depolarizing(acetylcholine agonist )& non-depolarizing (acetylcholine antagonists) agents , its useful 1- during surgery to produce complete muscle relaxation ,2- facilitating intubation. Other central muscle relaxant like diazepam(bindGABA receptor) , baclofen act at GABA receptor in CNS , dantrolene(interferwith calicium release from sacroplasmic reticulum). Depolarizing agent like succinylcholine Use as IV but of short duration of action so used as continuous infusion , unlike to acetylcholine its persist for long time in the synaptic cleft(time depend on diffusion from motor end plate & hydrolysis by plasma cholinesterase) within synaptic cleft not metbolise by cholinesterase till diffuse to circulation. Mode of action :-attach to nicotinic receptor & depolarize the junction , 1st open Na channel →depolarize of the receptor (phase l) →transient musle fasciculation ,then within few minutes , on contiue attachment to receptor make receptor incapable to transmit further impulses , continous depolarizing give way to gradual repolarization as Na channel closed or block this cause resistance to depolarization(phase ll) & flaccid paralysis. Uses:1-endotracheal intubation(anesthesia induction),2- electoconvulsive shock treatment. Side effects: 1- apnea , 2-hyperthermia , 3-hyperkalemia. Non-depolarizing (competive) blockers :1st agent is curare , while tubocurarine consider as prototype of this group , replace by other due to their side effects(lowering BP & cause histamine release promote ganglionic blockade ) , its ↑ safety of anesthetic agent since it ↓amount of anesthesia to induce muscle relaxant & recover patient quickly after surgery (high anesthesia dose cause respiratory paralysis , cardiac depression & prolong recover time ). Mode of action :-at low dose ; its interact with nicotinic receptor so prevent acetylcholine bind , so prevent muscle depoloarization& inhibit muscle contraction (so called competitive blockers ). Its effects over come by either ↑conc. of acetylcholine in the synaptic cleft or by adminstration of chloinesterase inhibitors like()neostigmine , pyridostigmine or edrophonium)→short the duration of NM blocker. But at high conc. it can block ion channel of the end plate→ further weakening of NM trasmission &↓ ability of acetylcholinesterase inhibitors to reverse the action of nondepolarizing muscle relaxant. =1st muscle paralyzed is muscle of[ eye & face → fingers→limbs→neck→trunk→intercostal →diaphram]. Some agents release histaminelike()tubocurarine, mivacurium , atracurium)→ BP↓, flushing & bronchconstriction. Uses :-in anesthesia during surgery to relax skeletal muscle , facilitate intubation & in othropedic surgery. Kinetics :-used as IV , not used orally due to(1- their absorption minimal , 2- they possess 23 quaternary amine in their srtucture make them orally ineffective). Most of them excrete unchange in urine like(tubocurarine ,metocurine, mivacurium, pancuronium , doxacurium) ,while atracurium degreded spontaneously in plasm then ester hydrolysis , its release histamine & metabolite into laudanosine →provoke seizures so it replace by its isomer cisatracurium less likely cause these , (rocuronium& vecuronium) both are aminosteroid drug that deacetylated in liver (liver disease may prolong their clearance). Drugs interaction:-1-aminoglycoside antibiotics like getamycin & tobramycin (↓acetylcholine release) so ↑ blockade.2-Ca++ channel blocker ↑ blockade NM blockers.3halogenated hydrocarbon anesthetics like halothane sensitize NM junction for action of NM blocker(enhance blockade). 4- cholinesterase inhibitors , overcome the action of nondepolarizing NM blockers.