[PHA LEC - LE 2] 04 - Adrenergic and Ganglionic Antagonists (V1).pdf

PHARMACOLOGY | TRANS 04 LE Adrenergic and Ganglionic Antagonists PAUL VINCENT C. BAUTIST...

PHARMACOLOGY | TRANS 04 LE Adrenergic and Ganglionic Antagonists PAUL VINCENT C. BAUTISTA, RPH, MD | Lecture Date (09/24/2024) | Version #1 02 OUTLINE → These are now replaced with safer and newer 💬 I. Overview III. Ganglionic Blockers alternative drugs II. Adrenergic Antagonists A. Classification These are still being studied because it is still being A. Classification B. Mechanism of Action asked in the board exam, and when you are left with no B. Therapeutic Uses C. Therapeutic Uses choice but to use these types of drugs. C. Adverse Effects D. Pharmacokinetics D. Specific Agents E. Adverse Effects F. Specific Agents IV. Review Questions V. References VI. Appendix Must Lecturer Book Previous Youtube ❗️ Know 💬 📖 📋 Trans 🔺 Video SUMMARY OF ABBREVIATIONS BP Blood pressure DA Dopamine EPSP Excitatory postsynaptic potential JG Juxtaglomerular MAO Monoamine Oxidase NE Norepinephrine OTC Over-the-counter Figure 1. Sites of action of agent[Lecturer’s PPT] RAAS Renin angiotensin aldosterone system II. ADRENERGIC ANTAGONISTS TCAs Tricyclic antidepressants Drugs that inhibit activity at adrenergic synapses V-FIB Ventricular fibrillation → Do NOT directly block postsynaptic adrenergic VMAT-2 Vesicular Monoamine Transporter receptors V-TACH Ventricular tachycardia Similarly, some agents act on the adrenergic neuron, either LEARNING OBJECTIVES to: ✔ Review the basic physiology involved in the different → Interfere with neurotransmitter release sites of action affected by adrenergic antagonists and → Alter the uptake of the neurotransmitter into the ganglionic blockers adrenergic nerve ✔ Correlate the physiology involved in the said sites of However, due to the advent of newer and more effective action with pharmacologic principles behind the different agents, with relatively fewer side effects, these agents are agents in adrenergic antagonism and ganglionic rarely used therapeutically. blockade A. CLASSIFICATION ✔ Discuss the respective pharmacodynamic and ACCORDING TO MECHANISM OF ACTION (MOA) pharmacokinetic properties of the various adrenergic Drugs that affect NE release from nerve terminals antagonists and ganglionic blockers → Blockade of NE release from adrenergic nerve terminals I. OVERVIEW ▪ Guanethidine Adrenergic antagonists and ganglionic blockers are groups ▪ Bethanidine of drugs may act non-selectively or selectively on the ▪ Guanadrel respective cholinergic or adrenergic receptors at the ▪ Bretylium peripheral nerve terminals ▪ Debrisoquine Some of these drugs have a central action and are → Depletion of catecholamine stores — decrease the therapeutically used for this effect. available stores In contrast to other sympathetic blockers, adrenergic ▪ Reserpine neuron blockers do not have direct blocking action on ▪ Guanethidine post synaptic receptors because the other sympathetic Drugs that affect NE synthesis blockers act precisely on those postsynaptic receptors. → Formation of false neurotransmitters On the other hand, the ganglionic blocking drugs will be ▪ Methyldopa discussed more for academic and historical purposes ▪ Guanethidine → Faced with situations/localities with only these drugs ▪ Pargyline (MAO inhibitor) → Inhibition of catecholamine synthesis (rate limiting step 💬 available Most of these drugs are already obsolete; no longer in the synthesis of NE) clinically/commercially available ▪ Methyltyrosine/Metyrosine → Most of the drugs are nonspecific, which means they → Destruction of adrenergic nerve fibers 💬 have a lot of intolerable adverse effects related to ▪ 6-hydroxydopamine their primary action Guanethidine belongs to many groups. This accounts for the drug’s nonspecificity. LE 2 TG #15 | D. Li, K. Libatique, *B. Lim, D. Lim, K. TE | B. Lim, D. Lim AVPAA | C. Lee PAGE 1 of 8 TRANS 4 Lopez VPAA | P. Fabros PHARMACOLOGY | LE 2 Adrenergic Ganglionic/Neuron Blockers | Paul Vincent C. Bautista, RPh, MD B. THERAPEUTIC USES IRREVERSIBLY binds tightly to adrenergic storage Hypertension: reserpine and methyldopa are used in vesicles in the central and peripheral adrenergic neurons and inhibits ATP-magnesium dependent vesicular ❗️ patients with mild hypertension Methyldopa - drug of choice for pregnant patients monoamine transporter (VMAT-2) with hypertension Causes the passive diffusion of catecholamines into → Guanethidine - used clinically for severe hypertension the cytoplasm where they are metabolized by the ▪ However, its use has been superseded by other intraneuronal MAO drugs with less adverse effects → Leads to decreased to low level of NE content in the Anti-arrhythmia tissues that results in blockade of sympathetic → Bretylium (Class III) - was used before, but other safer transmission (pharmacologic sympathectomy) drugs are preferred Reserpine also depletes NE, dopamine, and → One of the oldest anti-arrhythmic drugs 5-hydroxytryptamine from neurons in the CNS and to a lesser extent in the adrenal medulla C. ADVERSE EFFECTS Antihypertensive effects of reserpine are probably related Orthostatic hypotension to both its peripheral and central actions → Often caused by guanethidine and its congeners Recovery of sympathetic function from reserpine effects → Produce greater degree of postural hypotension than requires synthesis of new storage vesicles 💬 reserpine and methyldopa, as well as clonidine → Takes days to weeks after discontinuation of reserpine → Clonidine - also known as Catapres (brand name) Reflex tachycardia THERAPEUTIC USES → Guanethidine produces greater degree of reflex Treatment of patients with mild hypertension at low tachycardia compared to reserpine, methyldopa doses, in combination with diuretics, especially in the → The decrease in BP is due to the sympathetic blockade elderly → This will stimulate the baroreceptor reflex mechanism to However, the availability of newer drugs that are effective produce reflex tachycardia and well tolerated, the use of reserpine has declined Peripheral edema because of its CNS effects → Decrease in BP will stimulate the JG cells which in turn Considered as obsolete in highly developed countries; still will lead to activation of the Renin Angiotensin used in developing countries because it is less expensive Aldosterone (RAA) System that newer antihypertensive agents → When the RAA System is stimulated, this leads to PHARMACOLOGIC ACTIONS/EFFECTS increase in water and sodium absorption, resulting in CARDIOVASCULAR SYSTEM peripheral edema. Low dose with long term treatment Parasympathetic predominance due to sympathetic → Decreases peripheral vascular resistance, heart rate, blockade and cardiac output resulting in decreased blood → GI disturbances: diarrhea, nausea, vomiting, increased pressure gastric acid secretion Orthostatic hypotension may occur in low doses but it does → Nasal stuffiness or congestion not usually cause symptoms → Miosis Decrease in BP may activate RAA system and produce Sexual dysfunction due to sympathetic blockade salt and water retention → Delayed or retrograde ejaculation → Guanethidine causes the worst of this effect CENTRAL NERVOUS SYSTEM Sedation Depletion of cerebral amine stores → Produced by drugs that are lipid soluble and can → Sedation traverse the CNS → Depression ▪ Reserpine and methyldopa → Extrapyramidal (aka Parkinsonian) symptoms ▪ No sedative effect with guanethidine because it is Patients with history of depression should NOT be given reserpine 💬 POLAR (cannot cross the blood-brain barrier) Therefore, guanethidine has less CNS effects GASTROINTESTINAL TRACT D. SPECIFIC AGENTS Due to parasympathetic predominance as a result of 1. RESERPRINE sympathetic blockade at adrenergic synapses, it causes: Reserpine - plant alkaloid from Rauwolfia serpentina → Mild diarrhea Blocks Mg2+ / adenosine triphosphate dependent → Abdominal cramps transport of biogenic amines from the cytoplasm into → Increased gastric acid secretion storage vesicles in the adrenergic nerves of all body ADVERSE EFFECTS/PRECAUTIONS 💬 tissues Mostly result from its actions on the CNS (mental status) Recall: competitive antagonism and GIT → Causes depletion of biogenic amines At low doses, → Sympathetic function, in general, is impaired because of → Small degree of hypotension decreased release of norepinephrine → Mild diarrhea, abdominal cramps Slow onset, long duration of action = effects that persist for → Nasal stuffiness many days after discontinuation → Sedation MECHANISM OF ACTION → Inability to concentrate or perform complex tasks At very low concentration - blocks transport of NE and Less frequent adverse effects other amines into the synaptic vesicles → May occur at any time even after months of uneventful treatment PHARMACOLOGY Adrenergic Ganglionic/Neuron Blockers PAGE 2 of 8 PHARMACOLOGY | LE 2 Adrenergic Ganglionic/Neuron Blockers | Paul Vincent C. Bautista, RPh, MD → Extrapyramidal symptoms - result from dopamine ▪ Initial depressor is followed by a pressor response depletion in the corpus striatum due to rapid release of NE from the storage vesicles ❗️ → Exacerbation of peptic ulcer brought about by displacement of guanethidine Therefore, should NOT be given to patients with a → Followed by late progressive depressor response history of mental depression or peptic ulcer to avoid due to sustained ↓ total PVR and ↓ BP worsening of the condition THERAPEUTIC USES At high doses, Treatment of severe hypertension and Raynaud’s → Central Nervous System phenomenon ▪ Hypothermia Control pressor episodes associated hyperreflexia ▪ Sedation, lassitude, nightmares, severe mental secondary to high spinal cord lesions depression, bizarre dreams However, because of the severe adverse effects of this ▪ Most serious adverse effect is occasional psychotic drug, it is no longer available in US, and rarely used if depression that can lead to suicide available in other countries ▪ Discontinue the drug if depression occurs → Replaced by newer antihypertensive drugs with lesser 2. GUANETHIDINE adverse effects that are better tolerated by patients Blocks release of stored NE as well as displaces NE PHARMACOKINETICS from storage vesicles Polar drug, therefore does NOT traverse body → Produces a transient increase in BP → Leads to gradual depletion of NE in nerve endings except for those in the CNS ❗️ membranes including the CNS Variable oral bioavailability which may be low that ranges from 3-50% Adrenergic Neuron Blocker 50% of the drug is metabolized and the remainder is → Commonly causes orthostatic hypotension and excreted unchanged in the urine interferes with male sexual function Long half-life: 5 days Supersensitivity to NE Produces a gradual onset of sympathoplegia and its → Due to depletion of the amine can result in hypertensive maximal effect is reached in 1 to 2 weeks (not to be used if crisis in patients with pheochromocytoma (adrenal patient has to be treated aggressively) tumor that secretes excessive catecholamines) Effect persists for a comparable period after cessation of MECHANISM OF ACTION therapy Initially blocks NE release by blocking impulse ADVERSE EFFECTS conduction in nerve terminals (local anesthetic action In therapeutic doses, often associated with symptomatic similar to Bretylium) postural hypotension but more evident if given in high Possibly interferes with ability to undergo exocytosis doses Responsible for most of the sympathoplegia that occurs → More of an augmented adverse effect because it’s Produces little effect on the adrenal medulla dose-dependent Exhibits cocaine-like action by inhibiting NE neuronal Resultant sympathoplegia causes pharmacologic uptake sympathectomy → Also transported by across the presynaptic membrane Causes diarrhea as a result of ↑ gastrointestinal motility → Uptake is essential for guanethidine’s action Causes nasal congestion or stuffiness due to → Enters the vesicle where it may be concentrated parasympathetic predominance Table 1. Guanethedine’s Similarities with Reserpine, Produces delayed or retrograde ejaculation (into the Tyramine, and Norepinephrine[Lecturer’s PPT] bladder) Similarities Similarities Similarities w/ → Remember: Shoot (ejaculation) = Sympathetic w/ Reserpine w/ Tyramine Norepinephrine Causes marked reflex tachycardia as a result of Replaces NE If given IV, it Transport by neuronal compensatory baroreflex mechanism by promoting promotes uptake (or uptake 1) Profound ↓ in BP also activates RAAS that will cause fluid its release rapid release can be blocked retention and edema causing a of NE from also by drugs that Precaution: Dose should not be increased at interval gradual stores block the shorter than 2 weeks to avoid drug accumulation and depletion of catecholamine uptake toxicity NE stores in or those that displace Because of these ADRs, it is now rarely used especially the nerve amines from the nerve with the advent of newer drugs that are efficacious or more endings terminal superior and with lesser adverse effects that are better ▪ TCAs tolerated ▪ Amphetamine DRUG INTERACTIONS ▪ Ephedrine Over the Counter (OTC) cold preparations can produce ▪ Phenylpropanolamine 💬 hypertension in patients taking guanethidine especially ▪ Phenothiazines with chronic administration ( Principle: antagonism) ▪ Phenoxybenzamine ❗️ TRIPLE RESPONSE (if given by rapid IV only, not observed with oral administration) → Contain sympathomimetic drugs like phenylephrine → In the presence of these agents, the adrenergic receptors are more sensitive to the presence of → Initial depressor response due to ↓ HR and relaxation sympathomimetic drugs and will produce ↑ sympathetic of capacitance vessels and ↓ CO discharge → Tyramine-like action → α receptors are activated and will cause ↑ PVR and ↑ BP PHARMACOLOGY Adrenergic Ganglionic/Neuron Blockers PAGE 3 of 8 PHARMACOLOGY | LE 2 Adrenergic Ganglionic/Neuron Blockers | Paul Vincent C. Bautista, RPh, MD Chronic use may cause upregulation of the number of Initially releases NE from the nerve terminals causing a receptors and denervation supersensitivity brief sympathomimetic effect, followed by inhibition of → Result of pharmacological sympathectomy with the use NE release (local anesthetic action) by depressing of guanethidine adrenergic nerve terminal excitability In patients with pheochromocytoma, it can produce Does NOT depress axonal conduction along the hypertensive crisis by releasing catecholamines sympathetic nerves Concurrent TCAs or cocaine administration to patients who Blocks K+ channels are on guanethidine therapy It may also inhibit the Na+/K+-ATPase by binding to the → Guanethidine’s antihypertensive effect will be reduced extracellular K+ site and can result in severe hypertension THERAPEUTIC USES ▪ Remember principle: antagonism Prophylaxis and treatment of ventricular fibrillation → TCAs and cocaine block the neuronal uptake of NE as (V-fib) well as that of guanethidine Treatment of life-threatening ventricular arrhythmias such → Neuronal uptake is necessary for guanethidine’s as ventricular tachycardia (V-tach) that have failed to hypotensive activity respond to first-line antiarrhythmic drugs like lidocaine or ❗️ 3. METHYLDOPA Therapeutically indicated as the drug of choice in the procainamide III. GANGLIONIC BLOCKERS treatment of hypertension in pregnant patients because of its efficacy and safety profile both in the mother Cholinergic Antagonists RECALL ❗️ and fetus → a.k.a. cholinergic blockers, parasympatholytics or ❗️ MECHANISM OF ACTION Major action: Stimulation of central α2 receptors → Results in reduced central sympathetic outflow from the anticholinergic drugs ▪ “lytic” = to cut / inhibit Bind to cholinoceptors but do NOT trigger usual vasomotor centers in the brainstem receptor-mediated intracellular effects → Produce ↓ total PVR and BP Most useful of these agents that selectively block ❗️ ADVERSE EFFECTS Mostly CNS related due to depletion of NE and DA stores muscarinic synapses of parasympathetic nerves Structural analogs of acetylcholine act at receptors on the end plate of the neuromuscular junction → Most frequent: Sedation → Antagonists (nondepolarizing type) → Relatively infrequent: nightmares and depression → Agonists (depolarizing type) Lactation (a.k.a. galactorrhea) Effect of parasympathetic innervation are interrupted → Excess excretion of breastmilk → Actions of sympathetic stimulation left unopposed ▪ Caused by inhibition of dopaminergic mechanism in ▪ Remember: you oppose one arm, you don't need the hypothalamus to stimulate the other arm. It still becomes the Autoimmune Hemolytic Anemia predominant arm - you block the parasympathetic, → Detected by positive (+) Coomb’s Test ▪ Presence of autoantibodies against the red blood cells ❗️ the sympathetic arm becomes predominant. 2nd group of drugs: Ganglionic blockers → Show preference for nicotinic receptors of Drug induced hepatitis sympathetic and parasympathetic ganglia Drug fever → Clinically least important of the anticholinergic drugs 4. ALPHA-METHYLTYROSINE (METYROSINE) 3rd family of compounds: Neuromuscular blocking agents Used as adjunct to phenoxybenzamine or to other α and → Interfere with transmission of efferent impulses to β adrenoceptor blockers (i.e., labetalol), or calcium skeletal muscles channel blockers → Used as adjuncts in anesthesia during surgery → Treatment of symptomatic patients with inoperable or metastatic pheochromocytoma to control BP and other symptoms ADVERSE EFFECTS Orthostatic hypotension Can traverse BBB and cause extrapyramidal symptoms due to reduced DA levels in the CNS → Sedation and Anxiety Diarrhea Risk of crystalluria 5. BRETYLIUM Quaternary ammonium compound with poor oral bioavailability Directly acting on ischemic myocytes Class III antiarrhythmic MECHANISM OF ACTION Accumulates in the sympathetic ganglia and postganglionic adrenergic neurons Figure 2. Ganglionic blocking agents[Lecturer’s PPT] PHARMACOLOGY Adrenergic Ganglionic/Neuron Blockers PAGE 4 of 8 PHARMACOLOGY | LE 2 Adrenergic Ganglionic/Neuron Blockers | Paul Vincent C. Bautista, RPh, MD A. CLASSIFICATION THERAPEUTIC USES - CAVEAT Chemical structure or mechanism of action Ganglionic blockers are rarely used because of availability → Persistent Depolarizing Blockers of more selective autonomic antagonists that are effective, ▪ Nicotine (prototype) tolerable, with less adverse effects. ▪ Lobeline Severe, intolerable toxicities were the major reasons for ▪ Coniine their abandonment in the treatment of hypertension. ▪ Tetramethylammonium (TMA) These drugs have been supplanted by superior agents ▪ Dimethylphenylpiperazine D. PHARMACOKINETICS ▪ Decamethonium (C10) Quaternary ammonium compounds → Non-depolarizing or Competitive Ganglionic → Absorption from the GIT is incomplete and Blockers unpredictable ▪ Quaternary Ammonium Compounds → Generally excreted via urine mostly in unchanged form − Pentolinium tartrate Trimethaphan − Chlorisondamine → Polar drug with rapid onset and brief duration of action − Tetraethylammonium chloride (TEA) → Excreted by glomerular filtration and active secretion, ▪ Triethylsulfonium compounds with 30% unchanged in the urine − Trimethaphan camsylate Mecamylamine ▪ Secondary Amines → Secondary amine − Pempidine chloride → Rapidly and almost completely absorbed from the GIT → Noncompetitive Blockers → Crosses blood brain barrier and readily enters the ▪ Quaternary Ammonium compounds CNS and blocks central nicotinic receptors − Hexamethonium → Concentrates in the liver and kidneys ▪ Secondary amine → Fast onset = 37 minutes − Mecamylamine → Long duration of action = 22 hours o recently found newer uses and applications → Excreted slowly via the kidneys B. MECHANISM OF ACTION → Take note for patients who have impaired renal function Ganglionic blockers specifically act on nicotinic receptors E. ADVERSE EFFECTS of both parasympathetic and sympathetic autonomic Since ganglionic blockers block parasympathetic and ganglia sympathetic actions, pharmacologic effects depend upon → Some also block ion channels of autonomic ganglia the dominant tone in a given organ system These drugs show no selectivity toward the parasympathetic or sympathetic ganglia and are not Table 2. Usual Predominance of Sympathetic or effective as neuromuscular antagonists Parasympathetic Tone at Various Effector Sites, and These drugs block the entire output of the autonomic Consequences of Autonomic Ganglionic Blockade[Lecturer’s PPT] nervous system at the nicotinic receptor Predominant Effect of Ganglionic Site Except for nicotine, other drugs mentioned in this Tone Blockade category are nondepolarizing, competitive antagonists Arterioles Sympathetic Vasodilation Responses observed are complex and unpredictable, (adrenergic) Increased peripheral making it impossible to achieve selective actions blood flow → Therefore, at present ganglionic blockade is rarely used Hypotension therapeutically Veins Sympathetic Dilation → However, ganglionic blockers often serve as tools in (adrenergic) Peripheral pooling of experimental pharmacology blood C. THERAPEUTIC USES Decreased venous return Decreased cardiac output Acute hypertensive emergencies: trimethaphan camsylate Heart Parasympathetic Tachycardia Adjunct during anesthesia to produce controlled (cholinergic) hypotension during surgery Iris Parasympathetic Mydriasis → Minimize bleeding in the operative field (cholinergic) → Decrease blood loss in various orthopedic procedures Ciliary Parasympathetic Loss of visual → Facilitate microsurgery on blood vessels muscle (cholinergic) accommodation Tourette’s syndrome GIT Parasympathetic Reduced tone and motility → Neurological disorder characterized by repetitive (cholinergic) Constipation stereotype involuntary movements. Decreased gastric and ▪ Patients often exhibit coprolalia (impulsive cursing). pancreatic secretions → Mecamylamine is currently licensed by the US FDA as Urinary Parasympathetic Urinary retention an orphan drug for this condition bladder (cholinergic) → May be used if series of more usually used agents had Salivary Parasympathetic Xerostomia failed glands (cholinergic) Adjunct to smoking cessation therapy: mecamylamine Sweat Sympathetic Anhidrosis → Used with transdermal nicotine patch to reduce nicotine glands (cholinergic) craving in patients attempting to quit smoking Genital Sympathetic and Decreased stimulation → Blocks central nicotinic receptors tract parasympathetic PHARMACOLOGY Adrenergic Ganglionic/Neuron Blockers PAGE 5 of 8 PHARMACOLOGY | LE 2 Adrenergic Ganglionic/Neuron Blockers | Paul Vincent C. Bautista, RPh, MD How do they exert their therapeutic effect? → Autonomic ganglia → (See Table 2) Ex. The blood vessels predominant tone → Neuromuscular junctions is sympathetic, therefore once you inhibit this, the → Adrenal medulla parasympathetic arm will predominate causing dilation. → Brain Adverse effects of ganglionic blockers are direct Although therapeutically employed for smoking cessation extensions of their pharmacologic effects to relieve withdrawal symptoms, there are other drugs Sympathoplegia used for this purpose → Postural hypotension → Varenicline → Sexual dysfunction may occur with moderate doses and → Bupropion may prevent both erection and ejaculation MECHANISM OF ACTION Parasympathoplegia Initially stimulates the ganglia by an Ach-like membrane → Urinary hesitancy depolarization with influx of sodium and calcium ions → May precipitate urinary retention in men with BPH causing generation of fast excitatory postsynaptic → Constipation may be marked due to profound inhibition potential (EPSP) of GIT motility This is followed by persistent depolarization, which may → Predictable cycloplegia with loss of accommodation lead to depolarization blockade because the ciliary muscle is primarily innervated by the → This mechanism is analogous to that of succinylcholine parasympathetic nervous system Results in inhibition of ganglionic transmission → Moderate pupillary dilation due to dominant PSNS tone in the iris PHARMACOKINETICS → Moderate tachycardia results because the sinoatrial Half-life = 1-2 hours and that of its active metabolite is 20 (SA) node usually dominated by the PSNS hours → Reduce secretion of exocrine glands, causing → This accounts for those who are addicted, they xerostomia, anhidrosis consume a lot of sticks because it has a relatively short CNS half-life. → Mecamylamine causes sedation, tremor, choreiform Primarily metabolized in the liver by CYP2A6 and CYP2B6 movements, and mental aberrations 2. TRIMETHAPHAN CVS Competitive Ganglionic Blocker → Since blood vessels are primarily innervated by the Compete with Ach for binding with ganglionic receptors to sympathetic nerve fibers, ganglionic blockade causes a stabilize membrane against Ach stimulation marked decrease in arteriolar and venomotor tone → Blood pressure will profoundly diminish resulting from 3. HEXAMETHONIUM decreased peripheral vascular resistance and venous Noncompetitive Channel Blocker return Blocks ion channel/s that have been opened by → Blockade of vasoconstrictive or postural reflexes causes acetylcholine venous pooling of blood Produces most of its blockade by occupying sites in or on → These effects will produce marked postural hypotension nicotinic ion channel not by occupying cholinoceptor itself → Changes in heart rate following ganglionic blockade 4. MECAMYLAMINE depend largely on existing vagal tone Produces a competitive nicotinic blockade of the → Cardiac effects include ganglia ▪ Diminished contractility Shares properties associated with both hexamethonium ▪ Moderate tachycardia and the competitive ganglionic blockers F. SPECIFIC AGENTS Non-selective, noncompetitive antagonist 1. NICOTINE Binds to a site located deep within the nAChR channel Persistent Depolarizing Blocker pore, interfering with the ability of cations to permeate the Component of cigarette smoke, nicotine is a poison with channel many undesirable actions Duration of action is about 10 hours after a single Without therapeutic benefit and is deleterious to health administration Available as patches, lozenges, gums, and other forms Uptake of drug via oral absorption is good, in contrast to ▪ Patches are available for application on skin that of trimethaphan ▪ Drug is absorbed and is effective in reducing craving As with trimethaphan, it is primarily used to lower blood for nicotine in people who wish to stop smoking pressure in emergency situations Depending on dose, nicotine depolarizes autonomic Newer applications ganglia, resulting first in stimulation and then in → Smoking cessation - in conjunction with nicotine paralysis of all ganglia → Tourette’s syndrome Stimulatory effects are complex due to effects on both IV. REVIEW QUESTIONS[2026 Trans] sympathetic and parasympathetic ganglia 1. Ganglion blocking agents are important drugs to Effects due to release of transmitter from adrenergic know for solving cardiovascular problems like terminals and from the adrenal medulla hypertensive emergencies because they can block → ↑ blood pressure which of the following? → ↑ cardiac rate a. All muscarinic receptors ❗️ Natural alkaloid found in tobacco plant Addictive CNS stimulant → Causes ganglionic stimulation in low dose b. All nicotinic receptors c. All autonomic reflexes d. All neuromuscular reflexes → Causes ganglionic blockage in high doses Act as an agonist at the nicotinic cholinergic receptors PHARMACOLOGY Adrenergic Ganglionic/Neuron Blockers PAGE 6 of 8 PHARMACOLOGY | LE 2 Adrenergic Ganglionic/Neuron Blockers | Paul Vincent C. Bautista, RPh, MD 2. Prior to an eye exam, a patient is given a drug that 12. Only reserpine is available as the antihypertensive causes mydriasis with cycloplegia. What is the most agent in a mountainous rural area. What patient’s likely drug given? characteristic or condition will serve as relative a. Mecamylamine contraindication in prescribing reserpine? b. Pilocarpine a. Cognitive dysfunction c. Neostigmine b. Signs of Parkinson’s disease d. Phenylephrine c. Propensity of manic behavior 3. Ganglionic blocking agents are rarely used because d. Beginning Alzheimer’s disease of the numerous side effects they may produce. One 13. Norepinephrine is synthesized from what amino acid? such side effect is? a. Tryptophan a. Urinary urgency b. Valine b. Increased cardiac output c. Tyrosine c. Vasoconstriction d. Erectile dysfunction ANS: 4. Which of the following is NOT an effect of ganglionic 1. C. Ganglionic agents block not only the receptors but in blocking agents? general blocks the reflexes that come after binding with a. Xerostomia the nicotinic and muscarinic receptors. b. Blurring of vision 2. A. Recall sympathomimetic and cholinomimetic drugs. c. Hypertension Neostigmine is an indirect acetylcholinesterase inhibitor d. Tachycardia causing miosis and spasm. Although Phenylephrine is an α1 agonist that causes the contraction of the radial 5. What drug causes mydriasis and cycloplegia? muscle pulling the muscle outward causing mydriasis a. Atropine but it doesn't have an innervation to ciliary muscle to b. Pilocarpine cause cycloplegia. Pilocarpine is a direct acting c. Neostigmine cholinomimetic alkaloid that also causes miosis. d. Phenylephrine 3. D. Recall: Ganglionic blocking agents block both 6. All of the following are characteristics of PANS sympathetic and parasympathetic; “Point and Shoot” except: 4. C. Ganglionic blocking agents are used to treat a. Uses Adenylyl cyclase to activate pKA hypertension. b. Active during anabolism 5. A. Atropine is an antimuscarinic drug that blocks effects c. Active when dephosphorylated in the pupils, sphincter muscles, and the ciliary muscles d. Gq coupled - increase cGMP from contracting. 7. Choose the correct receptor-effect pair. 6. A. PANS uses IP3-DAG plus Ca2+ to activate pKC. a. β2 - Bronchoconstriction 7. C. Bronchoconstriction is for M3, ↑ in gastric acid b. α2 - Increase gastric acid secretion secretion is for M1, ↑ in renin is for β1 c. α1 - Vasoconstriction 8. B. Parasympathetic effects of ganglionic blockers d. M2 - Increase in renin include mydriasis, tachycardia,cycloplegia, reduced 8. Ganglionic blocker administration can produce this tone and motility of GIT. 9. B. Acetylcholine is the neurotransmitter which parasympathoplegic effect: ganglionic blockers competitively block at nicotinic a. Decreased cardiac output receptors. b. Tachycardia 10. C. Guanethidine is a polar drug and cannot traverse the c. Miosis BBB. The rest have access to the CNS. Methyrosin d. Diarrhea inhibits tyrosine hydroxylase and synthesis of 9. Ganglionic Blockers competitively block the action of catecholamines. Reserpine and methyldopa reduce __________________at neuronal nicotinic receptors dopamine levels. of both parasympathetic and sympathetic autonomic 11. D. Guanethidine inhibits the release of NE from ganglia. sympathetic nerve endings. It is also taken up via NET a. Acetylcholinesterase into storage vesicles, depleting NE stores in the nerve b. Acetylcholine endings. c. Dopamine 12. B. Reserpine blocks storage of amine d. Serotonin neurotransmitters via the irreversible binding of VMAT 10. All of these drugs produce extrapyramidal in central (crosses BBB) and peripheral neurons. manifestations due to reduced central dopamine Depletion of cerebral amine stores can cause sedation, levels, EXCEPT: depression, and symptoms of Parkinsonism. This is a. Methyldopa why reserpine is contraindicated for patients who (1) are prone to develop depression, (2) need to be awake, b. Metyrosine or (3) have existing parkinsonism because symptoms c. Guanethidine may worsen with depletion of amine stores. d. Reserpine 13. C. Norepinephrine synthesis starts with the uptake of 11. A middle aged male who is a chronic cocaine user hid tyrosine into the cytoplasm through sodium-linked this history from his internist when he consulted for carriers. control of his hypertension. If his internist will prescribe guanethidine, what will be the effect of this V. REFERENCES drug on the patient? Adrenergic and Ganglionic Antagonists (Asynchronous) – Dr. Paul Vincent C. Bautista a. Further elevation of BP Adrenergic and Ganglionic Antagonists (Synchronous) – Dr. b. Severe hypotension Paul Vincent C. Bautista c. Adequate control of hypertension 2026 Trans d. No change in BP 2025 Trans PHARMACOLOGY Adrenergic Ganglionic/Neuron Blockers PAGE 7 of 8 PHARMACOLOGY | LE 2 Adrenergic Ganglionic/Neuron Blockers | Paul Vincent C. Bautista, RPh, MD VI. APPENDIX [2026 Trans] Table 3. Classification of Adrenergic Antagonists Drugs that affect NE release from nerve terminals Drugs that affect NE synthesis Blockade of NE release Depletion of catecholamine Formation of false Inhibition of Destruction of from adrenergic nerve stores thereby decreasing neurotransmitters catecholamine adrenergic nerve terminals the available stores synthesis fibers Guanethidine Reserpine Methyldopa Methyltyrosine 6-hydroxydopamine Bethanidine Guanethidine Guanethidine Metyrosine Guanadrel Pargyline Bretylium Debrisoquine Table 4. Classification of Ganglionic Blockers[2026 Trans] Persistent Depolarizing Non-depolarizing or Competitive Ganglionic Blockers Noncompetitive Blockers Blockers Nicotine Quaternary Triethylsulfonium Secondary Quaternary Secondary Lobeline Ammonium Compounds Amines Ammonium Amines Coniine Compounds Compounds Tetramethylammonium (TMA) Dimethylphenylpiperazine Pentolinium tartrate Trimethaphan Pempidine Hexamethonium Mecamylamine Decamethonium (C10) Chlorisondamine camsylate chloride Tetraethyl- ammonium chloride (TEA) PHARMACOLOGY Adrenergic Ganglionic/Neuron Blockers PAGE 8 of 8