Notes 155-194

155. Neurogenic diabetes insipidus is treated with desmopressin, a drug that is similar to vasopressin (ADH) but a selective activator of V2 receptors in the kidney. Remember that V1 receptors are present in smooth muscle, and their activation leads to vasoconstriction and bronchoconstriction. Nephrogenic diabetes insipidus (decreased response of vasopressin receptors) is treated with thiazides except in the case of that induced by lithium, when amiloride is preferred (because thiazides increase blood levels of lithium).



156. The release of insulin from the pancreas is stimulated by insulinogens (glucose), sulfonylurea hypoglycemics (glipizide), activators of beta2 adrenoceptors (e.g., albuterol), and activators of muscarinic receptors (e.g., pilocarpine). The only receptor that, when activated, inhibits insulin release is the alpha2 receptor, which could be stimulated by clonidine or methyldopa.


157. Mifepristone (RU 486) is both a glucocorticoid and progestin receptor antagonist, the latter being responsible for its abortifacient activity. Dinoprostone is also a stimulant of uterine smooth muscle, but is a PGE2derivative, not a progestin antagonist. Flutamide is an androgen receptor antagonist, and tamoxifen is a partial agonist (or mixed agonist-antagonist) at estrogen receptors.


158. The profile of lead toxicity includes decreased heme synthesis, anemia, nephropathy, and peripheral neuropathy, the last leading to foot drop or wrist drop. Garlic breath and watery stools are associated with arsenic poisoning. Chronic gingivitis and loose teeth are features of mercury poisoning.


159. Didanosine causes pancreatitis in a significant number of patients treated for AIDS. Amantadine is used in the prevention and treatment of influenza and causes CNS stimulation and light headedness. Ribavirin is used for the treatment of respiratory syncytial virus in infants and causes dose-dependent hemolytic anemia in about 10% of patients. Ritonavir, a protease inhibitor used in AIDS, causes hepatitis. Zidovudine another drug used in AIDS, causes neutropenia as its primary dose limiting effect.


160. Acyclovir is an acyclic guanine nucleoside analog that undergoes activation by phosphorylation by herpesviral thymidine kinase (but not the host thymidine kinase) to form the acyclovir triphosphate form and causes DNA chain termination.
Amantadine is a tricyclic amine that inhibits uncoating of influenza A virus. It is also used for the treatment of parkinsonism.
Foscarnet is a pyrophosphate analog that inhibits herpesvirus nucleic acid synthesis at the level of the viral DNA polymerase.
Saquinavir is an HIV protease inhibitor.
Zidovudine is an antiretroviral thymidine analog.
The triphosphate is a competitive inhibitor of reverse transcriptase and a DNA chain terminator. The monophosphate is a competitive inhibitor of thymidine kinase.



161. Resistance to tetracyclines such as doxycycline is associated with production of an efflux pump or alteration of the 30S ribosomal-binding site. Resistance to beta lactams such as amoxicillin usually results from production of beta lactamase. Macrolides such as clarithromycin, erythromycin, and azithromycin bind to the 50S ribosome in susceptible organisms and prevent protein synthesis. Simple methylation of the binding site prevents the bacteriostatic action of these drugs and many bacteria have such mutation. Resistance to aminoglycosides such as gentamicin is usually due to synthesis of inactivating enzymes by the bacteria. Resistance to vancomycin is still unusual but can occur through the modification of the D-ala-D-ala-binding site in peptidoglycan.



162. Rifampin selectively inhibits bacterial DNA-dependent RNA polymerase. It is very useful in treating mycobacterial infections since it can penetrate cells and kill intracellular organisms. It is one of the most potent inducers of cytochrome P450 known, leading to increased hepatic clearance of many other drugs including the oral anticoagulants, cyclosporine, propranolol, digitoxin, corticos teroids, and oral contraceptives.
Ethambutol is often combined with isoniazid in antitubercular regimens. Clearance is primarily via renal excretion.
Isoniazid is the most widely used antitubercular agent. It functions by inhibiting mycolic acid biosynthesis. Isoniazid is cleared by metabolism via N-acetylase and hydrolytic activity.
Streptomycin was the first effective drug for the treatment of tuberculosis, but, because of its ototoxicity and nephrotoxicity and the development of less toxic agents, use of streptomycin is limited to more severe forms of the disease.
Sulfisoxazole may rarely be used in antitubercular regimens in combination with other drugs. Clearance is primarily via glomerular filtration.



163. Losartan causes renal damage in the fetus, and renal impairment in renovascular disease. It is contraindicated in pregnancy. Clonidine causes some sedation and rebound hypertension when stopped suddenly, but is not contraindicated in pregnancy. Hydralazine causes a reversible type of lupus erythematosus. Hydrochlorothiazide may cause hypokalemia, dilutional hyponatremia, elevated lipids, hyperuricemia, and glucose intolerance. Methyldopa causes sedation and formation of red blood cell antibodies, but has been shown to be safe in pregnancy.
Clonidine the centrally acting alpha 2-receptor agonist, produces sedation and xerostomia but not cough. The alpha-1-receptor antagonist prazosin produces postural hypotension but not cough. The beta-blocker propranolol may produce a variety of side effects including precipitating heart failure and asthma in susceptible patients.


164. Cisplatin binds to DNA where it forms intra- and interstrand crosslinks. Cisplatin is particularly effective in testicular and ovarian cancers in combination with other antitumor agents. Cisplatin exerts a renal toxicity that may be prevented by the infusion of saline to maintain a high urine flow. Ototoxicity involving high-frequency hearing loss is an effect that is not prevented by hydration.
The natural product bleomycin binds to DNA and causes single- and double-strand breaks, leading to cytotoxicity. The drug is particularly useful against Hodgkin lymphoma and testicular tumors. Bleomycin has the serious toxicity of pulmonary fibrosis.
Cyclophosphamide is widely used in combination regimens. Nausea and vomiting are the most common toxicities. Hemorrhagic cystitis may be minimized by hydration and use of the drug mesna. Note that this toxicity is not at the level of the kidney.
The pyrimidine analog 5-fluorouracil (5-FU) is used to treat a wide variety of carcinomas. Toxicity from 5-FU is expressed as GI disturbances (anorexia, nausea, stomatitis, and diarrhea) and myelosuppression.
Paclitaxel is particularly useful in treating metastatic breast and ovarian cancer. The primary toxicity of paclitaxel is bone marrow suppression.



165. The pyrimidine analog 5-fluorouracil (5-FU) is metabolized by ribosylation and phosphorylation to the nucleotide level (F-UMP). F-UMP is further metabolized to F-dUMP, an inhibitor of thymidylate synthase. Cells then become starved for TTP and incorporate F-dUTP and dUTP in its place in DNA. 5-FU also becomes incorporated in RNA, leading to inhibition of RNAprocessing.
Anastrozole is a nonsteroidal inhibitor of aromatase, an enzyme required for synthesis of estrogens. This drug is useful against advanced estrogen or progesterone receptor-positive breast cancer.
Cytarabine (cytosine arabinoside, ara-C), is an S-phase-specific antimetabolite that is metabolized to the triphosphate form, which blocks DNAsynthesis. It is used exclusively in acute myelogenous leukemia.
Doxorubicin is an anthracycline antibiotic that intercalates into DNAcausing strand breakage and blockage of both DNAand RNAsynthesis. This agent is widely used in combination regimens for breast, endometrial, ovarian, testicular, and thyroid carcinomas, and several sarcomas and lymphomas.
Imatinib is an inhibitor of the tyrosine kinase activity of the Bcr-Abl oncogene product. It is a drug of choice in chronic myelogenous leukemia with the Philadelphia chromosome translocation.

Etoposide is a semisynthetic derivative of podophyllotoxin, a constituent of the mandrake plant. Etoposide is an inhibitor of topoisomerase II, an enzyme that relaxes supercoiled DNA by breaking one strand and passing the second strand through the break before closing the break. Etoposide inhibits the closure step and results in an accumulation of DNAstrand breaks, leading to cell death. Etoposide is used to treat testicular tumors and small cell carcinoma of the lung in combination with cisplatin. Leukopenia is the dose-limiting toxicity seen with this drug.
Dacarbazine is a synthetic prodrug activated in the liver to a metabolite that alkylates DNAleading to cytotoxicity. The drug is useful against melanoma and Hodgkin lymphoma.
Lomustine (CCNU) is a lipid-soluble nitrosourea agent that acts as an alkylating agent. The nitrosoureas are unusual in having relatively good access to the CNS and are therefore useful in treating brain tumors.
Prednisone is a potent, orally active corticosteroid with good lymphotoxic potency. Its mechanism is not fully understood but may involve activation of apoptotic pathways in lymphocytes.
Vincristine is a natural product isolated from the vinca plant. It is classified as a spindle poison and inhibits mitosis by inhibiting microtubule assembly. This drug is particularly useful in treating acute leukemias in children and Hodgkin lymphoma.



166. Long-term treatment of schizophrenia with potent dopamine D2 receptor antagonists is associated with a high incidence of the irreversible extrapyramidal dystonias called tardive dyskinesia. The phenothiazines (and haloperidol) are D2 receptor antagonists in the CNS; their success in the treatment of schizophrenia resulted in the hypothesis that the antipsychotic effect requires D2 blockade. Data from newer, atypical antipsychotic agents casts some doubt on this hypothesis because drugs, such as clozapine and risperidone, have a low affinity for D2 receptors. Older drugs in the phenothiazine class (e.g., chlorpromazine) have both antimuscarinic and antiemetic action; thus diarrhea, nausea, and vomiting are very unlikely. Because prolactin secretion from the anterior pituitary is inhibited by dopamine, blockade of D2 receptors by fluphenazine increases prolactin secretion. This may result in breast engorgement and galactorrhea in women. Tourette syndrome involves tics and other involuntary movements and obscene vocalizations. The neuroleptic agent haloperidol is the current drug of choice for the treatment of this disease. Weight loss is associated with the use of selective SSRIs, not phenothiazines. In fact, the phenothiazines are often associated with weight gain.




167. Clozapine (psychotropic drug) causes agranulocytosis in a small but consistent fraction of patients; monitoring is mandatory.
Buspirone is an antianxiety agent with minimal sedative action.
Haloperidol is an older, highlypotent antipsychotic drug used in schizophrenia.
Lithium carbonate is an important antimanic drug. It apparently acts by interfering with inositol phosphate cycling and second messenger synthesis in neurons.
Mirtazapine is a third-generation antidepressant related to antihistaminics and has significant sedative action.



168. Inhaled albuterol (or other beta-2-selective receptor agonists including bitolterol metaproterenol, pirbuterol, and terbutaline) are the usual agents of choice for treating bronchoconstriction in an acute asthma attack. These beta-2-selective agonists produce bronchial relaxation by stimulating cyclic AMP (cAMP) formation in bronchiolar smooth muscle and cause less tachycardia than nonselective beta agonists. Unfortunately, they do cause some tachycardia and skeletal muscle tremor.
Aminophylline and other methylxanthines are rarely used to terminate acute episodes of asthma because they must be administered parenterally for rapid onset of effect.
Cromolyn sodium must be used prophylactically to prevent acute episodes and probably acts by stabilizing mast cells. It is not a smooth muscle relaxing agent and is not effective in reversing bronchospasm.
Inhaled ipratropium has less general efficacy in acute attacks than beta agonists.
Salmeterol is an effective beta-2-selective agonist but has a slow onset and long duration of action. Therefore, it is used for prophylaxis, not treatment of acute attacks.





169. Allopurinol and its metabolite alloxanthine inhibit xanthine oxidase, thus preventing conversion of xanthine and hypoxanthine to uric acid. Although xanthine and hypoxanthine then accumulate, these compounds are more soluble than uric acid and less likely to deposit in joints or precipitate in the urine.
Most doses of aspirin increase retention of uric acid, especially low doses.
Colchicine is an inhibitor of microtubule function that brings relief in an acute gout attack by inhibiting the motility of granulocytes and preventing the formation of mediators of inflammation by leukocytes. Because of its toxicity at higher doses, it is now used chiefly at low doses to prevent acute attacks.
Indomethacin is an NSAID that inhibits COX and reduces formation of prostaglandins and eicosanoids involved in gouty arthritis. It has no effect on the formation of uric acid and very little on its excretion.
Sulfinpyrazone and probenecid are uricosuric agents—they increase the excretion of uric acid by the kidney. Renal uric acid excretion is determined by the balance between the amount filtered plus that actively secreted and the amount undergoing passive and active reabsorption. At very low doses, these agents inhibit active secretion and thus promote retention of uric acid. At higher (clinical) doses, both active secretion and active reabsorption are inhibited, with the result that excretion is enhanced.




170. NSAIDs have long been drugs of first choice in arthritis treatment. Their primary mechanism of action in arthritis appears to be inhibition of COX, an enzyme required for the synthesis of inflammatory and other prostaglandins. Two forms of COX are present in the body: COX-1, which is required for synthesis of several useful prostaglandins (e.g., PGE1 , a cytoprotective agent in the stomach), and COX-2, the isoform responsible for synthesis of prostacyclin as well as most of the damaging prostaglandins. Celecoxib is more selective for COX-2 and thus has a lower incidence of adverse GI effects. The older NSAIDs inhibit both COX-1 and COX-2 with less selectivity and thus reduce protective prostaglandins, resulting in a high incidence of GI disorders, especially peptic ulceration.
Misoprostol is a PGE1 analog that is used with NSAIDs to reduce peptic ulceration; unfortunately it causes a high incidence of diarrhea.



171. Bethanechol is a muscarinic agonist and typically causes vasodilation, with a drop in blood pressure and a compensatory tachycardia.
Epinephrine an alpha-1-, alpha-2-, beta-1-, and beta-2-agonist, causes hypertension at high doses, but usually also causes tachycardia.
Isoproterenol is a beta-1-, beta-2-agonist, and does not cause hypertension or bradycardia.
Norepinephrine and phenylephrine can both cause hypertension and reflex bradycardia. However, nor-epinephrine has beta-1-agonist action, whereas phenylephrine has only alpha effects. Thus, in the presence of an alpha-blocking agent, norepinephrine causes a beta-1-mediated tachycardia; phenylephrine has no effect on heart rate.



172. The benzodiazepine agents, including diazepam, facilitate the actions of the inhibitory neurotransmitter GABA, which acts on GABAA receptors to open chloride ion channels.
Bupropion is probably an inhibitor of norepinephrine and dopamine uptake and does not act on GABA receptors.
Fluoxetine is a selective inhibitor of serotonin uptake.
Pentobarbital is a modulator of the same GABA-sensitive chloride channel affected by benzodiazepines, although its mechanism of action is slightly different.
Tranylcypromine is an inhibitor of MAO rather than catechol-O-methyltransferase (COMT).




173. Apatient who is anemic, neutropenic, and thrombocytopenic requires stimulation of all three major cell lines in the bone marrow. The only drug currently available that accomplishes this broad-spectrum stimulant effect is sargramostim (granulocyte–macrophage colony stimulating factor [GM-CSF]).
Epoetin is a more selective stimulant of erythrocyte production and is useful in simple anemia.
Filgrastim is a somewhat selective stimulant of leukocyte production and has much less effect on erythrocytes and platelet production than sargramostim.

174. The blood-gas partition coefficient is a measure of the solubility of the inhalation anesthetic in the blood relative to its solubility in the inspired air. Circulating blood provides the means of anesthetic delivery to the brain and the partial pressure determines the rate of transfer into the CNS. The solubility of an agent in blood determines how rapidly the partial pressure rises in the blood. Agents with high solubility (large blood-gas partition coefficients) require large amounts of the anesthetic to dissolve in the blood before the partial pressure in the blood increases enough to effe-ctively deliver them to the brain. Thus, agents with lower blood solubilities (small blood-gas partition coefficients) have more rapid rates of onset of anesthesia. Desirable properties for inhalation anesthetic agents include high potency and low blood solubility. The halogenated hydrocarbons, such as desflurane and sevoflurane, fit these criteria and are used extensively.
The MAC value (median alveolar anesthetic concentration) required for anesthesia is a measure of the potency of the agent, but does not give an indication of the rate of onset of anesthesia.
Molecular size may play a role in determining the blood-gas partition coefficient, but it is only a partial determinant.
The oil–water partition coefficient is a measure of the lipid solubility of the anesthetic agent. This correlates with the potency as measured by the MAC.
Hepatic metabolism plays no role in onset of action, but may be important in terms of possible liver and kidney damage resulting from the production of toxic metabolites from some of the halogenated inhaled anesthetic agents.



175. Treatment of Liddle syndrome consists of direct inhibition of the abnormally expressed sodium channel by either amiloride or triamterene, both of which are classified as potassium-sparing diuretics. Triamterene is less useful than amiloride because of its low potency and low solubility, which may lead to the formation of stones.
Fludrocortisone is a synthetic mineralocorticoid used for replacement therapy in hypoaldosteronism. Although aldosterone levels are reduced in this patient, administration of a mineralocorticoid will exacerbate rather than relieve the hypertension and hypokalemic metabolic alkalosis.
Hydrochlorothiazide a thiazide diuretic, will exacerbate the problem because inhibition of the Na+/Cl− symporter in the distal convoluted tubule results in delivery of more sodium to the cortical collecting duct, where the hyperactivity of the sodium channel and resulting potassium extrusion along with increased proton exchange from type A intercalated cells results in greater hypokalemia andalkalosis.
Lisinopril is an ACE inhibitor used in the treatment of essential hypertension.
Spironolactone is a selective antagonist at the aldosterone receptor. It is used as a potassium-sparing diuretic. In thecase of Liddle disease, spironolactone has no utility; aldosterone does not play a causative role and its levels are already depressed.



176. Streptokinase has no intrinsic enzymatic activity, but instead forms a stable complex with the patient’s plasminogen, making it enzymatically active in cleaving free plasminogen to plasmin. The streptokinase–plasminogen complex is not inhibited by antiplasmin. The other thrombolytic agents
t-PA, reteplase, tenecteplase, and urokinase— activate plasminogen directly.
Competitive blocking of binding of plasminogen to fibrin is a property of aminocaproic acid (AMICAR), a lysine analog used to inhibit fibrinolysis.



177. Diplopia, abnormal gait, and other signs of cerebellar dysfunction are important symptoms of phenytoin toxicity. Other manifestations of toxicity include gingival hyperplasia, nystagmus, and vertigo.
Hyperprolactinemia is an adverse effect of antipsychotic dopamine antagonists such as the phenothiazines; dopamine inhibits prolactin secretion by the anterior pituitary.
Polydipsia and polyuria are symptoms of diabetes insipidus. These symptoms may be produced by lithium toxicity during treatment of bipolar depression, and are not associated with phenytoin toxicity.
Postural hypotension often occurs with levodopa treatment of Parkinson’s disease.
Rigidity and tremor are symptoms of parkinsonism. These symptoms may be produced by dopamine antagonists such as antipsychotic agents.


178. Ethambutol causes visual dysfunction and possible retinal damage, not hearing loss.
Isoniazid causes peripheral neuropathies and hepatic damage. Fortunately, hepatitis is uncommon in children treated with this drug.
Pyrazinamide causes joint pains and swelling, GI upset, and rash.
Rifampin causes proteinuria, rash, and thrombocytopenia.


179. Vasodilators act by one of three mechanisms: increasing cyclic GMP (cGMP) levels in vascu-lar smooth muscle cells; opening potassium channels; or blocking calcium channels.
The organic nitrates and nitroprusside (nitrova- sodilators) increase cGMP synthesis by generating nitric oxide (NO), which subsequently activates a soluble form of guanylyl cyclase. Activation of muscarinic receptors on vascular endothelial cells results in formation of NO (earlier identified as endothelium-derived relaxing factor) that diffuses to smooth muscle cells and relaxes them through increased cGMP levels. Erection of the penis involves neuronally regulated formation of NO, increased cGMP levels in the corpus cavernosum, and relaxation of cavernosal and vascular smooth muscle in erectile tissue. Rather than stimulating guanylyl cyclase, sildenafil (Viagra) acts as a selective inhibitor of cGMP phosphodiesterase type 5 to increase the half-life of cGMP in the tissues. The fact that sildenafil acts downstream of NO stimulation of guanylyl cyclase accounts for the toxic interactions between it and nitrovasodilators.
The mechanism for relaxation of vascular smooth muscle by hydralazine is unknown, but may involve NO.
Minoxidil is metabolized to minoxidil sulfate, which activates an ATP-sensitive potassium channel in smooth muscle.
Nitroprusside is a nitrovasodilator that spontaneously releases NO by a mechanism distinct from that of the organic nitrates.
Prazosin produces vasodilation by inhibiting alpha-1-adrenoreceptors on arteriolar smooth muscle.




180. Excellent analgesia and significant addictive properties are associated with drugs that act at mu-type opioid receptors.
Codeine is a weak agonist at mu-receptors, whereas the other opioid analgesics (Meperidine, Methadone, Morphine) are full agonists.
Therefore codeine is less efficacious but also has the lowest addiction and abuse liability; it is therefore the agent of choice within this list.
Diphenoxylate is a congener of meperidine (and the primary component of Lomotil) that is used to control GI motility in diarrhea. At therapeutic dose levels, neither analgesia nor addiction is observed.
Meperidine is a synthetic mu-opioid receptor agonist with high-addiction liability.
Methadone is a mu-opioid receptor agonist with good oral efficacy and a long plasma half-life (15–40 h). It is used in the treatment of opioid addiction and for severe cancer pain.
Morphine is the prototype mu-opioid receptor agonist and possesses high addiction liability.


181. The current drug of choice for acute AV nodal reentrant tachycardia (a supraventricular tachycardia [SVT]) is the nucleoside adenosine. This agent, when given as a bolus, causes marked hyperpolarization of AV node tissue and transiently blocks conduction of AV node action potentials. This abolishes the reentrant impulse and allows normal sinus rhythm to be reestablished. The half-life of adenosine is about 3 seconds and the duration of action of the dose used is about 15 seconds, so toxicities from this therapy are minimal. Calcium channel blockers such as verapamil and diltiazem are also effective in SVT.
Bethanechol is a muscarinic agonist and produces hypotension and other muscarinic effects. It is ineffective in SVT. Isoproterenol is a beta-selective adrenoreceptor agonist that causes hypotension and reflex sympathetic discharge to the heart, along with direct stimulation. It is more likely to cause than to abolish arrhythmias.
Metoprolol slows AV conduction and might abolish the AV reentrant rhythm. However, beta blockers are not very effective in converting preexisting SVT.
Procainamide and related group 1A antiarrhythmic drugs are not as effective as adenosine in converting SVT to normal sinus rhythm and much more toxic.




182. Salivary glands contain muscarinic receptors, primarily of the M3 subtype, that receive parasympathetic innervation. Direct-acting agonists such as bethanechol and indirect agents such as neostigmine mimic parasympathetic nerve stimulation. Blood vessel endothelial cells contain M3 receptors that are not innervated, but respond to circulating direct-acting muscarinic agonists. When these endothelial receptors are activated, nitric oxide synthesis is stimulated and smooth muscle relaxation occurs promptly with vasodilation and a drop in blood pressure.
Because no nerve endings are present, indirect-acting cholinomimetics such as cholinesterase inhibitors do not have this vasodilating effect. In the presence of hypotension induced by a direct-acting muscarinic agonist, a strong compensatory reflex originates in the baroreceptors and results in tachycardia.
In the case of cholinesterase inhibitors, the normal heart rate slowing effect of the vagus is amplified and at normal doses, bradycardia results.
Alpha receptor ligands have little effect on salivation, although indirectly acting agents like ephedrine can cause a sensation of dry mouth. However, ephedrine causes increased blood pressure.
Aganglionic stimulant drug causes increased salivation but also increases sympathetic discharge to the blood vessels and results in increased, not decreased, blood pressure.




183. Trastuzumab is a human antibody that reacts with the epidermal growth factor receptor HER-2/neu and is effective in slowing progression of breast cancer.
Adalimumab and etanercept are IgG1 antibodies to TNF-alpha and are used in advanced rheumatoid arthritis.
Infliximab is a chimeric antibody to TNF-alpha that is used in rheumatoid arthritis and several other autoimmune diseases.
Sirolimus is an inhibitor of B lymphocyte proliferation and immunoglobulin production. It is used to prevent transplanted organ rejection.


184. Ondansetron is a 5-HT3 antagonist.
Dronabinol is a cannabinoid agonist.
Dexamethasone is a corticosteroid.
Metoclopramide is a dopamine antagonist.
Diphenhydramine is a histamine antagonist.
Ondansetron is also effective in reducing postsurgical vomiting. Several congeners of ondansetron are available (granisetron, dolasetron).
Misoprostol is an orally active PGE1 analog that is used in the treatment or prevention of NSAID-induced ulcers.

185. Baclofen is an agonist at GABAB receptors and is useful in the treatment of chronic muscle
spasm.
Glutamate is an important excitatory transmitter in the CNS; agonists are not used clinically. Antagonists at neuronal nicotinic receptors are ganglion blockers; baclofen has no effect on these receptors.
Glycine is an important spinal inhibitory transmitter, but baclofen has no effect on its receptors.
Dantrolene is an antagonist at skeletal muscle ryanodine receptors ; baclofen has no effect at this
site



186. Beta blockers such as timolol reduce intraocular pressure by reducing synthesis of aqueous by the ciliary epithelium.
Dorzolamide is a topically active carbonic anhydrase inhibitor that inhibits the synthesis, not the outflow, of aqueous humor.
Latanoprost is a PGF-2 alpha analog used topically to increase aqueous outflow.
Pilocarpine is a muscarinic cholinomimetic that increases aqueous outflow.



187. The oral anticoagulants, such as warfarin, block the vitamin K-dependent step in the hepatic synthesis of coagulation factors VII, IX, X, and prothrombin. Carboxylation of descarboxy-prothrombin to form prothrombin containing gamma-carboxyglutamate residues requires the reduced form of vitamin K as a cofactor. Vitamin K epoxide is formed as a product. KH2 must be regenerated by an NADH-dependent epoxide reductase for the next round of carboxylation. It is the epoxide reductase step that is blocked by oral anticoagulants.
Heparin exerts its anticoagulant actions by acting as a template for combining thrombin and antithrombin III.



188. Sucralfate is a sucrose aluminum-sulfate compound that polymerizes in an acid environment and is able to form a protective coating over an ulcer bed. It must be taken four times a day, so it is less convenient than H2-blockers or proton pump inhibitors.
Because strong vasodilators evoke powerful compensatory responses (salt and water retention, tachycardia), drugs like minoxidil are almost always used together with drugs such as diuretics that prevent the compensatory responses.

189. Amitriptyline, desipramine, imipramine, and trazodone are members of the tricyclic/ heterocyclic group and all have mixed effects on both norepinephrine and serotonin reuptake.
Desipramine is the most selective agent for blocking uptake of norepinephrine.
The selective serotonin uptake inhibitors offer the advantage that they do not produce sedation or autonomic side effects, in contrast to many of the tricyclic and hetero-cyclic antidepressants.
Citalopram is one of the highly selective SSRIs, as is its (S) isomer, escitalopram. Most older, tricyclic, and heterocyclic antidepressants block—to varying degrees—reuptake of both norepinephrine and serotonin amine neurotransmitters into the presynaptic nerve terminals.




190. Chronic lead poisoning results in multiple toxicities including headache, hypertension, infertility, anemia, and renal insufficiency. Mental and growth retardation occur in children.
Acute lead intoxication usually presents as encephalopathy or severe abdominal colic, sometimes masquerading as pancreatitis. When blood lead levels exceed 50 mcg/dL, chelation treatment is indicated. The calcium ion in calcium disodium edetate (EDTA) is readily displaced by lead, forming a lead chelate that is excreted in the urine.
Arsenic poisoning is treated with chelation therapy using dimercaprol, succimer, or penicillamine.
Atropine is a lipophilic muscarinic receptor antagonist that blocks parasympathetic function and at toxic levels produces hallucinations and psychosis. Treatment of atropine intoxication consists of symptomatic management or administration of the lipid-soluble anti-cholinesterase physostigmine.
Toxicity from iron may arise from ingestion of iron supplements (as with children swallowing adult preparations) or hemolytic diseases such as thalassemia. Treatment consists of the use of the iron-chelating agents deferoxamine or deferasirox.
Inorganic mercury poisoning is treated by using chelation therapy with dimercaprol, succimer, or penicillamine. Organic mercury poisoning is more difficult to treat because of the lipophilic nature of organomercury compounds.




191. Mebendazole is a broad-spectrum anti-helmintic that is effective against a variety of nematodes including ascarids, hookworm (Necator, Ancylostoma), whipworm (Trichuris), threadworm (Strongyloides), and pinworm (Enterobius). Adverse effects are rare.
Diethylcarbamazine was developed as a treatment for filariasis. Because of adverse effects that include nausea, vomiting, headache, leukocytosis, and proteinuria, it has been largely supplanted by other antifilarial agents, except in the case of Loa loa, where it remains the drug of choice.
Ivermectin is used to treat Onchocerca volvulus, the agent responsible for river blindness in west and central Africa.
Niclosamide and praziquantel are agents with primary efficacy against flukes and tapeworms.
In the case of Fasciola hepatica (sheep liver fluke), however, bithionol or triclabendazole (a veterinary drug) are drugs of choice; in cysticercosis, albendazole is the drug of choice.



192. The leukotrienes LTC4, LTD4, and LTE4 are 5’-lipoxygenase metabolites of arachidonic acid. When lung tissue is challenged with antigen in sensitive individuals, LTC4 is formed and sub-sequently metabolized to LTD4 and LTE4. These leukotrienes are not stored but produce broncho-constriction, increased capillary permeability, and increased mucus formation for an extended time because of their slow tissue clearance. Because the first enzyme in synthesis of leukotrienes from arachidonic acid is 5’-lipoxygenase rather than COX, aspirin does not inhibit their biosynthesis. Another leukotriene, LTB4, is a potent chemotactic agent for polymorphonuclear leukocytes, but the cysteine-linked leukotrienes LTC4, LTD4, and LTE4 do not share this property.
Platelets do not contain 5’-lipoxygenase (although they do contain 12’-lipoxygenase), and leukotrienes are not stored in platelet granules.
The COX product of arachidonic acid, TXA2, is critical in platelet physiology, and acetylation of COX by aspirin accounts for the effect of this drug in inhibiting platelet function.
The leukotrienes possess significant cardiovascular effects; they produce hypotension by decreasing intravascular volume and reducing cardiac contractility by constricting coronary vessels, thus reducing coronary blood flow




193. Local anesthetic agents such as lidocaine inhibit nerve conduction through state- and use-dependent blockade of voltage-dependent fast sodium channels. As a result, the threshold of excitability of the nerve is increased, and the ability of the nerve to propagate an action potential is decreased. Ultimately, transmission of sensory stimuli to the CNS is suppressed, and motor function involving small fibers in the vicinity of the injection is also lost.



194. Pancreatic beta cells are electrically polarized. Depolarization causes entry of calcium and activation of insulin exocytosis. In hypoglycemia, the negative resting potential is maintained by the activity of an ATP-sensitive hyperpolarizing potassium channel and insulin secretion is inhibited. When extracellular glucose levels are high, glucose enters the beta cells via the GLUT2 transporter and is metabolized to yield ATP. The increased ATP levels cause closure of the potassium channel, allowing the cell to depolarize and secrete insulin.
Modulation of insulin release is the mechanism of action of the meglitinides such as repaglinide. Although the details are not full understood, these drugs share one binding site with sulfonylureas and have a second, independent binding site.
Acarbose is an inhibitor of intestinal alpha-glucosidase and thus reduces absorption of glucose.
Sulfonylureas such as glipizide bind to a cell-surface protein to cause inhibition of the hyperpolar- izing potassium channel, thereby allowing the beta cell to depolarize and secrete insulin.
Metformin and other biguanides are poorly understood, but do not inhibit the potassium channel that is the target of sulfonylureas.
Rosiglitazone and pioglitazone do not act by reduction of circulating glucagon; this is one proposed mechanism for the biguanides. These thiazolidinediones or “glitazones” appear to act by a peripheral mechanism that reduces insulin resistance, probably mediated by the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) nuclear receptor.