Pharmacology 2 Flashcards
Description and mechanism of action of prednisone
Immunosuppressive oral corticosteroid; most-prescribed oral corticosteroid. Used for TX of autoimmune disorders, allograft rejection, asthma, inflammatory bowel disease, rheumatoid arthritis, and other inflammatory states.
Prodrug of prednisolone, must be metabolized in vivo to prednisolone. Acts via nuclear receptors to modulate gene expression.
Anti-inflammatory: represses COX-2 expression; ↓ cytokine production, decreased formation and release of endogenous inflammatory mediators; causes apoptosis of eosinophils.
Pharmacokinetics of prednisone
Given PO, doses range from 5-100 mg QD depending on disease. Metabolized in the liver to prednisolone. t1/2 ~ 18-36 hr
Adverse effects and counterindications of prednisone
CNS: headache, insomnia, vertigo, depression, anxiety, euphoria, personality changes, psychosis
GI: NVD, anorexia, gastritis
Cataracts
Opportunistic infections
Cushing’s syndrome. High doses and long-term therapy can suppress hypothalamic-pituitary-adrenal system; avoid abrupt DC of prolonged therapy. Preexisting bacterial, viral, fungal infections.Patients receiving corticosteroids chronically should be periodically assessed for cataracts
Description and mechanism of action of cyclosporine.
Immunosuppressive cyclic peptide produced by the fungus Beauveria nivea. Immunosuppressive effect was discovered in 1972, approved by FDA in 1983.Used to prevent organ rejection after transplant; TX for rheumatoid arthritis, psoriasis, inflammatory bowel disease.
Calcineurin inhibitor (CNI); binds to cyclophilin, complex binds to calcineurin and inhibits phosphatase activity of calcineurin; this prevents the dephosphorylation and translocation of a transcription factor (NF-AT) that stimulates cytokine gene expression. Result is inhibition of T cell activation and decreased release of IL-2, IL-3, IL-4, TNF-a, IFN-g
Pharmacokinetics of cyclosporine
Given PO or IV for immunosupression at 2.5-15 mg/kg QD; narrow therapeutic window. Opthalmic formulation 0.05% or 0.1% (Restasis®) is used to increase tear production that has been suppressed by inflammation, usually 1 gtt BID. Metabolized by CYP3A4 (→ drug interactions!), metabolites mostly excreted in bile
Adverse effects and counterindication of cyclosporine.
Nephrotoxicity (20-38%); CNIs induce interstitial fibrosis and vasoconstriction of afferent arterioles, leading to tubular necrosis
CV: hypertension (8-28%)
Hirsutism (10-21%) occurs in both ♂ and ♀ receiving systemic cyclosporine
Gingival hyperplasia (4-16%)
CNS: tremor (10-12%)
Opthalmic application may causes burning (17%)
Hyperglycemia (
Description of Tacrolimus
Immunosuppressive derived from the fungus Streptomyces tsukubaensis. Used to prevent organ rejection after transplant; psoriasis, atopic dermatitis.
Mechanism of action of tacrolimus
Calcineurin inhibitor (CNI); forms complex with FK binding protein, complex binds to calcineurin and inhibits phosphatase activity of calcineurin; this prevents the dephosphorylation and translocation of a transcription factor (NF-AT) that stimulates cytokine gene expression; 50-100X more potent than cyclosporine. Result is inhibition of T cell activation and decreased release of IL-2, IL-3, IL-4, TNF-a, IFN-g.
Pharmacokinetics of tacrolimus
Given IV or PO; PO absorption is highly variable, necessitating individualized regimens
Extensively metabolized by CYP3A4 (→ drug interactions!), metabolites excreted in bile
Concentrated in the pancreas and may inhibit pancreatic insulin secretion
Adverse effects and counterindications of tacrolimus
Nephrotoxicity (40-52%); CNI induce interstitial fibrosis and vasoconstriction of afferent arterioles, leading to tubular necrosis
CV: hypertension (38-50%)
CNS: tremor (48-56%), insomnia (32-64%), headache (37-64%)
GI: NVD (32-59%), elevated LFTs
Hyperglycemia (33-47%)
Diabetes. Therapeutic drug monitoring, target blood concentration is 5-20 ng/mL. Hepatic disease, renal disease, hypertension.
Description of Sirolimus
Macrocyclic lactone produced by Streptomyces hygroscopicus. Used to prevent rejection after renal transplant, not recommended for liver or lung transplants.
Mechanism of action of sirolimus
Binds to FK binding protein, complex then binds to and inhibits mTOR, a key kinase involved in upstream regulation of protein synthesis, cell growth, proliferation; inhibits progression from G1 to S phase of the cell cycle
Cytostatic: T cells still produce IL-2 but fail to proliferate
Pharmacokinetics of sirolimus
Supplied as a solution or tablets for PO administration, commonly 2-5 mg QD. Cypher® is a sirolimus-eluting stent used to inhibit restenosis after stenting to treat coronary artery occlusion; 80% of sirolimus is released in 30 days and the rest in 90 days. CYP3A4 substrate (→ drug interactions!), metabolites excreted in bile. Long, ca. 60 hr half-life
Adverse effects and precautions for sirolimus
PULM: dyspnea (22-30%), pharyngitis (16-21%)
HEME: myelosuppression (13-37%)
GI: NVD (19-42%), hepatotoxicity, elevated LFTs
MET: hyperlipidemia (35-57%), hypertriglyceridemia, electrolyte imbalances (11-23%), edema (54-64%)
Nephrotoxicity; may potentiate CNI-induced nephrotoxicity
Therapeutic drug monitoring, target concentration is 12-24 ng/mL
Description of azathioprine
Historically, first drug to be used for immunosuppression after transplantation
Cytotoxic antimetabolite-class agent; prodrug of 6-mercaptopurine (6-MP)
Used to prevent rejection of kidney transplants and to reduce symptoms of rheumatoid arthritis and Crohn’s disease; 6-MP itself is used as an antileukemia agent
Mechanism of action of azathioprine
Azathioprine → 6-MP → 6-thioguanine → 6-thioguanine nucleotides, which are incorporated into DNA and RNA → impaired function
6-MP and 6-thioguanine also interfere with several enzymes in the de novo purine nucleotide biosynthetic pathway, resulting in depletion of purine nucleotides, decreased ATP and GTP, decreased glycoproteins, etc
Pharmacokinetics of azathioprine
Administered as PO or IV, good oral absorption; usual maintenance dose is 1-3 mg/kg QD
6-MP is inactivated by oxidation (by xanthine oxidase) and methylation (by thiopurine S-methyltransferase); excretion is mostly renal
Adverse effects and precautions of azathioprine
HEM: myelosuppression (up to 50%), with potentially severe leukopenia
GI: NVD (12%), abdominal pain, elevated LFTs
Rashes
Thiopurine methyltransferase deficiency (ca. 10%) → enhanced toxicity
TX with allopurinol → enhanced toxicity
Pregnancy Risk Category D
Description of Muromonab-CD3
Murine monoclonal antibody directed against CD3 protein on surface of T cells
First monoclonal antibody to be FDA-approved (1985)
Used to block acute rejection of heart, liver, kidney transplants and to deplete T cells from donor bone marrow prior to transplantation
Mechanism of action of muromonab-CD3
Binds to T cell receptor-associated CD3 complex, causes initial activation and cytokine release, followed by blockade, apoptosis, and depletion of T cells
Pharmacokinetics of muromonab-CD3
Supplied as 1 mg/mL solution for IV bolus administration, usual dose is 5 mg QD for 10-14 days
T cells begin to disappear from blood within minutes and reappear ca. 1 week after therapy is halted
Adverse effects and precautions for muromonab-CD3
Triggers cytokine release syndrome: fever (73%), chills (59%), headache, tremor, dyspnea (21%), chest pain (14%), NVD (12%); syndrome subsides after first day and can be minimized by pretreatment with glucocorticoids, acetaminophen, or diphenhydramine
Seizures (1-5%)
Rare, but potentially fatal, anaphylaxis
Allergy to mouse proteins
CV: heart failure, hypertension, hypotension
Epilepsy
Description of Basiliximab
“Nondepleting” immunosuppressive agent. Anti-CD25 antibody; recombinant human-mouse IgG vs. IL-2 receptor-CD25 complex. Used for prophylaxis of acute rejection following kidney transplant, combined with cyclosporine and a glucocorticoid.
Mechanism of action of Basiliximab
IL-2 receptor antagonist; binds with high affinity (KD ca. 0.1 nM) to CD25, the IL-2 receptor a chain on activated T cells, preventing activation by IL-2
CD25 is only expressed on activated T cells, so basiliximab is does not cause widespread depletion of T cells
Pharmacokinetics of basiliximab
Supplied as a lyophylized powder that is reconstituted for IV administration
20 mg is given IV as a bolus injection or as an infusion over 20-30 min
First 20 mg dose is given 2 hr prior to surgery
Second 20 mg dose is given 4 days after transplantation
Elimination half-life is ca. 7 days; normal T cell numbers return in 7-14 days
Adverse effects and precautions for basiliximab
Incidence and severity much lower than muromonab-CD3 GI (10%): NVD, pain MET: electrolyte imbalances (3-10%) CV (3-10%): hypertension, arrhythmias Rare, potentially fatal anaphylaxis
Pediatric patients
Description of adalimumab
Fully humanized monoclonal antibody
Immunosuppressive human IgG vs. TNF-a
TX for rheumatoid arthritis, Crohn’s disease, ankylosing spondylitis, psoriasis
Mechanism of action of adalimumab
Binds to TNF-a, preventing its interactions with p55 and p75 cell surface TNF receptors; decreases biological activity of TNF-a
Clinical response is ↓ levels of pro-inflammatory cytokines such as IL-1 and IL-6, ↓ leukocyte migration, ↓ activation of neutrophils and eosinophils, ↓ fibroblast proliferation, ↓ synthesis of prostaglandins, ↓ matrix metalloproteinases that produce tissue remodeling responsible for cartilage destruction
Pharmacokinetics of adalimumab
Supplied in prefilled syringes containing 20 mg or 40 mg for SC injection
Usual maintenance dose is 40 mg Q 2 weeks
Elimination half-life is 10-20 days (mean ca. 14 days)
Adverse effects and precautions for adalimumab
Mild injection site reactions Headache (12%) Rash (12%) CV: hypertension (5%) MET: hyperlipidemia (6-7%)
Chronic or recurrent infection; tuberculosis
Travel to regions where mycoses or tuberculosis are endemic
Description of mycophenolate mofetil
Prodrug; semisynthetic derivative of mycophenolic acid obtained from Penicillium species
Used concomitantly with or as an alternative to cyclosporine or tacrolimus to prevent organ rejection after renal, cardiac, or liver transplants; recommendation is mycophenolate mofetil + cyclosporine + corticosteroid
Less bone marrow suppression than azathioprine
Mechanism of mycophenolate mofetil
Mycophenolic acid is a reversible inhibitor of inosine monophosphate dehydrogenase, inhibits the de novo pathway of guanosine biosynthesis that is critical to lymphocyte proliferation and activation, resulting in blunted T and B cell responses
Selective for lymphocytes; other cells are able to recover purines via a separate salvage pathway and are thus able to escape the effect
Pharmacokinetics of mycophenolate mofetil
Supplied as PO and IV formulations; both routes offer essentially complete bioavailability of mycophenolic acid
Usual dose is 1 g BID for kidney and liver transplants, 1.5 g BID for heart transplants
The inactive phenolic glucuronide is the main metabolite; excreted almost entirely in the urine
Adverse effects and precautions for mycophenolate mofetil
GI: NVD (13-36%), abdominal pain CNS: headache (16-54%) CV: hypertension (28-77%) HEM: myelosuppression (9-35%) DERM: acne (10%) rash (8%)
Chronic renal insufficiency, pregnancy category D
Sympathetic NS actions
dilates pupil, inhibits saliva flow, accelerates heart rate, dilates bronchi, inhibits peristalsis and secretion, conversion of glycogen to glucose, secretion of adrenaline and noradrenaline, inhibits bladder contractions.
Parasympathetic NS actions
constricts pupil, stimulates saliva flow, slows HR, constricts bronchi, stimulates peristalsis and secretion, stimulates release of bile, contracts bladder.
Synthesis of Ach
Choline gets acetylated by choline-acetyl transferase using the acetyl group from acetylCoA
Metabolism of Ach
Permanent positive charge on acetylcholine, so doesn’t last long if not in vesicles. Hydrolyzed by acetylcholine esterase back to an acetyl group and choline.
Synthesis of catecholamines.
Starts w/ tyrosine–> dihydroxyphenylalanine (DOPA) via tyrosine hydroxylase adding an –OH to the 5 C on the ring. DOPA then converted to DA via action of aromatic amino acid decarboxylase that removes the COOH moiety on the side chain. DA converted to NE by dopamine beta hydroxylase that adds an –OH to beta position of the side chain. This occurs inside the vesicle. NE gets converted to E via phenylethanolamine-N-methyltransferase that adds methyl group to the NH on the side chain.
Metabolism of catecholamines
Dopamine metabolism: via MAO and aldehyde DH to convert to DOPAC, then COMT converts to HVA by methylation of a catecholhydroxylation. Another pathway uses COMT to give 3-methoxytyramine, then MAO and ALDH to give HVA. NE and E metabolism: all ends up as VMA, excreted in urine and measured as marker for NE and E funct. If NE and E metabolized by MAO and ALDH first, give dihydroxymandelic acid, then COMT to VMA. If NE by COMT first, give normetanephrine then metabolized by MAO/ALDH to VMA. E w/ COMT first give metanephrine, then metabolized by MAO/ALDH to VMA.
Effects of beta receptor activation on cardiac function
Gs prot incr cAMP via activation of adenyl cyclase, activating PKA to phosphorylated Ca++ channels that increase Ca++ influx leading to incr HR at SA node, incr conduction velocity at AV node, and incr force of contraction at myocardium.
Description of Carbachol
Synthetic carbamoyl ester of choline
Main uses are for obtaining miosis during surgery and for reducing IOP elevation in the initial 24 hr following cataract surgery
Mechanism of action of carbachol
Agonist at muscarinic receptors; significant NN activity
Constricts the iris and ciliary body resulting in reduction in IOP
Pharmacokinetics of carbachol
Supplied as a 0.01% solution that is instilled into the anterior chamber of the eye
Miosis is usually maximal within 2-5 min after administration
Not susceptible to AChE inactivation
Duration of miosis ~ 24 hr
Adverse effects and counterindications of carbachol
Rarely iritis or corneal clouding
Acute cardiac failure; bradycardia Asthma Hyperthyroidism Peptic ulcer Urinary tract obstruction Parkinsonism
Description of methacholine
Synthetic acetylcholine analog
Indicated for the diagnosis of airway hyperreactivity
Mechanism of action of methacholine
Agonist at muscarinic receptors; slight nicotinic activity
Pharmacokinetics of methacholine
Supplied as a lyophilized powder that is reconstituted in isotonic saline for inhalation via nebulizer
Three-fold more resistant to AChE than acetylcholine
Most subjects return to baseline pulmonary function after 30-45 min
Adverse effects and counterindications of methacholine
Headache
Throat irritation
Lightheadedness
Itching
Acute cardiac failure; bradycardia Asthma Hyperthyroidism Peptic ulcer Urinary tract obstruction
Description of Bethanechol
Synthetic acetylcholine analog
DOC for promoting GI and urinary bladder motility for postop and postpartum nonobstructive urinary retention, neurogenic atony of the urinary bladder, and postop gastric atony or gastroparesis
Mechanism of action of bethanechol
Muscarinic agonist with no nicotinic activity
Pharmacokinetics of bethanechol
Available as tablets for PO dosing, usually 10-50 mg TID-QID
Onset occurs in 60-90 min and duration is usually 60 min
Not susceptible to AChE inactivation
Adverse effects and counterindications of bethanecol
Rare, but reflect cholinergic stimulation
Acute cardiac failure; bradycardia Asthma Hyperthyroidism Peptic ulcer Urinary tract obstruction Parkinsonism
Description of Pilocarpine
Plant alkaloid obtained from Pilocarpus microphyllus
Particularly active on the sweat and salivary glands and eyes; used as TX for xerostomia caused by Sjögren’s syndrome or salivary gland dysfunction and for miosis induction, postop and following ophthalmic examination; second-line TX for chronic open-angle glaucoma
Mechanism of action of pilocarpine
Muscarinic agonist
In open-angle glaucoma, pilocarpine contracts the ciliary and circular muscles, producing miosis resulting in increased outflow of aqueous humor; in closed-angle glaucoma, pilocarpine-induced miosis opens the angle of the anterior chamber of the eye through which aqueous humor exits
Pharmacokinetics of pilocarpine
0.5-6% ophthalmic solution has a duration of 4-14 hr; PO dose is usually 5-10 mg TID, has a 3-5 hr duration
Ocusert® delivers pilocarpine for 7 days via a contact lens-like system
Adverse reactions and counterindications of pilocarpine
Blurred vision
Exocrine glands: hypersalivation, diaphoresis
Flushing
Headache
Asthma Iritis Posterior synechiae (adhesion between iris and lens) Retinal detachment Heart disease Parkinsonism
Description of nicotine
Plant alkaloid obtained from Nicotiana tabacum
Used to help smokers quit smoking
Mechanism of action of nicotine
Agonist at NM and NN receptors
Complex action, affects CNS and all branches of peripheral nervous system; stimulates catecholamine release from adrenal medulla
Pharmacokinetics of nicotine
Dosage forms: gum, lozenge, inhaler, nasal spray, transdermal patch
Widely distributed in body tissues, especially CNS
Mostly metabolized in liver; unchanged nicotine and metabolites are excreted by the kidney
t1/2 = 30-120 min
Adverse effects and counterindications of nicotine
CNS: dizziness, insomnia, irritability
CV: ↑ BP and can have positive inotropic and chronotropic actions
GI: constipation, diarrhea
Angina, arrhythmia, myocardial infarction
Caution in patients with hypertension, pheochromocytoma, insulin-dependent diabetes, vasospastic diseases, or thyroid disease resulting in thyrotoxicosis
Pregnancy Risk Category D (transdermal)
Describe onset, duration of action, and clinical applications of succinylcholine.
Fast onset (
Adverse effects of succinylcholine
related to agonist activity at other AchR’s: stim autonomic ganglia AchR (HTN, tachycard), and stim cardiac muscarinic R’s (bradycard). Histamine release. Myalgias, incr intracranial and intraocular pressure, hyperkalemia (prolif of extrajunctional nAChRs, denervation, burns, trauma, prolonged immobility, myopathies)
Description of Varenicline
Smoking cessation aid
Mechanism of action of varenicline
High-affinity partial agonist a4b2 nicotinic receptors. Moderate affinity at 5-HT3 receptor.
Pharmacokinetics of varenicline
0.5 and 1 mg tablets for PO use, 1 mg BID after one-week ramp up. Peak plasma conc after 3-4 hours, t1/2= 24 hours. Minimal metabolism, 92% excreted as is.
Adverse effects and precautions for Varenicline
GI-related: transient nausea, constipation, flatulence. CNS: insomnia and vivid dreams
Renal insufficiency (don’t exceed 0.5 mg if in kidney failure). Risk of neuropsychiatric symptoms: hostility, irritability, agitation, depression, suicidal thoughts, attempted suicide.
