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Pharm > Block 2 > Flashcards

Block 2 Flashcards

1
Q

Aldosterone

A

Zona glomerulosa (outermost zone): cholesterol –> pregnenolone –> desoxycorticosterone –> aldosterone (mineralocorticoid)

  • synthesis controlled by angiotensin II and plasma potassium
  • 90% in plasma bound to corticosteroid binding globulin and albumin
  • inactivated in liver by: reduction of A ring, sulfate conjugation, glucuronide conjugation
  • structures necessary: 4,5 double bond; 3-ketone; 11-hydroxyl; 17-hydroxyl; 21-hydroxyl; 1,2 double bond; 16 substitution = INCREASE glucocorticoid activity, DECREASE mineralocorticoid activity
  • Specific mineralocorticoid receptor agonist
  • Inhibited by spironolactone and eplerenone
  • Kidney: increased sodium reabsorption), potassium secretion
  • Heart: cardiac hypertrophy, remodeling (increased morbidity and mortality), cardiac fibrosis, left ventricular hypertrophy, sodium and water retention (increased preload)
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2
Q

Cortisol

A

Zona fasciculata & reticularis: cholesterol –> pregnenolone –> desoxycortisol –> cortisol (glucocorticoid)

  • synthesis controlled by ACTH (adrenocorticotropic hormone)
  • 90% bound in plasma to CBG and albumin
  • inactivated in liver by: reduction of A ring, sulfate conjugation, glucuronide conjugation
  • structures necessary: SAME AS ALDOSTERONE
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3
Q

Glucocorticoid mechanism of action

A
  1. Crosses cell membrane
  2. Binds to cytosolic steroid receptor
  3. Translocates to nucleus
  4. Stimulates transcription of mRNA
  5. Stimulates mRNA directed protein synthesis
  6. Proteins mediate glucocorticoid effect
  • *NOT rapid acting drugs, but have 30-60 min delay
  • *stim IkBalpha production which prevents the TNF-REC complex from activating NF kbeta to move into the nucleus where it activates cytokine and other genes
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4
Q

Glucocorticoid Effects

A
  • Carb & Protein Metabolism: INCREASE liver gluconeogenesis, STIM aa mobilization in periphery (skel musc, skin), INCREASE plasma glucose, INCREASE liver glycogen, INCREASE urinary nitrogen excretion, REDUCE peripheral glucose use (skel musc, conn tissue)
  • Lipid metabolism: REDISTRIBUTION of body fat (moon face, buffalo hump) when on drugs long term, STIM release of FA from adipose tissue
  • Mineral & Electrolyte Metabolism: (via mineralocorticoid receptor in kidney) Cortisol = Aldosterone»Cortisone affinity for Receptor, INCREASE Na reabsorption, INCREASE K and H+ excretion, **responsible for cardiovascular effects (hypertension)
  • CNS: sleepiness, lability of mood
  • Immune system: (immunosuppressant) 1.reduces access of cells to target tissue–lymphocytopenia and monocytopenia (redistribution of cells out of vascular space), prevents neutrophil adherence to endothelium, inhib action of chemotactic factors 2. Inhibits cell functions–Macrophage: inhib antigen processing, inhib binding to Fc receptors, inhibits syn/release IL-1; B/T Lymphocytes: interferes with macrophage Ag processing, absence of IL 1 thus no activation, reduces IL 2 syn
  • Anti inflammatory: INHIB signs/symptoms of inflammation by inhibiting immune system, INHIB arachadonic acid release (via Lipocortin inhibiting Phospholipase A2) so syn of prostaglandins and leukotrienes is reduced, INHIB induction of cyclooxygenase 2 (COX2) by cytokines, DECREASES capillary permeability
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5
Q

Glucocorticoid Therapeutic uses

A
  • dose is variable and may change during therapy, reevaluate frequently
  • single dose, no harmful effects; prolonged therapy can be lethal
  • not curative but palliative/symptomatic therapy
  • abrupt discontinuation-life threatening due to adrenal insufficency
  • Adrenal Insufficiency: steroid replacement therapy
  • Rheumatoid arthritis: only in progressive desease in combination with salicylates, gold salts and physical therapy
  • Osteoarthiritis: given into joint for acute inflammation
  • Allergic Diseases: hay fever, serum sickness, drug reaction, anaphylaxis, bronchial asthma
  • Inflammatory diseases: of eye, ear, skin etc- use locally
  • Cerebral edema
  • shock
  • miscellaneous: organ transplantation, thrombocytopenia, liver diseases, collagen diseases, renal diseases
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6
Q

Corticosteroid drugs

A
  • Cortisol
  • Dexamethasone
  • Prednisolone
  • Fludrocortisone
  • Aldosterone

Potency:
Dexamethasone (20) > Fludrocortisone (12) > Prednisolone (3) > Cortisol (1) > Aldosterone (0.2)

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7
Q

Contraindication of steroid drugs

A

Existing infection

*particularly TB

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8
Q

Toxicity of Steroid drugs (corticosteroids)

A

-rapid withdrawl: acute adrenal insufficiency occurs - salt wasting, cardiovascular collapse

  • prolonged therapy:
    - supression of pituitary/adrenal function : related to dose/duration of therapy, may last for longer than 12 mo, reduce dosage slowly
    - Cushings syndrome: moon face/buffalo hump, poor wound healing, thin skin, hypertension, thin extremities, striae
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9
Q

Metyrapone

A
  • corticosteroid synthesis inhibitor
  • blocks 11-beta hydroxylation so synthesis stopped at 11-deoxycortisol
  • 11 deoxycortisol does NOT inhibit ACTH release, thus plasma ACTH levels increase
  • ACTH stim syn/ exretion of 17-hydroxycortioids as 11-deoxycortisol
  • used as a diagnostic test
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10
Q

Mifepristone

A
  • competitive antagonist at progesterone and glucocorticoid receptor
  • TERMINATES PREGNANCY
  • treats cushing disease
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11
Q

Spironolactone & Eplerenone

A
  • competitive antagonists at mineralocorticoid receptor
  • diuretics
  • treat hypertension
  • cardiac hypertrophy and heart failure
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12
Q

Drospirenone

A
  • Progesterone receptor agonist: used with estrogen to supress ovulation, used with estorgen as hormone replacement therapy in post menopausal women
  • Mineralocorticoid receptor antagonist: diuretic, antagonizes the salt retaining effect of estrogen
  • Androgen receptor antagonist
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13
Q

Infliximab

A
  • monoclonal antibody against TNF alpha chimeric (human 90%, mouse 10%)
  • useful in rheumatoid arthritis and Chrohn’s disease
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14
Q

Why use immuno supression drugs and what are the side effects?

A
  • why: prevention of allograft rejection, treatment of autoimmune diseases
  • SE: affect rapidly proliferating cells (bone marrow, liver, gi), increase incidence of infection
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15
Q

3 Classes of Immuno supression drugs:

A

1-Corticosteroids (Prednisolone)

2-Cytotoxic Agents (Azathioprine, Cyclophosphamide, Methotrexate, Mycophenolate Mofetil)

3- Cyclosporine like drugs (Cyclosporine, Tacrolimus, Sirolimus)

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16
Q

Cytotoxic Agents

A
  • kill rapidly proliferating cells
  • best if used at initial exposure to antigen (kills high percent of precursor cells)
  • clones stimulated by antigen will be killed
  • usually admin in low daily dosage to block immunoproliferation continually
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17
Q

Azathioprine

A
  • metabolized to 6-mercaptopurine
  • orally active
  • inhibits purine biosyn, thus inhib dna syn
  • inhibits de novo and salvage pathways of the purines
  • USE: inhibit rejection of transplanted organs and in some autoimmune diseases such as rheumatoid arthritis
  • Side effects: bone marrow supression, GI and hepatic toxicity
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18
Q

Cyclophosphamide

A
  • alkylating agen that results in cross linking of dna to kill replicating and non replicating cells
  • toxicity more on B cells, thus supresses humoral immunity
  • orally active
  • USE: treatement of autoimmune diseases in combination with other drugs, NOT effective in preventing graft rejection
  • Side Effects: bone marrow depression
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19
Q

Methotrexate

A
  • inhibitor of dihydrofolate reductase (inhib folate dependent steps in purine synthesis, inhibits dna syn)
  • USE: treat autoimmune disease
  • Side effects: hepatic toxicity
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20
Q

Mycophenolate Mofetil

A
  • metabolized to the active mycophenolic acid
  • mechanism of action: Lymphocyte selective immunosuppressant –1.inhibits IMP Dehydrogenase (imp to gmp; necessary for de novo syn, NO effect on salvage pathway) 2.selectively toxic for lymphocytes 3.inhibits lymphocyte proliferation and expression of cell surface adhesion molecules 4. MORE SELECTIVE than azathioprine or methotrexate but equally effective
  • USE: with cyclosporine and corticosteroids to prevent renal allograft rejection, allows lower dose of cyclosporine to be used thus less toxicity
    - treat autoimmune diseases rheumatoid arthritis and refractory psoriasis
  • orally active
  • USE WITH CAUTION in patients with active gi disease, reduced renal function and infections
  • side effects: infection, leukopenia, anemia
  • DO NOT USE IN PREGNANCY – assoc with pregnancy loss and congenital malformations
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21
Q

Glucocorticoid

A

Affect glucose metabolism

-not stored, synthesized when needed

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22
Q

Cyclosporine

A
  • lipophilic peptide antibiotic
  • Mechanism of action:
    - binds to cellular receptor (cyclophilin) and inhibits calcium dependent phosphatase (calcineurin) –blocks activation of transcription factor (NFAT) necessary for IL2 production
    - inhibits mRNA synthesis that codes for lymphokines as IL2
    - by blocking IL2 synthesis, it blocks T cell helper function so inhibits T cell proliferation and cytotoxicity
    - does NOT alter T cell response to IL2
    - not lymphotoxic thus more selective in its action
  • orally active
  • USE: prevent rejection of transplanted organs; more effective than others and less side effects; used in some autoimmune diseases
  • Side effects: nephrotoxicity in 25-40% of patients with high doses–reversible with reduction in dosage or discontinuation; hepatotoxicity may occur
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23
Q

Tacrolimus

A
  • binds FK binding protein (a cycophilin related protein); same mechanism as cyclosporine
  • USE same as cyclosporine but 50-100 times more potent
  • less nephro/hepatotoxicity
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24
Q

Sirolimus

A
  • inhibits T cell activation and proliferation downstream of IL2 (inhib ACTION of IL2, where cyclosporine and tacrolimus inhib the synthesis of IL2)
  • binds FKBP12; FKBP12-sirolimus complex does NOT bind calcineurin or affect calcineurin activity; it binds and inhibits mTOR (kinase incolved in cell cycle progression); Blocks G1 to S transition
  • USE: same as cyclosporine; coating of cardiac stents
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25
Q

Nitroglycerin

A

Venous dominant dilator - relaxation of venous smooth muscle and coronary arteries.
Metabolized to NO by mitochondrial aldehyde reductase (mtALDH), and enzyme enriched in venous smooth muscle, accounting for potent venodilating activity of this molecule.

Venous dilation DECREASES CARDIAC PRELOAD - leads to anti-anginal actions. Thus, treats ANGINA and CAD.

Sublingual administration. Liver contains high capacity organic nitrate reductase that removes Nitrate groups, thus F

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26
Q

Aliskiren

A
  • Inhibits renin
  • Potent active site, non-peptide inhibitor
  • Orally active (long acting)
  • Treat HTN
  • Decreases plasma angiotensin II and aldosterone concentrations
  • Side effects comparable to placebo (fatigue, headache, GI symptoms)
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27
Q

Losartan

A
  • Angiotensin II receptor competitive antagonist: blocks AT1 receptors
  • Although competitive, inhibition is insurmountable
  • Orally active
  • Reduces BP without increasing HR
  • Improves heart failure (decreases afterload, preload)
  • Contraindicated in pregnancy
  • Actions enhanced by diuretics
  • S/E: dizziness, cough, angioedema, hyperkalemia
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28
Q

Captopril

A
  • Sulfhydryl-containing ACE inhibitor
  • Inhibitor of ACE – block angiotensin II formation and bradykinin degradation
  • Reduce BP without increasing HR
  • Improves heart failure (decreases afterload, reduces L ventricular filing pressure, increases CO, decreases aldosterone and preload)
  • Orally active, treatment of essential hypertension
  • Actions enhanced by diuretics
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29
Q

Enalapril

A
  • Dicarboxyl-containing ACE inhibitor
  • Inhibitor of ACE – block angiotensin II formation and bradykinin degradation
  • Reduce BP without increasing HR
  • Improves heart failure (decreases afterload, reduces L ventricular filing pressure, increases CO, decreases aldosterone and preload)
  • Orally active, treatment of essential hypertension
  • Actions enhanced by diuretics
  • PRODRUG -> Enalaprilate (active)
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30
Q

Lisinopril

A
  • Dicarboxyl-containing ACE inhibitor
  • Inhibitor of ACE – block angiotensin II formation and bradykinin degradation
  • Reduce BP without increasing HR
  • Improves heart failure (decreases afterload, reduces L ventricular filing pressure, increases CO, decreases aldosterone and preload)
  • Orally active, treatment of essential hypertension
  • Actions enhanced by diuretics
  • PRODRUG -> Lisinoprilate (active)
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31
Q

Propranolol

A

-Beta adrenergic blocker, reduces renin release

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32
Q

Metoprolol

A

-Beta adrenergic blocker, reduces renin release

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33
Q

Renin

A
  • Major enzyme (acid protease) that determines the rate of angiotensin II production
  • Synthesized, stored, and secreted by the granular juxtaglomerular cells located in the walls of afferent arterioles
  • Splits leucine-leucine bond of angiotensinogen to yield angiotensin I
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34
Q

Angiotensinogen

A
  • Alpha2 globulin
  • Substrate for renin
  • Amino-terminal sequence contains angiotensin I
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35
Q

Converting Enzyme (ACE)

A
  • Ectoenzyme and glycoprotein that rapidly converts angiotensin I to angiotensin II
  • Removes C-terminal His-Leu dipeptide from angiotensin I
  • Vascular endothelium, lung, kidney, plasma
  • Inactivates Bradykinin
  • Inhibited by Captopril, Enalapril, and Lisinopril
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36
Q

Angiotensin II

A
  • Couples to AT1 and AT2 (GPCRs) – AT1 has a higher affinity and mediates most biological effects (AT1 -> Gq -> PLC -> IP3 -> Ca)
  • AT1 effects: arteriolar vasoconstriction (increased BP), hypertrophy
  • AT2 effects: endothelium-dependent vasodilation (NO mediated), inhibition of proliferation of smooth muscle, promotes apoptosis
  • Overall, slightly reduces GFR
  • Heart: Vasoconstrictor (increase afterload), activates SNS, arrhythmogenic, promotes myocardial hypertrophy and apoptosis, releases aldosterone (increase preload)
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37
Q

Fenoldopam

A
  • Vasodilator
  • Increase RBF without reducing GFR
  • Filtration fraction (FF=GFR/RBF) decreases, which reduces the protein concentration and hydroosmotic forces in the peritubular capillaries
  • Decreases in osmotic forces allow sodium and water to leak back into the tubule, which reduces net absorption, and increases Na excretion
  • Weak as diuretic due to compensatory Na reabsorption in more distal nephron segments
  • Limited pharm use
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38
Q

Dopamine

A
  • Vasodilator
  • Increase RBF without reducing GFR
  • Filtration fraction (FF=GFR/RBF) decreases, which reduces the protein concentration and hydroosmotic forces in the peritubular capillaries
  • Decreases in osmotic forces allow sodium and water to leak back into the tubule, which reduces net absorption, and increases Na excretion
  • Weak as diuretic due to compensatory Na reabsorption in more distal nephron segments
  • Limited pharm use – may be used to increase RBF in shock
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39
Q

Atriopeptin

A
  • Vasodilator
  • Increase RBF without reducing GFR
  • Filtration fraction (FF=GFR/RBF) decreases, which reduces the protein concentration and hydroosmotic forces in the peritubular capillaries
  • Decreases in osmotic forces allow sodium and water to leak back into the tubule, which reduces net absorption, and increases Na excretion
  • Weak as diuretic due to compensatory Na reabsorption in more distal nephron segments
  • Limited pharm use
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40
Q

Mannitol

A
  • Osmotic diuretic, acts mostly on proximal tubule
  • Freely filtered at glomerulus, limited reabsorption by tubule, NOT metabolized by kidney, pharmacologically inert
  • Na is reabsorbed without water, and the Na concentration in tubule falls; this continues in ascending limb and distal tubule; enhanced K excretion occurs in distal tubule to increase Na available for exchange
  • Urine flow increases as does excretion of Na, K, and Cl
  • IV admin; excreted by glomerular filtration within 30-60 min
  • Uses: prophylaxis of acute renal failure, edema (when volume load not detrimental), glaucoma, reduce intracranial pressure
  • Toxicity: extracellular volume expansion, dehydration, hyperkalemia, hypernatremia; also hyponatremia in patients with severe renal impairment
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41
Q

Acetazolamide

A
  • Inhibits carbonic anhydrase (which catalyzes the formation of carbonic acid from CO2 and H2O) – blockade decreases bicarb reabsorption and thereby Na reabsorption in prox tubule, leading to increased urine pH; K secretion in distal tubule increases
  • Secreted into proximal tubule by OAT
  • Results in increased urine volume, increased excretion of Na, K, and bicarb; decreased secretion of Cl
  • Uses: Glaucoma (reduce aqueous humor formation), alkalinize urine to decrease drug toxicity, metabolic alkalosis, treat symptoms of acute altitude sickness
  • Toxicity: hyperchloremic metabolic acidosis, renal stones, renal potassium wasting *but generally a safe drug
  • Contraindication: pts with cirrhosis can develop hyperammonemia and hepatic encephalopathy
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42
Q

Furosemide

A
  • Loop/high ceiling diuretic
  • Na-K-2Cl symport inhibitor
  • Secreted into prox tubule by OAT; acts on cortical and medullary segments of the ascending limb to inhibit active Cl reabsorption, resulting in decreased reabsorption of both Na and Cl
  • In high doses, may inhibit carbonic anhydrase and have prox tubule effect
  • POTENT
  • Increase renal blood flow, and often GFR
  • Impairs the ability to make conc or dilute urine
  • Urine volume increases, as does the excretion of Na, Cl, and K
  • Uses: oral and IV; rapid onset, short DOA; edema (cardiac, hepatic, renal disease), acute pulmonary edema, HTN
  • Toxicity: hypokalemia, hyperuricemia, hyperglycemia
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43
Q

Bumetanide

A
  • Loop/high ceiling diuretic
  • Na-K-2Cl symport inhibitor
  • Secreted into prox tubule by OAT; acts on cortical and medullary segments of the ascending limb to inhibit active Cl reabsorption, resulting in decreased reabsorption of both Na and Cl
  • In high doses, may inhibit carbonic anhydrase and have prox tubule effect
  • POTENT
  • Increase renal blood flow, and often GFR
  • Impairs the ability to make conc or dilute urine
  • Urine volume increases, as does the excretion of Na, Cl, and K
  • Uses: oral and IV; rapid onset, short DOA; edema (cardiac, hepatic, renal disease), acute pulmonary edema, HTN
  • Toxicity: hypokalemia, hyperuricemia
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44
Q

Ethacrynic Acid

A
  • Loop/high ceiling diuretic
  • Na-K-2Cl symport inhibitor
  • Secreted into prox tubule by OAT; acts on cortical and medullary segments of the ascending limb to inhibit active Cl reabsorption, resulting in decreased reabsorption of both Na and Cl
  • POTENT
  • Increase renal blood flow, and often GFR
  • Impairs the ability to make conc or dilute urine
  • Urine volume increases, as does the excretion of Na, Cl, and K
  • Uses: oral and IV; rapid onset, short DOA; edema (cardiac, hepatic, renal disease), acute pulmonary edema, HTN
  • Toxicity: hypokalemia, hyperuricemia
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45
Q

Chlorothiazide

A
  • Thiazide diuretic
  • Orally active, Na-Cl symport inhibitor
  • Secreted into prox tubule by OAT, act on cortical diluting segment of ascending limb
  • In higher doses, inhibits carbonic anhydrase and has prox tubule effect
  • Intermediate potency
  • Reduced GFR
  • Impairs kidneys ability to make dilute urine
  • Urine volume increases as does excretion of Na, Cl, and K (hypertonic urine)
  • Uses: rapid onset, long DOA; edema (congestive heart failure), HTN, hypercalciuria (in pats with renal calculi composed of calcium salts)
  • Toxicity: hypokalemia, hyperuricemia, hyperclycemia (decreased insulin secretion)
  • *should NOT be used when GFR
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46
Q

Hydrochlorothiazide

A
  • Thiazide diuretic
  • Orally active, Na-Cl symport inhibitor
  • Secreted into prox tubule by OAT, act on cortical diluting segment of ascending limb
  • In higher doses, inhibits carbonic anhydrase and has prox tubule effect
  • Intermediate potency
  • Reduced GFR
  • Impairs kidneys ability to make dilute urine
  • Urine volume increases as does excretion of Na, Cl, and K (hypertonic urine)
  • Uses: rapid onset, long DOA; edema (congestive heart failure), HTN, hypercalciuria (in pats with renal calculi composed of calcium salts)
  • Toxicity: hypokalemia, hyperuricemia, hyperclycemia (decreased insulin secretion)
  • *should NOT be used when GFR
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47
Q

Metolazone

A
  • Thiazide diuretic
  • Orally active, Na-Cl symport inhibitor
  • Secreted into prox tubule by OAT, act on cortical diluting segment of ascending limb
  • In higher doses, inhibits carbonic anhydrase and has prox tubule effect
  • Intermediate potency
  • Reduced GFR
  • Impairs kidneys ability to make dilute urine
  • Urine volume increases as does excretion of Na, Cl, and K (hypertonic urine)
  • Uses: rapid onset, long DOA; edema (congestive heart failure), HTN, hypercalciuria (in pats with renal calculi composed of calcium salts)
  • Toxicity: hypokalemia, hyperuricemia, hyperclycemia (decreased insulin secretion)
  • *should NOT be used when GFR
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48
Q

Spironolactone

A
  • Competitive aldosterone antagonist at mineralocorticoid receptor
  • Diuretic, orally active – treat HTN or heart failure
  • Reduce mortality from heart failure; use with thiazide or loop diuretic to treat HTN or edema
  • Has an additive effect in presence of ACE inhibitor
  • Aldosterone antagonist, potassium-sparing diuretic
  • Synthetic steroid, acts as competitive antagonist to aldosterone; inactivation of spironolactone occurs in the liver; slow onset of action – needs several days to reach full therapeutic effect
  • Acts on distal tubule, requires endogenous aldosterone
  • Urine volume increases, increased excretion of Na, decreased excretion of K
  • Weak diuretic
  • Uses: HTN, refractory edema, primary aldosteronism; usually used with thiazide or loop diuretic; long DOA
  • Toxicity: hyperkalemia, gynecomastia
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49
Q

Eplerenone

A
  • Competitive aldosterone antagonist at mineralocorticoid receptor
  • Diuretic, orally active – treat HTN or heart failure
  • Reduce mortality from heart failure; use with thiazide or loop diuretic to treat HTN or edema
  • Has an additive effect in presence of ACE inhibitor
  • Aldosterone antagonist, potassium-sparing diuretic
  • Spironolactone analog, with greater selectivity for mineralocorticoid receptor; has fewer adverse effects because it is much less active on androgen/progesterone receptors
  • Acts on distal tubule, requires endogenous aldosterone
  • Urine volume increases, increased excretion of Na, decreased excretion of K
  • Weak diuretic
  • Uses: HTN, refractory edema, primary aldosteronism; usually used with thiazide or loop diuretic; long DOA
  • Toxicity: hyperkalemia, gynecomastia (gynecomastia not as severe in eplerenone as in spironolactone)
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50
Q

Triamterene

A
  • Sodium channel inhibitor, potassium sparing diuretic
  • Inhibit entry of Na into principal cells, so Na-K exchange does not occur
  • Effects are independent of aldosterone
  • Urine volume increases, increased excretion of Na, decreased secretion of K; at high doses, reduces GFR
  • Weak diuretic
  • Uses: edema or HTN; usually used with thiazide or loop diuretic
  • Toxicity: hyperkalemia, azotemia (mild)
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51
Q

Amiloride

A
  • Sodium channel inhibitor, potassium sparing diuretic
  • Inhibit entry of Na into principal cells, so Na-K exchange does not occur
  • Effects are independent of aldosterone
  • Urine volume increases, increased excretion of Na, decreased secretion of Kn7
  • Weak diuretic
  • Uses: edema or HTN; usually used with thiazide or loop diuretic
  • Toxicity: hyperkalemia, azotemia (mild)
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52
Q

Absorbed in proximal tubule

A
  • Na (50-70% filtered load)
  • K
  • Bicarb (80-90%)
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53
Q

Absorbed in ascending limb of Henle

A
  • Na and Cl (20-30%)

- NO water reabsorption

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54
Q

Absorbed in distal tubule and collecting duct

A
  • Na (8-9%)

- Water permeability regulated by ADH

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55
Q

Nitroglycerin

A

Venous dominant dilator - relaxation of venous smooth muscle and coronary arteries.
Metabolized to NO by mitochondrial aldehyde reductase (mtALDH), and enzyme enriched in venous smooth muscle, accounting for potent venodilating activity of this molecule.

Venous dilation DECREASES CARDIAC PRELOAD - leads to anti-anginal actions.

Treats: Angina and CAD

Sublingual administration. Liver contains high capacity organic nitrate reductase that removes nitrate groups, thus F

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56
Q

Nitroprusside

A

Relaxation of arterial and venous circulations. Nitroprusside is a complex of iron, cyanide groups, and nitroso moiety. Rapidly metabolized by uptake of RBCs with release of NO and cyanide. Sodium Nitroprousside breaks down to generate FIVE cyanide molecules and a single NO. Cyanide in turn is metabolized by mitochondrial enzyme RHODANESE to less toxic, thiocyanate.

Leads to RAPID REDUCTION OF ARTERIAL PRESSURE by reducing afterload and preload. Effect disappears after 1-10min after discontinuation. Nitroprusside in aqueous solution is sensitive to light and must be made fresh before admin, and covered with opaque foil. Infusion should be changed after several hours.

Treats: Hypertensive emergencies.

Tolerance does not occur with nitroprusside– it retains activity over long periods of time.

Toxicity: Hypotension, cyanide accumulation, metabolic acidosis, and arrhythmias.

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57
Q

Hydralazine

A

Relaxation of arterial circulation– it dilates arterioles (NOT VEINS). It was initially thought not be effective in treating HTN because tachyphylaxis developed rapidly. Benefits of hydralazine as a part of combination therapy is now recognized for HTN therapy = Hyrdalazine + nitrates = effective in heart failure and best for patients with both HTN AND HEART FAILURE.

Treats: Heart failure and hypertension.

Toxicity: Headache, nausea, anorexia, palpitations, sweating, and flushing.

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58
Q

Minoxidil

A

Arterial circulation dilation (NOT VEINS)- Minoxidil sulfate activates potassium channels in smooth muscle membranes resulting in hyperpolarization.

Treats: Heart failure and hypertension.

Toxicity: Fluid and salt retention, cardiovascular effects, and hypertrichosis (excessive hair growth)

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59
Q

Diazoxide

A

Arterial circulation dilation - activates potassium channels in smooth muscle membranes resulting in hyperpolarization. Effective and LONG ACTING. DECREASES systemic vascular resistance and mean arterial blood pressure.

Treats: Hypertensive emergencies and hypoglycemia secondary to insulinoma.

Parenterally administered (injection/infusion).

Toxicity: Hypotension, and hypoglycemia

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60
Q

Ca2+ Channel Blockers Classes

A

Dihydropyridines, Phenalkylamine, Benzothiazepines.

Calcium channel splice variants in the structure of the alpha-1 channel subunit appears to account for the differences in drug classes.

Generally, calcium channel blockers can reduce cerebral damage AFTER thromboembolic stroke.

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61
Q

1,4 DIHYDROPYRIDINE Ca channel blockers

A

Nifedipine, Nicardipine, Amlodipine*, and Nimodipine

These are the VASODILATING CCBS. This class of calcium channel blockers have a greater ratio of vascular smooth muscle effects relative to cardiac effects. THUS, they act preferentially on arterial muscle cells. (Little effect on veins)
These also differ in their potency in different vascular beds.

Binding site: outside surface of the channel protein in the DEPOLARIZED (resting) STATE OF L-type Ca2+ CHANNEL - high affinity. The resting membrane potential of vascular smooth muscle cells is more depolarized, that’s why dihydropyridine drugs bind preferentially to vascular smooth muscle.
PROTEIN BINDING IS STRONGER in dihydropyridines than the other classes.

NET EFFECT: REDUCE CARDIAC AFTERLOAD (but not preload). Also produce reductions in myocardial oxygen demand and in arterial pressure.

Pharmacokinetics: Slow release of dihydropyridines causes LESS reflex tachycardia.

Adverse effects: hypotension, headache, flushing, and peripheral edema.
Dihydropyridines are MOST associated with greatest incidence of adverse effects.

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62
Q

What is the phenylalkylamine Ca channel blockers?

A

Verapamil - A ‘MYOCARDIAL CCB’

Phenylakylamine selectivity: preferentially on cardiac cells

Verapamil that lacks cerebral vascular selectivity can be administered intra-arterially for stroke.

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63
Q

What is the Benzothiazepine Ca channel blocker?

A

Diltiazem - A ‘MYOCARDIAL CCB’

Benzothiazepine selectivity: preferentially on cardiac cells

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64
Q

Nifedipine

A

Dihyropyridine calcium channel blocker.
Function: Arterial circulation dilation.

Short acting preparation of nifedipine have highest frequency of adverse effects; sustained release nifedipine preps are better.

Treats: Hypertension, Angina, Cerebral, and Coronary vasopasm

Pharmacokinetics:
Oral abs: >90%
F= 45-86%
Protein bound = 92-98%
Elimination half-life: 1.9-5.8 hours

Contraindication: ++ for hypotension, and + severe cardiac failure

Overall adverse effects: 9-39%
Cardiac toxicity: bradycardia, atrioventricular block, cardiac arrest, heart failure.

Other: flushing, dizziness, nausea, peripheral edema

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65
Q

Nicardipine

A

Dihyropyridine calcium channel blocker.
Function: Arterial circulation dilation.

Nicardipine used by IV and intracerebral arterial infusion to prevent cerebral vasospasm associated with stroke.

Treats: Hypertension, Angina, Cerebral, and Coronary vasopasm

Administration: IV and intracerebral arterial infusion to prevent cerebral vasospasm associated with stroke.

Cardiac toxicity: bradycardia, atrioventricular block, cardiac arrest, heart failure.
Other: flushing, dizziness, nausea, peripheral edema

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66
Q

Amlodipine

A

Dihyropyridine calcium channel blocker.
Function: Arterial circulation dilation.

Has a longer half-life than most older CCBs - allows for once-daily administration. Thus, this is a really well tolerated dihydropyridine.

Treats: Hypertension, Angina, Cerebral, and Coronary vasopasm

Pharmacokinetics:
Oral abs: >90%
F= 64-90%
Protein bound = 97-99%
Elimination half-life: 30-50 hours

Contraindication: ++ for hypotension, and + severe cardiac failure

Overall adverse effects: 9-39%
Cardiac toxicity: bradycardia, atrioventricular block, cardiac arrest, heart failure.
Other: flushing, dizziness, nausea, peripheral edema

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67
Q

Verapamil

A

Phenylakylamine calcium channel blocker.
Function: Arterial circulation dilation.

MOA: Binds to L Type Ca channels in vascular smooth muscle cells to cause vasodilation. Has a higher ratio of cardiac to vascular selectivity than the dihydropyridines (nif, nic, amlo)

EFFECTS: 
Increase peripheral vasodilation 
Really increases coronary vasodilation 
Decreases afterload 
Really decreases contractility, heart rate, and AV conduction

Treats: Hypertension, Angina, Cerebral, and Coronary vasopasm

Can be administered intra-arterially for stroke; lacks cerebral vascular selectivity.

UNIQUE TO VERAPAMIL: Undergoes extensive first pass metabolism that may result in wide variations in plasma levels and marked differences between oral and IV doses.

Pharmacokinetics:
Oral abs: >90%
F= 10-35% 
Protein bound = 83-92% 
Elimination half-life: 2.8-6.3 hours

Contraindications + for hypotension, sinus bradycardia. ++ for AV conduction defects and severe cardiac failure.

Overall adverse effects: 10-14%
Cardiac toxicity: bradycardia, atrioventricular block, cardiac arrest, heart failure. COULD worsen CHF (negative inotropic effects). 2nd/3rd degree Heart block in some patients (due to dampening effect on AV node conduction)

Other: flushing, dizziness, nausea, peripheral edema

VERAPAMIL SPECIFIC - Toxicity: CONSTIPATION - due to the high affinity of L type Ca channels in GI smooth muscle

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68
Q

Diltiazem

A

Benzothiazepine calcium channel blocker
Function: Arterial circulation dilation.
Main therapeutic use: ANGINA and Supraventricular arrhythmias!
Is best tolerated of the original CBCs - less potent cardiac effects than Verapamil, and less dramatic vasodilation than nifedipine.

Effect: REDUCES CARDIAC AFTERLOAD by causing increased peripheral vasodilation and decreasing SA node firing rate (lowers high HR). Also potential dilator of coronary arteries (allowing more blood flow to myocardium).

Overall: 
Increase peripheral vasodilation 
Really increases coronary vasodilation 
Decreases afterload, contractility, and AV conduction
Really decreases heart rate

Tx for: Hypertension, Angina, Cerebral, and Coronary vasopasm

Pharmacokinetics:
Oral abs: >90%
F= 41-67%
Protein bound = 77-80%  
Elimination half-life: 3.5-7 hours

Contraindication + for hypotension, sinus bradycardia, severe cardiac failure, and also ++ for AV conduction defects.

Overall adverse effect: 0-3%
Cardiac toxicity: bradycardia, atrioventricular block, cardiac arrest, heart failure.

Less likely than Verapamil, but: COULD worsen CHF (negative inotropic effects). 2nd/3rd degree Heart block in some patients (due to dampening effect on AV node conduction)

Other: flushing, dizziness, nausea, peripheral edema

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69
Q

PDE-3 Inhibitors

A

Milrinone, Inamrinone, Cilostazol

Intracellular signaling MOA: PDE3 inhibition leads to more cAMP&raquo_space; more PKA phosphorylation&raquo_space; more activation of cardiac Ca channels and vascular smooth muscle K channel. Effect: positive cardiac ionotropic and vasodilator actions.

Treats heart failure.

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70
Q

Milrinone

A

PDE 3 inhibitor.

Treats heart failure.

Administered IV for short term treatment of life-threatening heart failure. Oral forms withdrawn from market due to sudden cardiac death.

Contraindication - cilostazol (oral) is contraindicated in heart failure.

Toxicity: Arrhythmias, headache, thrombocytopenia

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71
Q

Inamrinone

A

PDE 3 inhibitor.

Treats heart failure.

Administered IV for short term treatment of life-threatening heart failure. Oral forms withdrawn from market due to sudden cardiac death.

Contraindication - cilostazol (oral) is contraindicated in heart failure.

Toxicity: Arrhythmias, headache, thrombocytopenia

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72
Q

PDE-5 Inhibitors

A

Sildenafil, Tadalafil

Intracellular signaling MOA: PDE5 inhibition leads to increase in cGMP that mediates PKG phosphorylation.

Treats erectile dysfunction and pulmonary hypertension.

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73
Q

Sildenafil

A

PDE5 Inhibitors

Relaxes the non-vascular smooth muscle of the corpora cavernosa resulting in inflow of blood into the sinuses of the cavernosa to cause erection.

Treats erectile dysfunction and pulmonary hypertension.

Adverse effects with nitrates.

COLOR VISION DEFICITS.

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74
Q

Tadalafil

A

PDE5 inhibitors

Relaxes the non-vascular smooth muscle of the corpora cavernosa resulting in inflow of blood into the sinuses of the cavernosa to cause erection.

Treats erectile dysfunction and pulmonary hypertension.

Adverse effects with nitrates.

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75
Q

Fenoldopam

A

Dopamime D1 Receptor Agonist
Arterial circulation dilation via peripheral arteries and natriuresis (excretion of Na in urine).

Treats: Hypertensive emergencies and postoperative hypertension

IV administration.

Avoid using this in GLAUCOMA patients, because it increases INTRAOCULAR PRESSURE.

Toxicity: Reflex tachycardia, headache, flushing.

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76
Q

Prazosin

A

Alpha-adrenergic blocker - selectively blocks alpha-1 receptors in arterioles and venules leading to arterial AND venous circulation dilation.

Treats: Hypertension

Toxicity: Reflex tachycardia, dizziness, and headache.
Long term tx of Prazosin causes relatively little postural hypotension, however a precipitous drop in standing BP develops in some patients shortly after the first dose is absorbed (first dose phenomenon).

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77
Q

Atosiban

A

Oxytocin receptor antagonist.
Nonapeptide analog of oxytocin that competitively inhibits the interaction of oxytocin with its membrane receptor on uterine cells resulting in decreased frequency of uterine contractions.

Prevents preterm labor.

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78
Q

PGE1 analogs

A

Misoprostol, Alprostadil

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79
Q

Misoprostol

A

PGE1 analog.

Stimulate uterine contractions and prevents/treats postpartum hemorrhage.

Orally or sublingually administration.

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80
Q

Alprostadil

A

PGE 1 analog.

Smooth muscle relaxing effects to maintain arteriosus patent in neonates awaiting cardiac surgery.

Suppository or injection administration used for ED.

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81
Q

Oxytocin

A

Uterine contraction

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82
Q

Ergonovine

A

Uterine contraction. In very small doses this can evoke rhythmic contractions of the uterus and at higher concentrations induces powerful and prolonged uterine contraction. Uterus at term is more sensitive to ergonovine compared to earlier in pregnancy. FAR more sensitive than non-pregnant uterus.

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83
Q

Metoclopramide

A

Dopamine D2 receptor antagonist. GI tract activation of dopamine receptors inhibits cholinergic smooth muscle stimulation, blockage of this effect is believed to be primary prokinetic mechanism of action.

Increases lower esophageal sphincter pressure, and hances gastric emptying. No effect on small intestine or colonic motility.
Inhibits D2 receptors in the chemoreceptor trigger zone of the medulla resulting in potent ANTI-NAUSEA and antiemetic action.

Treats: GERD, impaired gastric emptying, and preventing/treating emesis

Toxicity: Restlessness, drowsiness, insomnia, anxiety, agitation, short term use acute dystonias (involuntary muscle contractions), and long term use tardive dyskinesia (impairment of voluntary movement)

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84
Q

Bethanechol

A

Muscarinic receptor agonist. Selectively stimulates muscarinic receptors without effect on nicotinic receptors. Not hydrolyzed by cholinesterase and will therefore have a long duration of action.

Muscarinic receptor activation in bladder leads to bladder contraction, and expulsion of urine.

Treats dry mouth, and urinary retention (from diabetic neuropathy of the bladder).

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85
Q

Erythromycin

A

Macrolide antibiotic that stimulates motilin receptors on smooth GI muscle and promote onset of migrating motor complex.

Treats gastroparesis. Can be used before endoscopy to promote gastric emptying of blood in patients with acute upper GI hemorrhage.

IV administration can be beneficial in patients with gastroparesis - tolerance rapidly develops though.

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86
Q

Classes of Bronchodilators

A

B2 Receptor Agonists, Anticholinergic, Methylxanthine

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87
Q

B2 Receptor Agonists

A

Albuterol, Pirbuterol, Terbutaline, Salmeterol, Formoterol
Mechanism of Action: B2 receptors are present in several different airway cell and b2 agonists can cause bronchodilation via a direct action on airway smooth muscles - INHIBITS release of bronchoconstrictors mediators from inflammatory cells, and inhibiting bronchoconstrictor neurotransmitters from airway nerves.

Relaxation of airway smooth muscle occurs via lowering of intracellular Ca, activation of K channels, and activation of myosin light chain phosphatase.

Pulmonary airway actions: BRONCHODILATION, PREVENT MICROVASCULAR LEAKAGE AND BRONCHIAL MUCOSAL EDEMA, INCREASE MUCUS CLEARANCE

Toxicity: Tachycardia, muscle tremor, hypokalemia, V/Q mismatch. Side effects NOT COMMON with inhaled therapy, but quite common with oral or IV admin.

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88
Q

Albuterol

A

B2 receptor agonist.

Toxicity: Tachycardia, muscle tremor, hypokalemia, V/Q mismatch. Side effects NOT COMMON with inhaled therapy, but quite common with oral or IV admin.

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89
Q

Pirbuterol

A

B2 receptor agonist.

Toxicity: Tachycardia, muscle tremor, hypokalemia, V/Q mismatch. Side effects NOT COMMON with inhaled therapy, but quite common with oral or IV admin.

90
Q

Terbutaline

A

B2 receptor agonist. Can be used to inhibit uterine contractions associated with premature labor.

Toxicity: Tachycardia, muscle tremor, hypokalemia, V/Q mismatch. Side effects NOT COMMON with inhaled therapy, but quite common with oral or IV admin.

91
Q

Salmeterol

A

Long acting B2 receptor agonist. Lasts >12 hours and has been proved to be a significant advance in asthma and COPD therapy.

Toxicity: Tachycardia, muscle tremor, hypokalemia, V/Q mismatch. Side effects NOT COMMON with inhaled therapy, but quite common with oral or IV admin.

92
Q

Formoterol

A

Long acting B2 receptor agonist. Lasts >12 hours and has been proved to be a significant advance in asthma and COPD therapy.

Toxicity: Tachycardia, muscle tremor, hypokalemia, V/Q mismatch. Side effects NOT COMMON with inhaled therapy, but quite common with oral or IV admin.

93
Q

ANTICHOLINERGIC DRUGS for Bronchodilation

A

Ipratropium, Tiotropium

MOA: Muscarinic Receptor ANTAGONISTS; completely inhibit the action of Acetylcholine at muscarinic receptors.
In pulmonary airways, Ach released from efferent ending of vagal nerves. Muscarinic antagonists block contraction of airway smooth muscle and the increase in secretion of mucus that occurs in response to vagal activity.

Treats COPD and Asthma.

Distinct for each drug.

94
Q

Ipratropium

A

Muscarinic Receptor ANTAGONISTS
Effect: Opens airway by stopping vagal activity.

Treats COPD and Asthma.

Toxicity: Paradoxical bronchoconstriction

95
Q

Tiotropium

A

Muscarinic Receptor ANTAGONISTS
Effect: Opens airway by stopping vagal activity.

Treats COPD and Asthma.

Toxicity: Dry mouth

96
Q

METHYLXANTHINE drugs for bronchodilation

A

Theophylline, and Aminophylline

Aminophylline does not have any specific information listed, just know that is a Methylxanthine tx for COPD

Treats: COPD

97
Q

Theophylline

A

Methylxanthine tx for COPD.
MOA is not completely understood - it has bronchodilator action, but also has non-bronchodilator actions that are relevant to its effects in asthma and COPD.

Possible mechanisms:

  • PDE inhibition: nonselective PDE inhibitor that results in increases in cAMP and cGMP&raquo_space; causes bronchodilation
  • Adenosine receptor antagonism: Theophylline antagonizes adenosine receptors at therapeutic concentrations - adenosine causes bronchoconstriction and inflammation in airways of asthmatic patients by releasing histamine and leukotrienes.
  • Others: works by increasing release if IL-10 (anti-inflammation), preventing translocation of pro-inflammatory transcription factor NF-kB into the nucleus, promotes apoptosis in T lymphocytes, eosinophils and neutrophils, and activates histone deacteylase-2 (HDAC2) to enhance the anti-inflammatory effects of corticosteroids.

Toxicity: Nausea, vomiting, tremulousness, arrhythmias.

Theophylline has a narrow therapeutic index and requires monitoring of serum levels.

98
Q

PULMONARY HYPERTENSION drugs

A
  1. Epoprostenol, Iloprost
    Mechanism of action: Prostacyclin (PGI2)
    PGI2 lowers peripheral, pulmonary, and coronary vascular resistance. Synthetic PGI2 (epoprostenol) and PGI2 analog (iloprost) treats pulmonary and secondary pulmonary hypertension. Prostacyclin has been used to treat post-pulmonary hypertension that occurs in liver disease also.
  2. Bosentan
    Mechanism of Action: Eta Receptor ANTAGONIST
    Endothelin1 (ET1) potent pulmonary vascoconstrictor that is produced in arterial hypertension (PAH) – ET1 contracts vascular smooth muscle cells and casues proliferation mainly via ETa receptors. ETb receptors release NO and PGI2 from endothelium to cause vasorelaxation
  3. NO

IV and inhalation administration.

Toxicity: Flushing, headache, hypotension, nausea, diarrhea.

99
Q

Epoprostenol

A 
SYNTHETIC PROSTACYCLIN (PGI2) 
PGI2 lowers peripheral, pulmonary, and coronary vascular resistance. Synthetic PGI2 (epoprostenol) and PGI2 analog (iloprost) treats pulmonary and secondary pulmonary hypertension. Prostacyclin has been used to treat post-pulmonary hypertension that occurs in liver disease also.

Extremely SHORT PLASMA HALF LIFE (3-5 minutes) that necessitates continuous IV infusion through central line for long-term tx.

Treats primary and secondary pulmonary hypertension

IV and inhalation administration.

100
Q

Iloprost

A

PROSTACYCLIN (PGI2) ANALOG
PGI2 lowers peripheral, pulmonary, and coronary vascular resistance. Synthetic PGI2 (epoprostenol) and PGI2 analog (iloprost) treats pulmonary and secondary pulmonary hypertension. Prostacyclin has been used to treat post-pulmonary hypertension that occurs in liver disease also.

HALF LIFE is about 30 minutes (longer than epoprostenol) - usually inhaled six to nine times a day.

Treats primary and secondary pulmonary hypertension

IV and inhalation administration.

101
Q

Bosentan

A

ET(ALPHA and BETA) RECEPTOR ANTAGONIST
Endothelin1 (ET1) potent pulmonary vascoconstrictor that is produced in arterial hypertension (PAH) – ET1 contracts vascular smooth muscle cells and causes proliferation mainly via ETa receptors. ETb receptors release NO and PGI2 from endothelium to cause vasorelaxation.

ORALLY ACTIVE NON SELECTIVE - reduces symptoms and improves mortality in primary PAH.

Treats: Pulmonary arterial hypertension (PAH)

IV and inhalation administration .

Toxicity: Liver toxicity (requires monthly monitoring of liver aminotransferases), anemia, headaches, peripheral edema.

102
Q

Ambrisentan

A

ET(alpha) receptor antagonist.
Endothelin1 (ET1) potent pulmonary vascoconstrictor that is produced in arterial hypertension (PAH) – ET1 contracts vascular smooth muscle cells and causes proliferation mainly via ETa receptors. ETb receptors release NO and PGI2 from endothelium to cause vasorelaxation.

ORALLY ACTIVE SELECTIVE! Blocks Eta receptors only and then allows Etb receptors to stimulate release of PGI2 and NO – but clinically IRL, its efficacy is similar to Bosentan (NONSELECTIVE).

Toxicity: Liver toxicity (requires monthly monitoring of liver aminotransferases), anemia, headaches, peripheral edema.

103
Q

Nitric Oxide

A

Inhalation of NO results in reduced pulmonary artery pressure and improved perfusion of ventilated areas of the lung.

Effect: SHORT TERM improvements in pulmonary function

Treats pulmonary hypertension, acute hypoxemia, and cardiopulmonary resuscitation.

Inhalation administration only.

Toxicity: Inhaled NO is provided as a compressed gas mixture with Nitrogen that does not readily react with NO. NO can react with O to form NO2 that is a pulmonary irritant (leading to deterioration of lung function). NO can induce formation of methmoglobin a form of hemoglobin that does not bind O2. thus NO2 and methomoglobin levels are carefully monitored during inhaled NO treatment.

104
Q

Nimodipine

A

Dihyropyridine calcium channel blocker. ^^NOT BOLDED, but discussed a lot?

Nimodipine has high affinity for cerebral blood vessels and appears to reduce morbidity after subarachnoid hemorrhage.

105
Q

What CCB can you use for angina?

A

Diltiazem

106
Q

What CCB can you use for supraventricular arrhythmias?

A

Diltiazem and Verpamil - both reduce firing rate of the SA node and reduce conduction through AV node (this reduces ventricular response rates if the atria is firing too fast).

107
Q

What CCB can you use for hypertension?

A

Dihydropyridine type -
Nifedipine, Nicardipine, Amlodipine*, and Nimodipine due to their potent vasodilator action.

What could go wrong? Reduced BP may trigger reflex tacycardia, which can increase workload of heart. Thus a beta blocking drug often administered in conjuction with dihydropyridines to prevent reflex tachycardia.

108
Q

H1 Blockers General Characteristics

A

Specific reversible competitive antagonism of H1 receptors located in periphery and CNS. An inverse agonist because reduces constitutive activity of the receptor and compete with histamine.

MOA: Inhibit capillary permeability, suppresses the immediate hypersensitivity reactions seen in anaphylaxis and allergy. NO effect on BP or bronchoconstriction.

Clinical uses (see each drug to see specific uses): Allergies, motion sickness, sleeping, vestibular disturbances

Pharmacokinetics: Well-absorbed following oral administration, also there are nasal and ophthalmic formulations available. It is distributed widely throughout the body (see: difference between 1st and 2nd gen – 1st gen enters CNS much more than 2nd)

Toxicity/Major side effects:
SEDATION (much more common in first gen) by inhibition of BOTH CHOLINERGIC AND HISTAMINERGIC pathways in CNS.
GI side effects: Loss of appetite, nausea/vomiting, other GI distress. In some rare cases, drugs associated with increased appetite and weight gain.
Anti-muscarinic side effects seen only in 1st gen: dry mouth, dryness of respiratory passages

Toxicity: Cardiovascular effects of drugs; particularly with Terfenadine and Astemizole. Most notable effect in prolongation of QT interval and polymorphic ventricular contractions (torsade de pointes). This is more likely to occur with increased dosage, and in combination with other drugs that inhibit P450 drugs metabolism (macrolide, antibiotics, and antifungal drugs)

109
Q

FIRST GENERATION H1 Blockers

A

Can stimulate and depress CNS (CNS stimulation seen with overdose in children; whereas CNS depression is more commonly seen generally- sedation, slowed reaction times, decreased alertness).
Some 1st gen H1 blockers prevent motion sickness via CNS anti-cholinergic effect.

Peripheral and Central anticholinergic side effect- many 1st gens have atropine-like effects (inhibits respond to Ach via blockade of muscarinic receptors) - leading to dry mucus membranes, urinary retention, aka other anticholinergic syndrome symptoms. This is seen only in 1st gen.

Some 1st gens also lead to local anesthetic effect (block nerve conduction).

CNS effects in 1st gen H1 blocker leads to heavy SEDATION side effect by inhibition of BOTH CHOLINERGIC AND HISTAMINERGIC pathways in CNS.

110
Q

What are the H1 Blockers: Ethanolamines ?

A

Diphenydramine, Dimenhydrinate, Clemastine

111
Q

Diphenydramine

A

First generation H1 Blocker: Ethanolamines
AKA Benadryl- Used for allergy tx.
Profound sedation, thus can be used for sleeping (nonprescription).
Also used in early stage Parkinson’s disease.

H1 blocking activity: + to ++
Sedative Effects: +++
Anticholinergic effects: +++

112
Q

Dimenhydrinate

A

First generation H1 Blocker: Ethanolamines

AKA DRAMAMINE- Used for motion sickness and vestibular disturbances.

113
Q

What are the H1 Blockers: Alkyalmines ?

A

Chlorpheniramine*, Brompheniramine

114
Q

Chlorpheniramine

A

First generation H1 Blocker: Alkyalmines
Most potent, less prone to cause drowsiness but still significant number of patients are effects.
Used for allergy tx.

H1 blocking activity: ++
Sedative Effects: +
Anticholinergic Effects: ++

115
Q

What are the H1 Blockers: Phenothiazines ?

A

Promethazine*

116
Q

SECOND GENERATION H1 Blockers

A

AKA NONSEDATING
Little to no anticholinergic side-effects; do not easily cross the blood brain barrier to CNS, and thus have much less CNS effects as 1st generation H1 blockers (SEDATION IS NOT a side effect in 2nd gen drugs, except CETIRIZINE).

Second generation drugs are metabolized extensively in the liver by P450 enzymes (CYP3A4/CYP2D6), and some have active metabolites.

117
Q

What are the H2 Blockers: Piperidines ?

A

Fexofenadine, Loratadine, Desloratadine*

118
Q

Fexofenadine

A

Second generation H1 Blocker: Piperidines
AKA Allegra - used for allergies.

H1 blocking activity: +++
Sedative Effects: +/-
Anticholinergic effects: +/-

Terfenadine is metabolized to foexofenadine.

119
Q

Loratadine

A

Second generation H1 Blocker: Piperidines
AKA Claritin - used for allergies.

H1 blocking activity: ++ to +++
Sedative Effects: +/-
Anticholinergic effects: +/-

Metabolized to descarboethoxyloratadine (aka desloratadine) BY CYP3A4 and 2D6. Despite the fact that certain drugs inhibit these enzymes, no cardiac toxicity has been associated with this drug.

120
Q

Desloratadine

A

Second generation H1 Blocker: Piperidines
AKA Clarinex - used for allergies.

Loratadine metabolizes to this via descarboethoxyloratadine.

121
Q

H2 Blockers General Characteristics

A

Function: relief of symptoms of gastric upset/peptic ulcer disease

Physiology: Histamine released from mast cells and ECL, stimulated by vagus nerve and gastrin. Once released, histamine acts on H2 receptors of the parietal cells to cause increase in adenylate cyclase, activation of cAMP, and protein kinases that ultimately result in increased gastric acid (lowers pH). Ach and gastrin also directly increase gastric acid secretion.

Pharmacology: competitive inhibitors of histamine at H2 receptors located on the basolateral membrane of the parietal cells. Inhibits gastric acid secretion, and reduces the volume of gastric acid/H+ concentration.

Pharmacokinetics: rapidly absorbed following oral administration, small amounts of drug undergoes liver metabolism, and parent drug + metabolites are excreted by kidneys

Side effects: low incidence of side effects, usually minor and include: diarrhea, headache, and drowsiness. Less common include CNS effects like confusion, delirium, slurred speech (occurs primarily with IV use or in elderly patients).
All agents that inhibit gastric acid secretion may alter the rate of absorption and subsequent bioavailability of certain drugs.

Therapeutic uses: treat uncomplicated GERD- major use.
Also promote healing of gastric and duodenal ulcers; prevents stress ulcer occurrence (these occur in profound illness or trauma, or IV administration of H2 antagonists).

ALL H2 blockers bock the stimulatory effect of histamine on acid secretion from parietal cells. But POTENCY DIFFERS.

122
Q

What are the H2 blockers?

A

Cimetidine, Ranitidine, Famotidine, Nizatidine

123
Q

Cimetidine

A 
H2 Blocker (see H2 Block General Characteristics Card)
AKA Tagamet- low potency.

Historically, cimetidine was used for ZOLLINGER-ELLISON syndrome (non-beta cell tumor of the pancreas; over production of gastrin preferred tx today is Proton Pump Inhibitor)

Side effects (highest side effects compared to other H2 blockers): inhibits cytochrome P450 enzymes, and long term use of this at high doses (seldom used clinic today): decreases testosterone binding and inhibits a CYP enzyme that hydroxylates estradiol. Men: gynecomastia, reduced sperm count, and impotence

124
Q

Ranitidine

A 
H2 Blocker  (see H2 Block General Characteristics Card)
AKA Zantac- medium potency.
125
Q

Famotidine

A 
H2 Blocker  (see H2 Block General Characteristics Card)
AKA Pepcid - HIGHEST potency.
126
Q

What are the H1 Blockers: Piperazines ?

A

Cetirizine*

127
Q

Cetirizine

A

Second generation H1 Blocker: Piperazines
AKA Zyrtec- used for allergies.
Higher incidence of sedation compared to other 2nd generation drugs.

Active metabolite of hydroxyzine

128
Q

Cromolyn

A

Function: Inhibit the release of histamine; inhaled anti-inflammatory agent.

MOA: Stabilizes most mast cell membranes and prevents release of histamine

Inhalation route of administration

Safe drug/ few side effects

Therapeutic uses:

  • preventive management of asthma
  • allergic rhinitis, conjunctivitis
  • food allergies?
129
Q

Omalizumab

A

Function: Inhibits the release of histamine; monoclonal antibody

Decreases the amount of antigen specific IgE that normally binds to and sensitizes mast cells

Subcutaneous administration

Major adverse effects include life threatening anaphylaxis and also bleeding related effects

Tx for allergic asthma

130
Q

Cardinal signs of acute inflammation

A
  • rubor (red discoloration)
  • calor (heat)
  • dolor (pain)
  • tumor (mass effect/swelling)
  • loss of function
131
Q

Histamine

A
  • biogenic amine
  • cell source: mast cells, basophils
  • physio response: vasodilation, increased vascular permeability, pain
  • mech: activation of GPCRs
  • antihistamines (H1 antagonists) used to block histamine
132
Q

Bradykinin

A
  • peptide
  • cell source: endothelial cells
  • physio response: vasodilation, increased microvessel permeability, pain
  • mech: activation of GPCRs
133
Q

Complement system

A
  • plasma proteins
  • cell source: synthesized by liver, circulate in blood
  • physio response: chemotaxis (recruit inflam cells to site of injury); promote release of mediators from neutrophil; increase vascular permeability; excessive activation may contribute to tissue injury
  • mech: complement protein complexes cause osmotic lysis activation of GPCRs
134
Q

C reactive protein

A

-plasma protein
-cell source: produced in liver in response to cytokines, also produced in adipocytes
-physio response: “acute phase reactant”; activates complement cascade; mediates phagocytosis; marker of inflammation
-mech: bind to phosphatidylcholine containing substance (cell wall?) in bacteria and damaged cells
-pharm: elevated CRP may be associated with increased risk of diabetes, HTN, CV disease. Drugs like statins may be effective in these patients.
-
-

135
Q

Cytokines

A
  • secreted proteins; pro inflammatory: IL 1 (alpha and beta), TNF alpha
  • cell source: all inflammatory cells
  • physio response: TNF alpha–>acute phase reaction, fever, sepsis; IL-1–>acute phase reaction, fibroblast, lymphocyte proliferation, fever
  • mech: bind to specific receptor proteins to induce gene expression of number of proteins via activation of NFkB and AP-1. Thus, increase: cyclooxygenase (fever), lypoxygenases, adhesion molecule expression, induce collagenase (fibrosis)
  • pharm: Etanercept and Infliximab target cytokines
136
Q

Adenosine

A
  • purine nucleoside formed from breakdown of ATP
  • ANTI inflammatory molecule
  • cell source: all cells
  • physio response: increased extracellularly during injury (anti inflammatory); inhibit cytokine action
  • mech: activation of GPCRs
  • pharm: adenosine A2 agonists (anti inflam receptor); methotrexate (used tx rheumatoid arthritis); folic acid antagonist
137
Q

Cell adhesion molecules

A
  • cell source: endothelial cells, platelets, leukocytes
  • physio response: leukocyte adhesion to endothelium is a pivotal event in host defense and tissue repair; endothelial adhesion molecules contribute to recruitment of activated platelets
  • mech: contact molecules (mediate contact between 2 cells or cell and ecm); calcium dependent
138
Q

Oxygen derived free radicals

A
  • superoxide, hydroxy radicals
  • cell source: all cells
  • physio response: intracellular killing of bacteria by neutrophils
  • mech: protein oxidation (inactivates enzyme, alters 3D structure, increases degredation); lipid peroxidation (damage to phospholipids leading to membrane degredation); dna mutations
  • pharm: anti oxidants like Vitamin C and E
139
Q

Lipid mediators: Prostaglandins

A
  • cell source: all cells
  • physio response: vasodilation/vasoconstriction; pain; fever; platelet aggregation (via thromboxane)
  • mech: activation of specific GPCRs
  • pharm: NSAIDs
140
Q

Lipid mediators: Leukotrienes

A
  • cell source: macrophages, neutrophils
  • physio response: increase vascular permeability; bronchoconstriction
  • mech: activation of GPCRs
  • pharm: 5-lipoxygenase inhibitors (Zileuton); cys-leukotriene receptor antagonists (Zafirlukast)
141
Q

Glucocorticoids

A
  • cell source: adrenal cortex
  • physio response: inhibition of cytokines; inhibition of phospholipase A2 (via annexin/lipocortin); inhibition of COX2; inhibition of cell adhesion molecules
  • mech: activation of nuclear receptors
  • pharm: steroids (most potent and effective agents for controlling chronic inflammatory diseases)
142
Q

Anti inflammatory drugs

A
  • steroids (glucocorticoids)
  • NSAIDs–>aspirin (inhibits COX)
  • leukotriene antagonists–> zafirlukast (competitive antagonist); zileuton (inhib syn of leukotrienes)
  • inflammatory cytokine inhibitors–>etanercept; infliximab
  • immuno modulatory drugs
143
Q

Arachidonic acid

A
  • free level very low; esterified to membrane phospholipids

- A2 (calcium dependent) releases arachadonic acid

144
Q

Cyclooxygenases: COX1, COX2

A
  • both: oxygenate and cyclizes precursor fa to corm cyclic endoperoxide PGG2 (arachidonic acid–>PGG2); peroxidase activity PGG2–>PGH2
  • COX1 vs COX2: heme proteins; membrane bound; COX2 has larger active site; encoded on different chromosomes; COX1 is constitutive (does housekeeping, in all tissues), COX2 is inducible (turned on during inflammation)

-both increase during pregnancy

145
Q

Fate of PGH2

A

Turned into variety of products: PGI2, TXA2, PGE2, PGF2

146
Q

Cyclooxygenase inhibition

A

Aspirin/ other related NSAIDs inhibit COX1 and COX2

Glucocorticoids decrease expression of ONLY COX2

147
Q

Zileuton

A
  • inhibitor or 5-lipoxygenase
  • oral; half life 2.5 hours; metabolized by CYP enzymes
  • mech: inhibits cys-LTs(bronchoconstriction and increase vascular permeability and LTB4 chemotaxis)
  • SE: few; increase liver enzymes
  • Tx: for prophylactic tx of mild asthma
148
Q

Zafirlukast

A
  • cysteinyl leukotriene receptor antagonist
  • oral; half life 10 hrs
  • metabolized by CYP2C9/3A4
  • mech: inhibit cys-LTs
  • SE: minimal
  • Tx: prophylactic tx of mild asthma
149
Q

Eicosanoid receptor and 2nd messengers

A

See figure 4 in handout, eicosanoid lect

Receptors—>second messenger
TP, FP, EP1, EP3 —>calcium mobilization
EP2, EP4, IP, DP1 —> cAMP

150
Q

Eicosanoids causing pain

A
  • periphery: PGE2, PGI2 sensitize afferent nerve endings to effects of chemical/mechanical stimuli by lowering threshold of nociceptors; potentiate pain producing activity of bradykinin and other autocoids
  • cns: PGs lower threshold for pain stimuli; COX2 in dorsal horn, expression increased during inflammation

**alone PGs cause pain only in very high conc; upon injury they decrease threshold for pain so lower conc of other mediators activates pain fibers

151
Q

Eicosanoids causing fever

A

-PGE2: generate neuronal signals activating thermoregulatory center in hypothalamus

152
Q

TXA2

A

Promotes platelet aggregation (increases intracell calcium)

  • potent vasoconstrictor
  • constric bronchial smooth musc
153
Q

PGI2

A
  • *Increases cAMP
  • Inhibits platelet aggregation
  • quiescent state of uterine activity during early pregnancy;relaxation of uterine tone
  • IV admin=profound hypotension
  • vasodilator
  • relax bronchial smooth muscle
  • increase RBF due to vasodilation, promote diuresis, natriuresis
  • (IP receptor) inhibit gastric acid secretion, increase gastric mucosal blood flow
154
Q

PGE2

A

-initiation and progression of labor–induces uterine contractility, mediates ripening of cervix

  • reduces systemic BP
  • vasodilator
  • major PG that affects tone of ductus arteriosus (EP4 receptor)
  • relax bronchial smooth musc
  • increase RBF due to vasodilation, promote diuresis natriuresis
  • (EP3 receptor) inhibits gastri acid secretion, increase gastric mucosal blood flow, stimulates release of viscous mucus, stimulates bicarbonate secretion, (EP1) contracts GI smooth muscle
155
Q

PGF2

A
  • mediate uterine contractility during labor
  • concentrations increase in menstrual fluid and cause vasoconstriciton, uterine contraction, pain (primary dysmenorrhea)
  • vasoconstrictor
  • constrict bronchial smooth muscle (**leukotrienes are main constrictor)
156
Q

Dinoprostone

A
  • synthetic analog of PGE2
  • use: 1: cervical ripening in pregnancy
    • cervical gel
    • mech: promotes cervical ripening via activation of collagenase, relaxes smooth muscle (EP4 receptor)
  • use: 2: terminate early pregnancy/abortion (at much higher conc)
    • vaginal suppository
    • mech: uterine contractions via EP1/3 receptors
    • SE: GI related nausea vomiting diarrhea, fever, uterine rupture (contraindication: women with hx of C section/other uterine surgery)
157
Q

Carboprost Tromethamine

A
  • PGF2 analog
  • use 1: termination of pregnancy during 2nd trimester (wks 13-20 gestation)
    • mech: stimulate uterine contractility by action at FP receptors
  • use 2: control post partum hemorrhage that is not responding to conventional methods
    • mech: causes myometrial contractions via FP receptors; providing hemostasis at site of placenta formation
    • SE: GI related, fever, uterine rupture (contraindication: c section or other uterine surgery hx), rare cases of bronchoconstriction
158
Q

Misoprostol

A
  • PGE1 analog
  • use: replacement therapy for prevention of ulcers caused by long term admin of NSAIDs
  • oral 4x/day
  • mech: supress gastric acid secretion by stim EP3 receptors on parietal cells, causes decrease in cAMP, increase mucin and bicarnonate seretion, increase mucosal blood flow
  • SE: diarrhea common, contraindicated in pregnancy

**use with methotrexate or mifepristone for termination of early pregnancy

159
Q

Alprostadil

A
  • PGE1
  • use 1: impotence/erectile dysfuction
    • intracavernous injection
    • mech: increase cAMP relaxes smooth muscle of corpus cavernosum
    • SE: pain at injection site, prolonged erection
  • use 2: maintenance of patent ductus arteriosus
    • IV
    • mech: cAMP mediated relaxation of ductus arteriosus smooth muscle
    • SE: apnea in about 10% neonates
160
Q

Epoprostenol

A
  • PGI2
  • use: primary pulmonary hypertension
  • IV
  • mech: cAMP mediated dilation of pulmonary artery vascular smooth muscle
  • SE: nausea, vomiting, headache, flushing
161
Q

Bimatoprost

A
  • synthetic molecule similar to prostamide F2
  • use 1: glaucoma
    • ophthalmic solution
    • mech: increases outflow of aqueous humor
    • SE: eye redness, itching, may cuase permanent changes in eye color/eyelid skin (increased brown pigment); may increase length and number of eyelashes
  • use 2: eyelash hypotrichosis
    • ophthalmic solution
    • mech: increase percent and duration of hairs in growth phase
    • SE: excess, unwanted hair growth, brown iris pigmentation, eye redness, itching
162
Q

General properties of NSAIDs

A
  • anti inflammatory
  • anti pyretic
  • analgesic
163
Q

Acetylsalicylic acid (aspirin)

A
  • *only IRREV inhibitor of COX1 and 2
  • crosses BBB and placenta
  • enters active channel of COX, adds acetyl group to serine in active site
  • hydrolized to salicylic acid then other less polar metabolites; renal elim
  • LOW DOSE–>competes w/uric acid secretion by OAT into renal tubules (INCR serum uric acid)
  • HIGH DOSE–>competes w/uric acid for both secretion and reabsorption(DECR serum uric acid)
  • CNS: (high dose) crosses bbb–>delirium, psychoses, nausea/vomiting=salicylate toxicity
  • reye’s syn: in kids, post viral infection, causes encephalophathy and liver failure
164
Q

Toxcity/Contraindications of NSAIDs

A
  • GI irritation: inhib of COX1 prevents prod of cytoprotective prostaglandins (PGE2, PGI2)
  • increased bleeding time: inhib of COX1 in platelet blocks production of TXA2 which stimulates platelet aggregation
  • hypersensitivity: bronchoconstriction, edema (action of leukotrienes, shunting of AA pathway from COX to lipoxygenase)
  • decreased RBF, GFR, salt/H2O retention
  • pregnancy: decreased uterine contractions, prolonged labor (inhib of COX prevents PG production)
165
Q

Ibuprofen

A
  • reversible inhib COX1, COX2
  • plasma half life 2 hours
  • Toxicity: GI effects (less than aspirin); hypersensitivty; decreased RBF, GFR, salt/water retention; increased bleeding time; drug interactions
  • USE: inflammatory disease and rheumatoid disorders; mild to mod pain; fever; dysmenorrhea; osteoarthritis
    • LYSINE INJECTION: induce closure of patent ductus arteriosus
166
Q

Naproxen

A
  • reversible inhib of COX1, COX2
  • plasma half life 14 hours
  • TOXICITY: GI effects (less than aspirin); hypersensitivity; decreased RBF, GFR, have salt/h20 retention; increased bleeding time; drug interactions
  • USE: (similar to ibuprofen) mgmt of ankylosing spondylitis; osteoarthritis; rhuematoid disorders; acute gout; mild to mod pain; tendonitis; bursitis; dysmenorrhea; fever
167
Q

Indomethacin

A

-reversible inhib COX1, COX2
-plasma half life 3 hours
-TOXICITY: **frequent adverse rxns; GI toxicity; CNS-severe frontal headache
-USE: acute gouty arthritis; acute bursitis/tendonitis; mod to severe osteoarthritis; rheumatoid arthritis; ankylosing spondylitis
-IV–>closure of patent ductus arteriosis
NOT For pain/fever

168
Q

Keterolac

A

-reversible inhib of COX1, COX2
-oral and intramusc
-highly plasma protein bound
-SE: same as other NSAIDS
-USE: short term mgmt mod to severe acute pain
LESS anti inflammatory activity

169
Q

Nabumetone

A
  • reversible inhibitor of COX2> COX1
  • prodrug; long half life
  • SE: well tolerated; less GI effects; more like COX2 inhibitor
  • USE: osteoarthritis, rheumatoid arthritis
170
Q

Piroxicam

A
  • reversible inhib of COX1, COX2
  • plasma half life 50hrs
  • SE: GI toxicity
  • USE: symptomatic tx of acute and chronic rheumatoid arthritis and osteoarthritis
  • *advantage in tx of osteoarthritis due to long half life
171
Q

Sulfasalazine

A
  • NO effect at COX; inhib production of IL1, TNFalpha, lipoxygenase pathway, NFkB
  • absorbed in upper GI
  • individual components of drug not liberated for absorption until colonic bacteria cleave bond
  • SE: (10-45% patients have side effects due to sulfa); headache, nausea; fatigue; allergic rxns; decreased motility of sperm; inhibits folate absorption
  • USE: local effect in GI to inhib inflammatory response; mild to mod active ulcerative colitis; rheumatoid arthritis; ankylosing spondylitis
172
Q

Celecoxib

A
  • selective COX2 inhibitor
  • contains sulfonamide side chain
  • MECH: binds tight to hydrophilic side pocket region, close proximity to active COX2 binding site
  • metabolized via CYP2C9
  • SE: hypersensitivity; increased risk GI irritation; increased risk adverse cv events (MI, stroke)
  • CONTRAINDICATIONS: patients w/sulfonamide toxicity; prior NSAID hypersensitivity; hx GI disease; do not use in patients post coronary artery bypass graft surgery; deficiency CYP2C9
  • USE: signs/sx’s rheumatoid arthritis and osteoarthritis; primary dysmenorrhea; mgmt acute pain; reduce number intestinal polyps in familial adenomatous polyposis
173
Q

Acetaminophen

A
  • don’t know mechanism
  • oral
  • absorbed from GI
  • plasma life 2 hrs
  • major metabolism via phase II, minor via CYPs (give rise to toxicity if glutathione store is depleted)
  • SE: no GI effects; well tolerated at normal doses; hepatic toxicity at high dose (nausea, vomiting, abdominal pain), alcohol use induces the cyp involved in production of toxic metabolite (NAPQI)
  • USE: mild to moderate pain and fever
174
Q

Synthesis of Serotonin

A

Tryptophan –(Tryptophan Hydroxylase) 5-hydroxytryptophan –(L-aromatic amino acid decarboxylase) Serotonin (5HT) –(Monoamine-N-acetyltryptamine) Melatonin (pineal gland)

  • Rate limiting step: tryptophan hydroxylase (but not in the CNS, because of low tryptophan levels); requires molecular oxygen and a reduced pteridine cofactor
  • Serotonin is synthesized in most all tissues except blood platelets
175
Q

Metabolism/Termination of Serotonin

A
  • Converted to 5-hydroxyindole acetic acid by monoamine oxidase and aldehyde dehydrogenase
  • May be reduced to an alcohol
  • Neuronal action terminated by high affinity active reuptake mechanism (SERT) and then converted to 5-hydroxyindole acetic acid
176
Q

Serotonin Effects on GI System

A
  • Enterochromaffin cells – largest stores in body (90%)
  • Contraction of GI smooth muscle (esophagus, stomach, intestine) increasing tone, peristalsis, and diarrhea
  • Emesis can be induced by 5-HT3 receptors in the brain and GI tract
  • Carcinoid Syndrome – serotonin secreting tumors (also secrete bradykinin). Cause severe diarrhea and asthma. Can be treated with serotonin antagonists or octreotide (somatostatin analog that blocks mediator secretion from tumor)
177
Q

Serotonin Effects on CV System

A
  • Vasoconstriction OR vasodilation – depends on mode of administration, dose, location of vascular bed, and the resting tone of the vascular bed
  • Potent vasoconstriction in large arteries and veins in most vascular beds (especially pulmonary and renal vessels); also cranial blood vessels
  • Vasoconstriction can be direct via 5-HT2 receptors on smooth muscle, and 5-HT1D in brain; or indirectly by amplification of alpha-mediated effects of catecholamines, or by displacement of NE from adrenergic nerves
  • Vasodilation in coronary arteries, arterioles, skeletal muscle, cutaneous blood vessels
  • Bezold-Jarisch reflex: Serotonin activates chemoreceptors in coronary vasculature which activates afferent vagal nerve endings (bradycardia, hypotension, hypoventilation)
  • Platelet aggregation
178
Q

Serotonin Effects on the CNS

A
  • Sensory perception (LSD)
  • Sleep – slow wave/deep sleep
  • Temperature regulation
  • Neuroendocrine regulation
  • Learning and memory (esp short term!)
  • Pain perception – spinal and brain sites
  • Drug abuse
  • Emesis – 5HT3 receptors
  • Mental illness: affective disorders, schizophrenia, OCD, anxiety disorders (5HT1A receptors)
179
Q

Lysergic acid diethylamide

A
  • LSD, a potent hallucinogen (1microgram/kilogram)

- Full/partial agonist at 5-HT2 receptors

180
Q

Buspirone

A
  • Partial agonist at 5-HT1A receptors

- Used as an antianxiety agent

181
Q

Sumatriptan

A
  • Agonist at 5-HT1D and 1B receptors
  • Inhibits release of vasoactive peptides – Calcitonin gene related peptide CGRP
  • Tx of migraines; stop existing headache
  • Side effects: nausea, vomiting, angina, dizziness, flushing
182
Q

Lorcaserin

A
  • Tx of obesity
  • Selective 5-HT2C receptor agonist; in the hypothalamus this is supposed to activate proopiomelanocortin (POMC) production, and consequently promote weight loss through satiety
183
Q

Fluoxetine

A
  • Serotonin specific reuptake inhibitor: blocks the active reuptake of serotonin into neurons; increases the amount of serotonin at synapse
  • Tx of major depressive disorder, OCD, panic attacks
184
Q

Phenelzine

A
  • Monoamine oxidase inhibitor: blocks metabolism of serotonin, NE, and DA
  • Tx of depression and narcolepsy
  • Side effects: food induced HTN crisis
185
Q

Duloxetine

A
  • Serotonin-norepinephrne reuptake inhibitor: blocks active reuptake of both serotonin and NE into neurons
  • Tx for major depressive disorder and neuropathic pain
186
Q

Cyproheptadine

A
  • 5-HT2 receptor antagonist; histamine H1 antagonist

- Tx of skin allergies, particularly pruritus and urticarial; also used in tx of carcinoid

187
Q

Ondansetron

A
  • 5-HT3 receptor antagonist
  • Very effective in tx of chemotherapy-induced nausea and vomiting, post-op and xray therapy induced nausea and vomiting
  • Acts both as GI and brain receptors
  • IV, oral, transdermal forms
188
Q

Alosetron

A
  • Selective 5-HT3 antagonist
  • Tx of women with diarrhea-predominant IBS who have failed to respond to conventional therapy
  • can produce severe GI adverse effects
  • a restricted prescribing program must be followed
189
Q

Heparin Mechanism of Action

A

There are no intrinsic anticoagulant properties.

Heparin binds to the pentasaccharide-binding site on AT (antithrombin) –> conformational chang making reactive site MORE accessible to the protease/coagulation factors. Thus heparin catalyzes the inhibition of several coagulation factors (proteases) by antithrombin (a glycosylated, single chain polypeptide synthesized in the liver).

AT inhibits activated coagulation factors (including thrombin, Xa, IX a) it is the ‘suicide substrate’ for these proteases. Protease attacks a specific Arg-Ser peptide bond in the reactive site of antithrombin and becomes trapped as a stable 1:1 complex. Binding site on heparin is a specific pentasaccharide sequence containing 3-O- sulfated glucosamine residue.

Heparin increases rate of thrombin-AT reaction at least 1000 fold by serving as a catalytic template to which both the inhibitor (AT) and protease (coagulation factor) bind.

**Heparin does NOT affect the synthesis of clotting factors.

190
Q

Heparin Adverse Reactions

A

Bleeding - obvious MAJOR adverse rxn. Major bleeding occurs in 1-5% treated for venous thromboembolism.

Heparin-induce thrombocytopenia (platelet count

191
Q

Heparin (UFH)

A

(Unfractionated, UFH), mW = 15kDA, ~40 monosaccharide units. Heterogeneous mixture of sulfated polysaccharides, highly NEGATIVE because so many sulfate and carboxylic acid residues.

Commercial source: porcine intestine

USP unit = quantity of heparin that prevents 1 mL of citrated sheep plasma from clotting 1 hour after addition of .2 mL of 1% CaCl2

Therapeutic/Clinical Inidcations:
Initial treatment of DVT or PE (oral anticoagulant usually started concurrently).

Initial management of unstable angina or acute MI, during and after coronary angioplasty or stent placement, or during surgery requiring cardiopulmonary bypass.

Low dose heparin used prophylactically to prevent DVT and thromboembolism.

Other uses: hemodialysis, in blood samples drawn for lab analysis and to maintain patency of indwelling arterial catheters

Drug choice for anticoagulation during pregnancy.

Absorption/Metabolism:
NOT absorbed in GI tract due to size/polarity.

Admin via IV (immediate onset of action) or subcutaneous (variable onset).

Half life dependent on dose administered.

Cleared by the REITCULOENDOTHELIAL SYSTEM and liver

Administration/Monitoring:
Venous thromboembolism - bolus injection followed by continuous IV infusion, usually aPTT 1.8-2.5 x normal is assumed to be adequate therapeutic response/decreased risk of recurrence if within 24 hours

How do you monitor action of heparin?
-activated PTT (partial thromboplastin time, aPTT): clot based test in which phospholipid reagent, an activator substance, and calcium are added to the patient’s plasm, and the time for a fibrin clot to form is measured. Clotting time of 1.5 to 2.5 x the normal mean aPTT (usually 50-80 sec) is THERAPEUTIC.
Cardiopulmonary bypass - very high dose/aPTT prolonged indefinitely

Prophylactic use of heparin to prevent venous thrombosis - subq admin, low dose, no effect on aPTT

Contraindication: Active bleeding, recents urgery (intracranial, spinal cord, eye), and severe uncontrolled hypertension.

192
Q

Low molecular weight heparins (LMWH)

A

Physical properties: 1000-10000 daltons, ~15 monosaccharide units.

Drug names: Enoxaparin (Lovenex), and Dalteparin (Fragmin)

Treatment of acute DVT, prophylaxis of DVT, acute unstable angina and MI, and hip replacement surgery (during and following hospitalization)

MOA: LMWH have a greater capacity to potentiate factor Xa inhibition by antithrombin than thrombin inhibition because at least half of the LMWH chains are TOO SHORT to bridge antithrombin and thrombin

Absorption: LMWH not absorbed through GI mucosa and must be given parenterally. They are absorbed MORE UNIFORMLY than heparin after subq injection.

Metabolism: Longer biological half life than heparin, up to 4-6 hours.

LMWHs cleared almost exclusively by the kidneys and can accumulate in patients with renal impairment, can lead to bleeding.

Adverse Effect: incidence of bleeding is somewhat less in patients treated with LMWH, and also lower incidence of thrombocytopenia (compared to heparin). Still occurs though and platelets should be monitored.

Contraindication: Active bleeding, recent surgery (intracranial, spinal cord, eye), renal impairment

193
Q

Enoxaparin (Lovenex)

A

Low molecular weight heparin (see notecard).

Treatment of acute DVT, prophylaxis of DVT, acute unstable angina and MI, and hip replacement surgery (during and following hospitalization)

194
Q

Dalteparin (Fragmin)

A

Low molecular weight heparin (see notecard).

Treatment of acute DVT, prophylaxis of DVT, acute unstable angina and MI, and hip replacement surgery (during and following hospitalization)

195
Q

DIRECT THROMBIN INHIBITORS - INJECTED ANTICOAGULANTS

A

Lepirudin (Refludan) and Bivalirudin (Angiomax)

Advantage of Direct Thrombin inhibitors OVER UFH/LMWH: Activation of circulating AND fibrin-bound thrombin

196
Q

Lepirudin (Refludan)

A

Direct thrombin inhibitors - anticoagulant.

Physical prop: 65 amino acid polypeptide

Indication: Used as an alternative to heparin in patients undergoing coronary angioplasty or cardiopulmonary bypass surgery.

MOA: Binds tightly to both the catalytic site and the extended substrate recognition site (exosite I) of thrombin.

Administered intravenously and excreted by kidneys.

Half life: 1.3 hours

Adverse effects: bleeding, use cautiously in patients with renal failure because drugs can accumulate and cause more bleeding in patients.

Contraindication: Active bleeding, recent surgery (intracranial, spinal cord, eye), severe uncontrolled HTN, and renal disease

197
Q

Bivalirudin (Angiomx)

A

Direct thrombin inhibitors - anticoagulant.

Physical prop: Synthetic, 20 amino acid polypeptide (contains Phe-Pro-Arg-Pro)

Used as an alternative to heparin in patients undergoing coronary angioplasty or cardiopulmonary bypass surgery.

MOA: “Phe-Pro-Arg-Pro” sequence occupies the catalytic site of thrombin, followed by a tetraglycine linker and a hirudin-like sequence that binds to exosite I. Thrombin slowly cleaves the Arg-Pro peptide bond and thus regains activity. (thus short half life)

Administered intravenously and excreted by kidneys.

Half life: 25 minutes, MUCH SHORTER THAN LEPIRUDIN

Adverse effects: bleeding, use cautiously in patients with renal failure because drugs can accumulate and cause more bleeding in patients.

Contraindication: Active bleeding, recent surgery (intracranial, spinal cord, eye), severe uncontrolled HTN, and renal disease

198
Q

Fondaparinux (Arixtra)

A

Selective factor Xa inhibitor/ anticoagulant.

Indication: FDA approved prophylaxis of DVT in patients undergoing surgery for hip replacement, knee replacement, hip fracture, or abdominal surgery. Treatment for acute PE and DVT.

Off-label use: prophylaxis of DVT in patients with history of HEPARIN INDUCED thrombocytopennia (HIT). Tx of acute thrombosis, and acute symptomatic superficial vein thrombosis.

Fondaparinux is a synthetic pentasaccharide that causes an antithrombin-mediated SELECTIVE INHIBITION of factor Xa.

Subq injection, reaches peak plasma levels in 2 hours.

Excreted in urine; half life = 17 hours.

Adverse effects: Bleeding, and hemorrhage can occur at any site. Risk increases by a number of factors (including renal dysfunction, age, and weight).

MUCH LESS likely to induce thrombocytopenia (compared to heparin and LMWH)

Contraindications: SHOULD NOT be used in patients with renal failure.
Active bleeding, recent surgery (intracranial, spinal cord, eye), severe uncontrolled HTN, and renal disease

199
Q

Protamine Sulfate

A

Heparin antagonist; low mW, POSITIVE charged, derived from FISH SPERM. High affinity for negative molecules, and thus binds 1:1 to heparin == inactivated complex.

Used to REVERSE heparin following cardiopulmonary bypass.

Weak anti-coagulant properties in high doses and if used alone.

Adverse effects: many cause anaphylactic reactions with bradycardia, cutaneous vasodilation, and hypotension. Observed in persons with fish hypersensitivity, previous protamine exposure in insulin products. Rate of infusion can potentiate these adverse effects.

Also, pulmonary hypertension.

200
Q

Warfarin (Coumadin)

A

Orally administered anticoagulant; Fat soluble derivative of 4-hydroxycoumarin, structural ANALOG OF VITAMIN K.

Long term tx of venous thromboembolitic disease. Prophylaxis against thromboembolism in atrial fibrillation, or in patient with prosthetic heart valves, or in patients with dilate cardiomyopathy.

Metabolism:Rapidly and completely absorbed after oral administration. Extensively bound to plasma albumin (>99%). Converted to inactive metabolites by the liver (cytochrome P450-mediated)

How to monitor:
Prothrombin time: Add thromboplastin (saline extract of brain containing tissue factors and phospholipids). Clots in 12 to 14 seconds. Because of variability in thromboplastin, use INR (international normalized ratio of patient PT to a control PT that would have been obtained by a standard method).

Therapeutic effect; DELAYED FOR SEVERAL HOURS TO DAYS bc circulating clotting factors are NOT affected. Results in altered balance between the partially inhibited rates of modification and UNALTERED rates of DEGRADATION OF FACTORS II, VII, IX, AND X

Kinetics of pharmacologic effect: dependent on the half-lives of existing clotting factors (range= 2-3 days for prothombrin to 5 hours for factor VII)

201
Q

Warfarin Mechanism of Action

A

S Warfarin acts as a VITAMIN K ANTAGONIST, BY inhibiting Vitamin K reductase step.

Background:
Vitamin K is required to catalyze the conversion of inactive precursors of the clotting factors II, VII, IX, and X into active forms. Activation requires 9-12 amino terminal glutamic acid residue CARBOXYLATIONs (creates Ca binding site for coagulation process). This gamma-carboxylation is L INKED to enzyme reactions of Vitamin K metabolism.

Vitamin K supplied to liver from dietary sources or as a metabolite of intestinal flora. 
Reduced Vitamin K (KH2) - required for enzymatic conversion of factor precurors to their carboxylic acid derivatives. 
 Oxidized form (KO) - coupled to CARBOXYLATION (ACTIVATION) OF glutamate residues in the precursor clotting factors.

So WARFARIN interferes with post-translational modification of vitamin K depednent clotting factors (II, VII, IX, and X). Inhibits the vitamin K epoxide reductase (VKORC1); this traps vitamin K in oxidized (KO) form. Reduced vitamin K is not formed….and you NEED reduced vitamin K (KH2) for the sustained synthesis of biologically active clotting factors.

In a racemic mixture of S and R enantiomers, it is S warfarin that is the most active (metabolized by CYP2C9).

How do you reverse this? Well, this is basically COMPETITIVE INHIBITION - so simple vitamin K administration results in displacement of warfarin and resumption of normal clotting. Can take days because new, active precursors of factors II, VII, IX, and X must be synthesized.
-immediate reversal will require EXOGENOUS ADMIN OF ACTIVE CLOTTING FACTORS (ie transfusion with whole blood or fresh frozen plasma)

-minor bleeding can be treated by just discontinuing the drug.
Overall, the reversal of anti-coagulant effects of warfarin IS NOT correlated to plasma warfarin concentrations, but rather with re-establishment of normal clotting factor activity.

202
Q

Warfarin Adverse Effects and Contraindications

A

Adverse effects: risk of bleeding increases with intensity and duration of warfarin therapy, the use of other medications that interfere with hemostasis, and the presence of potential anatomical source of bleeding.

WARFARIN METABOLISM is via CYP2C9– there are many polymorphisms for CYP2C9, so the the therapeutic window for warfarin is narrow and contributes to the increased risk of bleeding.
Genetic variations in VK receptor (subunit of Vitamin K1 epoxide reductase complex) may also contribute to warfarin’s variable effects.

Contraindications:
Warfarin can cross the placenta and is thus TERATOGENIC, contraindicated in pregnancy.

Actions may be prolonged in patients with liver or kidney disease or vitamin k deficiency.

Warfarin-induced SKIN NECROSIS is rare, but possible.

A reversible, sometimes painful, blue-tinged discoloration of the plantar surfaces and sides of toes that blanches with pressure and fades with elevation of legs (PURPLE TOE SYNDROME) may develop 3-8 weeks after initiation of therapy.

Drug interactions are common with warfarin and can lead to POOR CONTROL of anti-coagulation. Most serious drug intxns are those which INCREASE THE ANTI-COAGULANT effect of the drug and increase the risk of bleeding. Other drugs can decrease the action of warfarin.

203
Q

Warfarin Genetics

A

Genetics causes a hug difference in warfarin metabolism.

CYP2C9 and VKORC1 account for most of the genetic contribution to the variability in wafarin response:

CYP2C9 (*2, *3) AFFECTS PHARMACOKINETICS: decreased enzyme activity, leading to more drug in blood, and so you need to DECREASE warfarin dose.

VKORC1 AFFECTS PHARMACODYNAMICS: haplotypes A and B. most prevalent reason for dose variability (accounts for 30%).

These contribute to narrow TI, and adverse risk of bleeding (high).

204
Q

Novel ORAL ANTICOAGULANTS (NOACS)

A

DABIGATRAN and RIVAROXABAN

They are MORE EXPENSIVE than warfarin, BUT tend to be better for treatment. As seen in Warfarin card, warfarin has narrow TI, interacts with MANY DRUGS, has a slow onset of action, is teratogenic, and has many genetic considerations. Warfarin is only $50/year, whereas DABIGATRAN is ~$7 a day.

205
Q

Dabigatran etexilate (Pradaxa)

A

New oral anticoagulant.

Ideal patient not yet defined.

Used for post-op thromboprophylaxis in patients who have undergone total hip or knee procedures. Prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

MOA: Prodrug (dabigataran etexilate) lacking anticoagulant activity is CONVERTED IN VIVO to active DABIGATRAN = specific reversible DIRECT thrombin inhibitor that inhibits both free and fibrin-bound thrombin. It inhibits the coagulation by preventing thrombin-mediated effects, including the cleavage of fibrinogen to fibrin monomers, and the activation of factors V, VIII, XI AND XIII. It also prevents inhibition of thrombin-induced platelet aggregation.

The ability to INHIBIT FIBRIN-BOUND thrombin is important (advantageous over heparin) BECAUSE bound thrombin can continue to trigger thrombus expansion.

How to reverse? No antidote - you just have to discontinue it immediately, maintain adequate diuresis, and transfused fresh frozen plasma/RBCs if needed.

Orally available prodrug that is rapidly absorbed and converted by ESTERASES to its active form.

Plasma level peaks within 2 hours of administration.

Half life: 14-17 hours.

Eliminated mainly by kidneys, with more than 80% of drug excreted UNCHANGED in the urine.

How to monitor: Dabigatran has little effect on the prothrombin time, or the INR, even at therapeutic concentrations. So you cannot monitor using these methods.

Adverse effects: Dabigatran had comparable rates of serious bleeding to warfarin. Renal function should be assessed because risk of bleeding is high in patients with renal impairment.

Contraindications: DABIGATRAN ETEXILATE (prodrug) version is a substrate for P-glycoprotein (pgp) transporter in gut and kidney – should NOT be co-administered with inducers of Pgp (RIFAMPIN). That’s because inducers decrease the plasma concentration of DABIGATRAN. Drugs that inhibit PGP (keoconazole, amiodarone, verapamil) increase the concentrations of dapigatran.

Not metabolized by cytochrome P450, so it has few other drug interactions. EXCEPT: Rifampin (pgp inducer, thus it blocks the absorption of dabigatran), or QUINIDINE and/or AMIODARONE (pgp inhibitor, thus increasing blood levels of dabigatran)

206
Q

Rivaroxaban (xarelto)

A

New oral anticoagulant.

Reduces risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Also prophylaxis of DVT (which m ay lead to PE), in patients undergoing knee/hip replacement surgery.

MOA: Specific direct-acting factor Xa inhibitor. A small molecule of oxazolidinone derivative that binds directly and reversible to Factor Xa via the S1 and S4 pockets. Active site of factor Xa is divided into four sub pockets (S1-S4). S1 determines selectivity and binding. Factor Xa catalyzes conversion of prothrombin to thrombin.

Drug reaches peak plasma within 2-4 hours of oral administration. Oral bioavailability is >80%.

Half life: 5-9 hours in normal patients.

Has dual mode of elimination: 1/3 is eliminated UNCHANGED by kidneys. Remaining 2/3 metabolized by liver (CYP3A4 and CYP2J2) and metabolized fraction is excreted into urin and feces.
You need to decrease dose with decreased renal function.

Rivaroxaban is a substrate of effflux transporters (pgp)

Adverse effects: Bleeding, although LOWER THAN OTHER ANTICOAGS. Hepatotoxicity has NOT been noted.

207
Q

Tissue type plasminogen activator (t-PA)

A

Endogenous plasminogen activator synthesized by vascular endothelial cells and released at local sites of thrombosis.

MOA: t-PA binds to binding sites on fibrin that are in close proximity to plasminogen binding sites. t-PA binding activates fibrin-bound plasminogen to fibrin-bound plasmin, which initiates CLOT RESOLUTION.

In beginning of clot formation, little t-PA is released become plasminogen activator INHIBOTRS (PAI-1 and PAI-2) are released from platelets and endothelial cells, allowing for clot assembly. PAI production decreases and t-PA production increase – leading to breakdown of cloth and recanalization of the injured vessel.

208
Q

Complications of Thrombolytic therapy

A

Complications/Adverse Effects: Hemorrhage - an indiscriminant phenomenon. Lysis of fibrin at sites of vascular injury. Systemic lytic state resultings from systemic formation of plasmin (produces fibrinogenolysis, and destroys clotting factors, especially V and VII).

Minor bleeding in 3-4% of patients - related to puncture/injection sites. Major bleeding in 1%. Intracerebral hemorrhage occurs in 0.1-0.5%

Incidence of hemorrhagic complications may be higher when thrombolytic therapy is combined with aspirin and/or heparin. Proportional to the dose of thrombolytic agent used/duration.

209
Q

t-PA/ Alteplase (Activase)

A

Plasminogen activator that is acting as a thrombolytic agent. Identical to native tPA.

MOA: Serine protease with ONE pp chain (~527 amino acids, 70 kD). t-PA/Alteplase is a poor enzyme in the absence of fibrin. It binds fibrin with HIGH AFFINITY via lysine binding sites in amino terminus and activates fibrin-bound plasminogen MUCH MORE (several 100X) rapidly than circulating plasminogen.

Also has high affinity to PLASMINOGEN in presence of fibrin- allows for efficient degradation of clot fibrin.

Indications for thrombolytic therapy:

1. Management of st elevation mycocardial infarcation (STEMI) for lysis of thrombi in coronary arteries. Recommendation 
2. ALTEPLASE ONLY - ACUTE ISCHEMIC STROKE (onset of stroke symptoms within 3 hours of treatment)
3. ALTEPLASE ONLY- ACUTE PULMONARY EMBOLISM (under 75 yo and angiography)

Metabolism: Rapid hepatic clearance from plasma. Half-life = 1-4 minutes!
Requires constant IV admin.
Nonantigenic.

Adverse reactions: Incidence of bleeding is same in tPA alteplase and tPA tenecteplase (despite enhanced fibrin specificity).

Contraindications: Active bleeding, recent surgery (within

210
Q

t-PA/Tenecteplase (TNKase)

A

Plasminogen activator that is acting as a thrombolytic agent.
(~527 amino acid glycoprotein produced by RECOMBINANT DNA technology).

MOA: Binds to fibrin and CONVERTS PLASMINOGEN TO PLASMIN.
In presence of fibrin, conversion of plasminogen to plasmin is increased relative to its conversion in the absence of fibrin. Fibrin specificity decreases systemic activation of plasminogen and the resulting degradation of circulating fibrinogen.

Indications for thrombolytic therapy:

1. Management of st elevation mycocardial infarcation (STEMI) for lysis of thrombi in coronary arteries. Recommendation 
2. There are no SPECIFIC TNKase indications (technically there are studies suggestiong less bleeding complications compared to alteplase, it is not enough clinical data for tx for acute ischemic stroke)

Metabolism: Longer half-life that requires only SINGLE BOLUS - this is how it differs from native tPA.
Also TNKase is relatively resistant to inhibition by PAI-1.

Adverse rxns: Incidence of bleeding is same in tPA alteplase and tPA tenecteplase (despite enhanced fibrin specificity).

Contraindication: Active bleeding, recent surgery (within

211
Q

Aminocaproic acid (AMICAR)

A

PROCOAGULANT DRUG -
Potent inhibitor or FIBRINOLYSIS.
Synthetic lysine analog that binds to the lysine binding sites of plasminogen and plasmin, thus blocking the binding of plasmin to fibrin - thus COMPETITIVE INHIBITOR OF PLASMIN(OGEN) to fibrin.

Can reverse states associated with excessive breakdown of fibrin

Effective in decreasing hemorrhage with surgical procedures.

Useful tx for urinary tract bleeding.
Bc Concentration in urine can be 100x more than plasma.

212
Q

Aspirin (Bayer)

A

Irreversible inhibition of platelet COX 1 and 2, Acetylation of serine residue near active site of the enzyme; thereby blocking thromboxane formation in platelet.

Tx: MI prophylaxis, alone or in combo with thrombolytics in acute MI. Acute phase of ischemic stroke. Stroke prophylaxis. Unstable angina. Preeclamspsia prophylaxis.

Abs: Rapidly absorbed by upper GI tract with measurable effects within 1 hour. Enteric coating significantly impairs its absorption, taking up to 4 hours to reach peak plasma levels. Half life: only 20 minutes, effect on COX1 and platelet is permanent though (anucleate platelet is rendered useless); lifespan of platelet is ~7-10 days. After a single dose of aspirin, it can take 1- days for renewal of platelet population (you only need approx 20% of platelets with normal COX enzyme activity to achieve normal homeostasis.

Adverse effects include bleeding and GI irritation (dose related).

213
Q

Dipyridamole (Persantine)

A

Phosphodiesterase inhibition/blockage of uptake of adenosine. Basically INCREASES cAMP –> inhibits platelet aggregation.

Tx: Prevention of thromboembolism (with warfarin) in patients with prosthetic heart valves

Oral admin.

Adverse: Headache, GI upset, dizziness

214
Q

What are the ADP Blockers - Antiplatelet drugs?

A

Clopidogrel, Ticlopidine, Prasugrel, Ticagrelor

215
Q

Why is Prasugrel better than Clopidogrel in some ways?

A

Prasugrel has: Higher potency and more rapid onset of action thatn CLOPIDOGREL (Because more efficient active metabolite generation).
Produces higher and more consistent level of platelet inhibition (less response variability and decreased prevalent of non-responsiveness compared to clopidogrel).

216
Q

Clopidogrel (Plavix)

A

ADP BLOCKER - IRREVERSIBLE ANTAGONIST - inhibit platlet function for life of platelet.
Inhibit ADP binding to PDY12 receptor. ADP released from activated platelets bind to two types of ADP receptors: P2Y1 and PDY12 (located on platelet surface). Overall effect of platelet ADP receptor binding is to increase platelet activation/aggregation.

Sam in Ticlopiridine and Prasugrel.

Unstable angina or NSTEMI in combination with aspirin.

Pro drug metabolized to active metabolite by CYP2C19.

Potentially inhibited by proton pump inhibitors (PPIs) that are used for peptic ulcer (omeprazole) – so concurrent use w PPI may reduce levels of active metabolite and thus decreases efficacy. Might even increase CV risk

Increase risk of bleeding.

217
Q

Ticlopidine (Ticlid)

A

ADP BLOCKER - IRREVERSIBLE ANTAGONIST - inhibit platlet function for life of platelet.
Inhibit ADP binding to PDY12 receptor. ADP released from activated platelets bind to two types of ADP receptors: P2Y1 and PDY12 (located on platelet surface). Overall effect of platelet ADP receptor binding is to increase platelet activation/aggregation.

Same as Clopidogrel and Prasugrel

Pro drug metabolized to active metabolite by CYP2C19.

Increase risk of bleeding.

Severe neutropenia! Specific for ticlopidine - so patients must have CBC every two weeks from second to third month of treatment and any time they have infection. THUS the other ADP blockers have replaced ticlopidine.

218
Q

Prasugrel

A

ADP BLOCKER - IRREVERSIBLE ANTAGONIST - inhibit platelet function for life of platelet.
Inhibit ADP binding to PDY12 receptor. ADP released from activated platelets bind to two types of ADP receptors: P2Y1 and PDY12 (located on platelet surface). Overall effect of platelet ADP receptor binding is to increase platelet activation/aggregation.

Sam as Clopidogrel and Ticlopidine

Reduces rate of thrombotic CV events (including stent thrombosis) in patients who are to be managed with percutaneous coronary intervention for UA, NSTEMI, or STEMI.

Prodrug that undergoes esterase-mediated (primarily CYP3A4 and CYP2B6) oxidation, to an active metabolite.

Higher potency and more rapid onset of action than CLOPIDOGREL (Because more efficient active metabolite generation).
Produces higher and more consistent level of platelet inhibition (less response variability and decreased prevalent of non-responsiveness compared to clopidogrel).

Increase risk of bleeding.

219
Q

Ticagrelor

A

THIS IS A REVERSIBLE ADP BLOCKER… which is advantageous in situations where patients are undergoing surgery.

Inhibit ADP binding to PDY12 receptor. ADP released from activated platelets bind to two types of ADP receptors: P2Y1 and PDY12 (located on platelet surface). Overall effect of platelet ADP receptor binding is to increase platelet activation/aggregation.

This is DIFFERENT than prasugrel, clopidogrel, and ticlopidine (these are all irreversible)

Used in conjuction with aspirin for secondary prevention of thrombotic events in patients with UA, NSTEMI, STEMI managed medically or PCI and/or bypass.

NOT a prodrug -does not require metabolism for activation.

Adverse: Increase risk of bleeding.

220
Q

ANTIPLATELET DRUGS: Glycoprotein Iib/IIIa receptor blockers ?

A

Abciximab, Eptifibatide

221
Q

Abciximab (Reopro)

A

Antiplatelet drug - glycoprotein IIb and IIIa receptor blocker
MOA: Consists of Fab fragment of chimeric human-murine monoclonal antibody - prevents platelet aggregation by binding to platelet GP Iib/IIIa receptors to prevent fibrinogen binding and cross linking of platelets. Interacts with the GP Iib/IIIA receptor at sites DISTINCT from ligand binding RGD sequence site, and exerts its inhibitor effect noncompetitively.

Tx: Prevents platelet aggregation and thrombosis in patients undergoing percutaneous coronary interventions, including angioplasty and stent.

Admin WITH apsirin, heparin or LMWH.

Shown to significantly prevent vessel restenosis, reinfarction and death.

Also used in conjunction with ALTEPLASE for thomobolysis.

IV admin.

Biphasic plasma half life.
First half life: less than 10 min
Second half life: approximately 30 min

Due to its high affinity for receptor, it’s “biological half life” is 12-24 min (due to slow clearance from body), and “functional” half life of 7 days.

Adverse: Bleeding- major.
Other: thrombocytopenia, hypotension, bradycardia.

222
Q

Eptifibatide (Integrilin)

A

Antiplatelet drug - glycoprotein IIb and IIIa receptor blocker

Prevents platelet aggregation by preventing fibrinogen cross-linking of platelet.

Competitive REVERSIBLE inhibitor of fibrinogen binding to GP Iib/IIIa receptors. Molecular design based on BARBOURIN (73 aa isolated from rattlesnake venom). This has a Lys Gly Asp sequence (KGD) making it very specific for the GP Iib/IIIa receptor.

Used in people with unstable angina (UA) and MI - in combo with LMWH.

Used in two ways:

1. To prevent coronary thombosis in persons with UA or non-ST semgemnt elevation (non Q wave) MI 
2. To prevent thrombosis in persons having coronary angioplasty or stent placment for ST segment elevation MI

IV admin.

Achieves peak plasma concentration by 5 min with maximal inhibition of platelet aggregation by 15 min.

Reversible effect and platelet response returns to normal within 4-8 hours after discontinuing drug.

Renal clearance.
Careful to use this in patients with renal dysfunction (due to its clearance)

Adverse: Bleeding- major.
Other: thrombocytopenia, hypotension, bradycardia.

Pharm (4 decks)

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