Treatment of GERD

Drug

Mechanism

Acid-neutralizing capacity (mEq/15 mL of commercial product)

Dosage

Adverse reactions

Antacids

Aluminum hydroxide

Neutralizes hydrochloride in the stomach to form Al (Cl)₃ salt + H₂O, resulting in increased gastric pH and inhibition of pepsin activity

640 mg five to six times daily after meals and at bedtime (maximum, 3840 mg in 24 hours)

Constipation

Significant aluminum retention may occur in renal failure causing neurotoxicity

Calcium Carbonate

Neutralize gastric acidity resulting in increased gastric and duodenal bulb pH; inhibit proteolytic activity of pepsin if the pH is increased >4 and increase lower esophageal sphincter tone

One to four tabs as needed; (maximum, 8000 mg in 24 hours

Milk alkali syndrome is a rare complication of excessive calcium carbonate antacid intake along with other calcium containing compounds

Magnesium hydroxide

Reacts with gastric hydrochloric acid producing magnesium chloride and water raising pH

311 mg/tab: two to four tabs every 4 hours (maximum, 1244 mg in 24 hours)

Diarrhea

Use with extreme caution in patients with myasthenia gravis or other neuromuscular disease as may exacerbate muscle weakness

Significant magnesium retention may occur in renal failure leading to hypermagnesemia

Magnesium oxide

Reacts with gastric hydrochloric acid producing magnesium chloride and water raising pH

8–20

400 mg/tab: one tab twice a day (maximum, 800 mg in 24 hours)

Sodium bicarbonate

Dissociates to provide bicarbonate ion which neutralizes hydrogen ion concentration and raises blood and urinary pH

325 mg – 2 g tabs (maximum, one to four tabs in 24 hours)

When taken with calcium in excess, may lead to milk-alkali syndrome

Significant sodium retention may occur in renal failure

Alginate : aluminum hydroxide /magnesium carbonate /alginate

Viscous gel formation of near-neutral pH within minutes of contacting gastric acid triggering sodium bicarbonate in the formulation to release carbon dioxide, which becomes trapped in the alginate gel, causing it to float to the top of the gastric contents

Aluminum hydroxide 160 mg/magnesium carbonate 105 mg; 2–4 tabs 4 times daily (maximum, 16 tabs per 24 hours)

Significant aluminum retention may occur in renal failure causing neurotoxicity

Constipation

Some dosage forms may contain benzyl alcohol which may cause fatal toxicity in neonates taking large doses

Baclofen

Selective GABA(B) receptor agonist Inhibits the transmission of monosynaptic and polysynaptic reflexes at the spinal cord level, resulting in relief of muscle spasticity

Initial: 5 mg three times daily. Increase by 5 mg per dose every 3 days until optimal response is reached. Usual dosage range: 40 to 80 mg daily. (maximum, 80 mg per 24 hours)

Crosses the blood–brain barrier:

Somnolence

Confusion

Dizziness

Drowsiness

Headache

Nausea, vomiting

Studies comparing the different methods of delivery of antacids demonstrate that antacid chewing gums provider faster and more prolonged symptom relief and pH control than chewable tabs and liquids, respectively. This may be because chewable tabs remain in the mouth longer and expose the esophagus to numerous smaller boluses of antacid over a longer time period than do liquids [38, 40, 41]. While antacids have rapid onset, their effect is short acting, and because they do not significantly alter gastric pH, they do not prevent subsequent reflux episodes from exposing the esophagus to caustic gastric acids.

Limited data exists comparing antacids to other medications. Two studies evaluated the effect of antacids on healing rates of esophagitis and found no improvement compared to placebo [2, 42–44]. Two studies found an improvement in symptoms with antacids compared to placebo, though this was only significant in one study [2, 42, 43]. Three studies have compared cimetidine 1200 mg/day [45, 46] or ranitidine 300 mg/day [47] with antacids for 6 and 12 weeks. It was found that the symptomatic response was equivalent or better with H2Ras; however, this was significant in only one study [45].

Antacids are generally well tolerated, with adverse effects being of greater significance with higher doses and prolonged use. Antacids have many potential drug interactions, some of which are outlined in Table 14.2. Overall antacids have little effect on healing erosive esophagitis but are likely nearly as effective as H2RAs. For patients with milder disease, antacids are likely more effective than placebo and, because of their rapid onset, may be useful to those with milder symptoms or for use as breakthrough relief while on a PPI or H2RA.

Table 14.2

Drug interactions related to the use of antacids and drug interactions

Drug	Antacid drug interaction (effect on drug in first column)	Mechanism
Aspirin (enteric coated)	Increased rate of absorption	Enhanced drug release from dosage form
Beta blockers
Atenolol	Decreased bioavailability and prolonged half-life (Ca-containing antacids)	Unknown
Metoprolol	Increased bioavailability (Mg- and Al-containing antacids)	Unknown
Propranolol	Decreased bioavailability and rate of absorption (aluminum hydroxide containing antacids)	Decreased rate of gastric emptying
Corticosteroids (prednisone, dexamethasone)	Decreased absorption	Unknown, adsorption suspected
Digoxin	Decreased absorption	Adsorption and faster gastric emptying
Indomethacin	Decreased bioavailability	Increased gastric pH resulting in increased ionized indomethacin and less absorption
Ketoconazole	Decreased bioavailability	Increased gastric pH resulting in decreased dissolution in the stomach
Levodopa	Decreased breakdown in the stomach, with increased absorption	Increased gastric emptying rate
Lithium	Decreased serum concentrations with sodium bicarbonate	Alkalization of the urine enhances renal clearance
Methotrexate	Decreased effect with sodium bicarbonate	Alkalization of the urine enhances renal clearance
Phenytoin	Decreased absorption	Unknown
Salicylates	Decreased serum concentrations due to decreased urinary reabsorption	Increased urinary pH decreased urinary reabsorption
Sulfonylureas	Increased absorption with increased effect and possible hypoglycemia with Mg antacids	Unknown
Tetracycline	Decreased absorption of tetracycline (significant interaction)	Chelation
Drug	Baclofen drug interaction (effect on drug in first column)
Azelastine	Enhances CNS depressant effect
Bromperidol	Enhances CNS depressant effect
Orphenadrine	Enhances CNS depressant effect
Oxomemazine	Enhances CNS depressant effect
Thalidomide	Enhances CNS depressant effect

Related to the use of baclofen [39]

Alginate

An alternative method to managing GERD is to impede the flow of acidic refluxate. The acid pocket is an area of relatively unbuffered highly acidic material localized to the proximal stomach postprandially. Alginates are natural polysaccharide polymers that create a mechanical barrier to acid reflux. In the presence of gastric acid, they precipitate into a viscous gel of near-neutral pH and form a raft that floats within the stomach and displace the postprandial acid pocket away from the gastroesophageal junction. This mechanical barrier reduces reflux for up to 4 hours after ingestion [2, 48]. A 2017 meta-analysis of alginate-based therapy compared to placebo, antacids, H2RAs, and PPIs included 14 randomized controlled trials and demonstrated that alginate therapy was favored over placebo and antacids in resolution of symptoms in those with nonerosive GERD [48]. There was a trend toward alginates being less effective at symptom control than H2RAs and PPI therapy, but this was not statistically significant [48].

Alginate–antacid formulations can have variable compositions Table 14.1. Alginates should be considered as an alternative to other antacids in patients with infrequent, mild symptoms, especially if they occur predominantly postprandially. They can also be considered as adjunctive therapy for those on maintenance PPIs [49].

Sucralfate

The use of sucralfate is discussed later in this chapter in the section “Management of GERD in Pregnancy.”

Inhibitors of Transient Lower Esophageal Sphincter Relaxations (TLESRs)

Baclofen

Persistent GERD symptoms in patients on PPI maintenance therapy may be due to ongoing weakly acidic or alkaline reflux, in which further reduction of symptoms is unlikely to occur with increased gastric acid suppression [2, 50]. Inhibiting TLESRs via neurotransmitters and receptors such as gamma-aminobutyric acid (GABA), nitric oxide, cholecystokinin, and metabotropic glutamate receptor 5 (mGluR5) may improve symptoms. Thus far, GABA and mGluR5 are considered the dominant signaling pathways, but baclofen (a GABA-B agonist) is the only medication that has demonstrated efficacy in reducing TLESRs and reflux [2, 51].

A meta-analysis of nine randomized controlled trials comparing baclofen to placebo concluded that baclofen reduced the number of reflux episodes, average length of episodes, and the incidence of TLESRs [52]. Small uncontrolled trials have demonstrated a benefit for baclofen when used for refractory duodenal reflux in patients with ongoing symptoms on PPI therapy [53]. The use of baclofen three times a day before meals may be considered as an adjunct for patients with persistent symptoms on PPI therapy. Pharmacokinetics and adverse reactions are noted in Tables 14.1 and 14.2.

Antisecretory Agents

Histamine-2 Receptor Blockers (H2RAs)

H2RAs slow gastric acid production by competitively and reversibly binding to H2 receptors on gastric parietal cells. Compared to antacids, H2RAs have a slower onset of action (reaching peak concentrations 1–3 hours after administration) but have a longer duration of action (up to 4–10 hours) [1, 38]. A single dose of H2RA can be effective for short-term heartburn relief but has limited efficacy in patients with erosive esophagitis and is inferior to PPIs in symptom relief and maintenance of symptom remission at 6 months [2]. Repeated use of H2RAs can also lead to tachyphylaxis. The mechanism of this tolerance is unclear but has been observed in both fasting and fed conditions. Increasing the dose of H2RA does not overcome the tolerance, and the effects persist for several days after discontinuation of H2RAs [38, 54].

Despite H2RAs’ propensity for tolerance, they have been shown to be useful as short-term reflux relief and for PPI refractory nocturnal symptoms. Nocturnal acid breakthrough (NAB) occurs in more than 70% of patients on PPI therapy. Adding a bedtime H2RA to once or twice-daily PPI can reduce the percentage of NAB as well as improve reflux-associated sleep disturbance [55–58]. A recent meta-analysis comparing efficacy of different H2RAs showed that famotidine had the best short-term therapeutic benefit in GERD when compared to ranitidine, cimetidine , and nizatidine [59]. Pharmacokinetics and major drug interactions are listed in Tables 14.3, 14.4, and 14.5.

Table 14.3

Pharmacokinetics of H2RAs [1, 196]

	Cimetidine	Ranitidine	Nizatidine	Famotidine
Bioavailability (%)	80	50	70	40
Relative potency	1	5–10	5–10	32
Half-life (hours)	6	8	8	12
Time to peak concentration (hours)	1–2	1–3	1–3	1–3.5
Hepatic clearance (%)
Oral	60	73	22	50–80
Intravenous	25–40	30	25	25–30
Renal clearance (%)
Oral	40	27	57–65	25–30
Intravenous	50–80	50	75	65–80
Relative effect on P450 metabolism	1	0.1	0	0

Table 14.4

Dosing adjustments of H2Ras and adverse effects [1, 96]

	Creatinine clearance (mL/min)	Dose (mg/day)	Adverse effects
Cimetidine	>30	800	Gynecomastia, impotence, diarrhea, CNS: confusion, dizziness, agitation, headache^a
	15–30	600
	<15	400
Ranitidine	>75	300	Gynecomastia, CNS: confusion, dizziness, agitation, headaches^a
	30–75	225
	15–30	150
	<15	75
Famotidine	>75	40	CNS: confusion, dizziness, agitation, headaches
	30–75	30
	15–30	20
	<15	10
Nizatidine	>75	300	CNS: confusion, dizziness, agitation, headaches
	30–75	225
	15–30	150
	<15	75

^aRare adverse reactions (<1%), hepatitis, pancytopenia, polymyositis, anaphylaxis; cardiac, AV block, QT prolongation, hypotension (with rapid infusion)

Table 14.5

Cimetidine drug interactions [196]

Drug	Effect of cimetidine		Mechanism
Drug	serum concentration of drug	Clearance of drug (% decrease)	Mechanism
Caffeine	Increased	31–42	Decreased demethylation
Carbamazepine	Increased	10–20	Decreased epoxidation
Desipramine	Increased	36	Decreased hydroxylation in rapid metabolizers
Ketoconazole	Decreased	No change	Decreased absorption due to elevation of gastric pH, slowing dissolution
Lidocaine	Increased	14–30	Decreased N-dealkylation
Metronidazole	Increased	29	Decreased hydroxylation
Nifedipine	Increased	38	Uncertain
Phenytoin	Increased	21–24	Decreased hydroxylation
Propranolol	Increased	20–27	Decreased hydroxylation
Procainamide	Increased	28	Competition for renal tubular secretion
Warfarin	Increased	23–36	Decreased hydroxylation

Proton Pump Inhibitor Therapy

History of PPIs

In the late 1960s, the pharmaceutical company Hassle (division of Astra) initiated a gastrointestinal research division with the aim of finding a drug for inhibition of gastric acid secretion for patients with peptic ulcer disease. The momentous recognition that the H⁺/K⁺ ATPase (proton pump) was the final step of acid secretion resulted in the development of the class of drugs knows as proton pump inhibitors (PPIs) [60]. In 1975, timoprazole was found to inhibit acid secretion irrespective of stimulus; however, it caused enlargement of the thyroid gland due to inhibition of iodine uptake. After multiple animal models and trials, a derivative of timoprazole, omeprazole, was discovered in 1979. Omeprazole was found to be the most potent inhibitor of gastric acid secretion in rats and dogs in vivo, with no effect on iodine uptake [61, 62]. An Investigational New Drug (IND) application was filed in 1980, and omeprazole was taken into human trials in 1982. Omeprazole was found to be superior to H2RAs for GERD symptoms [63] and duodenal [64] and gastric ulcers [65]; thus omeprazole was launched in Europe as Losec in 1988 and in the United States as Prilosec in 1990 [62].

Omeprazole had significant inter-individual variability dependent on rapidity of metabolism. In Western populations, about 2–4% of people lack 2C19, one of the P450 enzymes, which is important for metabolism of many drugs, including omeprazole [66]. Thus, Astra started a new research program in 1987 with the goal of finding an acid suppression compound with reduced clearance by the liver and increased bioavailability. Several hundred compounds were screened, and finally an isomer of omeprazole was found to exceed omeprazole, esomeprazole [62]. Since then, several additional PPIs have been introduced into the market .

Benefits of PPI Therapy in GERD

Via inhibition of the final step in acid secretion, PPIs are the most potent acid suppressants available. In a Cochrane Review of 34 trials with 1300 patients, PPIs were more effective than H2RAs in reducing heartburn symptoms in those treated empirically for GERD and in those with nonerosive reflux on endoscopy [67]. PPIs have also been shown to be more effective than H2RAs and placebo in healing of erosive esophagitis and reducing relapse rates [68, 69]. Meta-analyses have demonstrated PPI superiority in healing of all grades of erosive esophagitis when compared to H2RAs, sucralfate , and placebo [70]. Thus PPIs are currently the first-line treatment of GERD [4] and are initiated for 8 weeks for symptom relief and healing of erosive esophagitis [4, 56].

Pharmacology of PPIs

As of 2015, the US Food and Drug Administration (FDA) had approved 6 PPIs: omeprazole , esomeprazole , lansoprazole , dexlansoprazole , pantoprazole , and rabeprazole (Table 14.6) [71]. All PPIs share a common structural motif. They accumulate selectively in the acid space (canaliculi) of the secreting gastric parietal cell, and within that space they undergo a conversion to permanent cations. These compounds bind to cysteine residues (cys 813 subunit) on the H⁺/K⁺ ATPase, thereby inhibiting acid secretion until replacement pumps are synthesized (up to 36 hours). All PPIs require accumulation and acid activation; thus their onset of action is delayed [1, 71].

Table 14.6

Pharmacodynamics of commercially available PPIs in the United States [71]

	Omeprazole	Esomeprazole	Lansoprazole	Dexlansoprazole	Pantoprazole	Rabeprazole
Dose (mg)	10, 20, 40	20, 40	15, 30	30, 60	20, 40	20
Treatment of erosive or nonerosive GERD	20 or 40 mg daily or 20 mg twice daily	20 or 40 mg daily	30 mg daily or 30 mg twice daily	30 mg daily or 30 mg twice daily	40 mg daily or 40 mg twice daily	20 mg daily or 20 mg twice daily
IV Formulation	Yes	Yes	Yes	No	Yes	No
Liquid or suspension	No	Yes	Yes	No	Yes	No
Generic	Yes	Yes	Yes	No	Yes	Yes
Over the counter	Yes	Yes	Yes	No	No	No
Bioavailability (%)	30–40	64–90	80–85	–	77	52
Time to peak plasma level (tmax, hours)	0.5–3.5	1.5	1.7	1–2, 4–5	2–3	2–5
Half-life (hours)	0.5–1	1–1.5	1.6	1–2	1–1.9	1–2
Protein binding (%)	95	97	97	96	98	96.3
Primary excretion	Hepatic	Hepatic	Hepatic	Hepatic	Hepatic	Hepatic
Liver metabolism	CYP2C19	CYP2C19	CYP2C19	CYP2C19, CYP3A4	CYP2C19, CYP3A4	CYP2C19

PPIs are the most potent inhibitors of gastric acid secretion; however, they are most effective when parietal cells are stimulated in response to a meal. Thus, PPIs should only be taken before meals (30–60 minutes prior) and should not be used along with H2RAs or other antisecretory agents, as this will reduce the acid-inhibitory effect of PPIs [72]. PPIs are most effective after a prolonged fast when a large amount of inactive H⁺/K⁺ ATPase is present [1]. During meals, not all of the parietal cells or proton pumps are active. Thus, the PPI will only inhibit activated H⁺/K⁺ ATPase, and only two-thirds of proton pumps are inhibited by a single dose of PPI. As more inactive enzyme is recruited, acid secretion will continue (although reduced). Once-daily dosing of PPI results in 66% inhibition of acid after 5 days, while initial twice-daily dosing may be helpful to achieve more rapid inhibition of acid secretion in the first 2–3 days. Due to these properties, sporadic use of PPIs is not likely to be effective [1, 73].

Omeprazole

Omeprazole was the first PPI to be developed in the 1970s. It has the fastest onset of action at 1.5 to 3.5 hours but the shortest half-life of all the PPIs. It is metabolized almost entirely by CYP2C19, thereby offering the greatest potential for drug interactions (Tables 14.6 and 14.7) [71].

Table 14.7

PPI drug interaction [197–199]

	Omeprazole	Esomeprazole	Lansoprazole	Dexlansoprazole	Pantoprazole	Rabeprazole
Phenazone (antipyrine)	↓ Clearance		↑ Clearance		None
Carbamazepine	↓ Clearance				↓ Clearance
Citalopram	↓ Clearance
Clopidogrel	↓ Absorption	↓ Absorption	None	None	None
Diazepam	↓ Clearance	↓ Clearance	None		None	None
Digoxin	↑ Absorption			None	None	↑ Absorption
Etravirine	↓ Clearance
HIV protease inhibitors	↓ Absorption		↓ Absorption
Methotrexate	↓ Clearance
Nifedipine	↑ Absorption ↓ Clearance				None
Phenprocoumon	↓ Clearance
Phenytoin	↓ Clearance	↓ Clearance	None	None	None	None
Tacrolimus			↓ Clearance		None	None
Theophylline			↑ Absorption	None
Warfarin	↓ Clearance	↓ Clearance	None	None	None	None

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