Pharmacology Flashcards
Is it correct to talk about ‘thinning the blood’ in reference to anti-coagulant drugs ?
no
What are the differences in thrombus formation in veins and in arteries?
In arteries Platelets are the dominating mass, in veins there is much more fibrin, and so it will break off much more easily.
What are the three pathways which contribute to thrombus formation?
Fibrinogen to fibrin.
RBC’s.
Collagen to platelet aggregation.
What roles do plasmin and plasminogen play?
Plasminogen is converted to plasmin and plasmin contributes to thrombolysis.
What is an enzyme amplification cascade?
Rapid generation of vast amounts of product by activation of a cascade of inactive precursor enzymes in plasma.
What are the three different pathways that make up the coagulation cascade?
Extrinsic pathway
Intrinsic pathway
Common pathway
What are the contents of the common pathway that leads to coagulation?
Prothrombin -> Thrombin (F2)
Fibrinogen —> Fibrin (F1)
Fibrin mesh.
What are the contents of the Extrinsic pathway that leads to coagulation?
F7 —– (tissue injury) —->F7a
F10 —-> F10a
What are the contents of the Intrinsic pathway that leads to coagulation?
F12 —-> F12a
F11 —–> F11a
F9 —–> F9a
F8 ——> F10 ——> F10a
What is the role of vitamin K on clotting factors?
Helps di-carboxylate glutamate residues on clotting factors especially in factor 7, 10 and prothrombin.
How does warfarin interfere with the clotting mechanism?
It competes with Vitamin K, without any efficacy.
What is warfarin sodium, how’s it work and what are the antidotes?
an oral solution that works in the liver to produce incomplete clotting factors that can’t be activated after their release into the plasma.
Slow onset (2 days) and a slow offset (4-7 days)
Antidotes include Vit. K, plasma and whole blood.
What are the disadvantages to warfarin?
Has a narrow therapeutic index
The metabolism of warfarin by P450 enzymes is highly variable
Warfarin has lots of drug interactions.
Examples of some drug interactions of warfarin?
Alcohol and Cimetidine inhibit P450 enzyme, unceasing affect of Warfarin.
phenobarbitone and phenytoin, induce P450 metabolism.
Antibiotics increase the action of warfarin.
Many herbal supplements interact.
What is unfractionated heparin?
Natural anticoagulant made from animal gut tissue, can only be taken parenterally (not by mouth)
What is the mechanism of Heparin?
Accelerates the activity of anti-thrombin (which inhibits thrombin and factor 10)
What is unfractionated heparin and it’s antidote?
Continuous Iv infusion of heparin, involves dose-depndent liver elimination.
Side effects of unfractionated heparin?
Haemorrhage, Osteoporosis, thrombocytopenia (antibodies cause thrombosis)
What are the differences and similarities of low MW heparins to standard heparin?
Twice the duration
Still cannot be given orally
Predictable effect, so clotting time monitoring is not necessary
Less risk of Osteoporosis and thrombocytopenia.
What is an example of a direct thrombin inhibitor and what are there advantages?
Lepirudin:
Independent of anti-thrombin III
No thrombocytopenia
No monitoring of clotting time necessary
What is an example of a Direct factor Xa inhibitor? and what does it do?
Rivaroxaban - it inhibits activated Factor 10, and so prevents conversion of prothrombin to thrombin.
Major risk factors for a thromboembolism?
Fracture or major surgery of pelvis, hips or legs
Major pelvic or abdominal surgery for cancer
Lower limb paralysis or amputation
Major surgery with history of DVT or PE
Minor risk factors for a thromboembolism?
Recent MI, HF, cancer, IBD
Trauma or burns
Aged >40 yrs
Clinical uses of heparins and warfarin?
Prevention of DVT
Prevention of embolism
Treatment of DVT
How do you monitor clotting time in unfractionated heparin and for warfarin?
APTT for unfractionated heparin.
Prothrombin test for warfarin.
What is an example of an in-vitro anti-coagulant?
Calcium chelators, this works because Ca2+ is essential for F10. e.g. oxalate, citrate.
What are the differences in asthma and COPD?
Asthma is bronchoconstriction caused by exposure to an allergen or non-specific stimuli such as cold air.
COPD is bronchoconstriction caused by long-term exposure to irritants such as cigarette smoke, air pollution and isocyanates.
What two receptors influence the contraction of bronchial smooth muscle? what can be given to relax the smooth muscle?
ß-adrenoceptors, ß-agonists can be given
Muscarinic receptors, muscarinic antagonists can given.
Difference in adrenaline and noradrenaline?
Adrenaline is a potent stimulus for both a and ß adrenoceptors
Noradrenaline is only potent for a adrenoceptors.
What is given in status asthmaticus (severe asthma attack) when there is respiratory failure.
Adrenaline.
What is Adrenaline’s effect on the heart? (3)
Increased Force of contraction
Increased Heart Rate
Reduced Cardiac efficiency
Advantages and disadvantages of ß-2 adrenoceptor agonists? and example?
Rapid action
Relaxes smooth muscle regardless of stimulus
Does not affect underlying airways inflammation.
Salbutamol.
Effects of too much salbutamol?
Skeletal muscle Tremor.
Hyperglycaemia in diabetic patients
Cardiovascular effects - arrhythmias acutely and in the long term potentially myocardial ischaemia.
Hypokalaemia.
What is an example of a longer acting ß-2 agonist?
Salmeterol
Why are ß-antagonists (beta blockers) not given to asthmatics?
The antagonise ß2 adrenoceptors and can cause severe bronchoconstriction.
Why are muscarinic antagonists effective? Give two examples.
Some irritants such as cigarette smoke can activate the Parasympathetic nervous system through muscarinic receptors and cause bronchoconstriction.
Ipratropium and oxitropium.
What is a better for asthma Muscarinic antagonists or ß2 agonists?
ß2 agonists.
Why are muscarinic antagonists of limited use in asthma, and more use in COPD?
They take 20-30 minutes to act and last over 4-6 hours.
Advantages and disadvantages for muscarinic antagonists?
Not absorbed into systemic circulation so side effects are minimal
Care has to be taken when prescribing to patients with glaucoma or prostate/bladder conditions
Side effects can include constipation and rarely tachycardia and atrial fibrillation.
What other drugs (apart from ß2 agonists) can be used for asthma?
Xanthines
Steroids
Anti-leukotrienes
Where is the anatomical location of the adrenal gland?
Sitting just above the kidneys.
What are the four zones of the adrenal gland that synthesise hormones and what hormones do they synthesise?
Zona glomerulosa: Mineralcorticoids (aldosterone)
Zona fasciculata: Glucocorticoids (cortisol)
Zona reticularis: Androgens - sex hormones (testosterone)
Adrenal medulla: adrenaline (not steroids)
What is the precursor to all Mineralcorticoids, Androgens and Glucocorticoids?
Cholesterol.
What is cholesterols role in cell membranes?
Present next to phospholipids, almost one cholesterol to every phospholipid.
Makes membrane less deformable and less water-permeable.
How is cholesterol transported in the body?
In lipoproteins.
How is cholesterol derived and synthesised in the body?
Derived from the diet or synthesised in hepatocytes by HMG CoA reductase.
What is Low-density Lipoprotein (LDL)’s role in Coronary artery disease?
Deposits cholesterol in fatty deposits to form atheroma’s.
What are the main mechanisms of action of corticosteroids?
Prepare for a period of starvation and dehydration:
- Mobilising energy stores into glycogen and glucose
- Conserving water (less urine production)
Most common Glucocorticosteroid in the body? what are it’s main actions?
Cortisol (hydrocortisone)
- Mobilising nutrients (metabolism)
- Anti-inflammatory
Four synthetic Glucocorticosteroids (GCS) and what they are used to treat?
Prednisolone and dexamethasone (systemic arthritis)
Betamethasone (eczema) - topical
Fluticasone (asthma) - inhaled
What is the hypothalamo-pituitary-adrenal (HPA) axis, and what is the effect of cortisol on it?
The combination of the hypothalamus, pituitary and adrenal cortex, cortisol inhibits their action and prepares the body for a period of starvation.
What are the effects of cortisol?
Catabolic: Hyperglycaemia, mobilisation of lipids, breakdown of proteins.
Anti-inflammatory: Decreased leucocyte activity, decreased inflammatory mediators.
What is the cellular mechanism of action of GCS’s?
They bind to cytoplasmic GCS receptors (GRs) and then modulate the transcription of many inflammatory genes.
What are some of the genes that GCS effects? (just need some)
Blocks pro-inflammatory genes:
- Cycloxygenase-2 (source of prostaglandins)
- Adhesions molecules, complement components.
- Immunoglobulins (IgG and IgE)
- Cytokines
Induces anti-inflammatory genes:
- Ribonucleases (breaks down inflammatory mRNA)
- Interleukin 10
Downsides to glucocorticosteroids?
Slow in onset, slow in offset.
Some examples of uses of GCS (glucocorticosteroids)?
Asthma
Allergic diseases (eczema)
Rheumatoid Arthritis
Oedema e.g. cerebral oedema.
What can be used to inhibit metabolic OVER-production of cortisol?
Metyrapone
What condition is caused by over-use of GCS’?
Cushing’s syndrome
Symptoms of Cushing’s syndrome?
Tinning of skin
Hypertension
Poor wound healing
Increased abdominal fat
How are GCS drugs withdrawn?
By tapering the dose (removing slowly)
In what situation is aldosterone (mineralocorticoid) released into the body, what is it’s mechanism of action and the molecular mechanism behind this?
Released in response to low plasma Na+ and by renin-angoitensin system.
It Acts on Mineralocorticoid Receptors (MR) in the cytoplasm of kidney tubule epithelial cells, and increases gene transcription of Na+ channels.
Increasing Na resorption and therefore water resorption. K+ and H+ are secreted instead.
What is Fludrocortisone and when is it used?
It is an MR agonist and is used in replacement therapy in adrenal insufficiency.
What is Spironolactone and when is it used?
Competitive MR antagonist, it has diuretic and K+ sparing actions, used with other diuretics to reduce blood volume.
How do GCS’ achieve their anti-inflammatory effects? (3)
They are inhibitors of Phospholipase A2, which is the enzyme that catalyses the production of arachidonic acid. Therefore production of prostaglandins and leukotrienes is reduced.
They reduce the activity of inflammatory leucocytes
They also reduce oedema
Two types of asthma?
Extrinsic: Identifiable external trigger causing allergic reaction.
Intrinsic: No obvious trigger, tends to be more severe and difficult to control.
What can trigger asthma?
Inflammation: Respiratory infections, allergens
Constriction: Exercise, cold air, strong odours.
What is the pathophysiology of asthma and of early and late phase asthma?
Early phase caused by mast cell degranulation and release of prostaglandins and leukotrienes.
Late phase caused by eosinophil granules, cytokines and leukotrienes.
What are the two main pharmacological approaches to asthma?
Relievers and preventers.
What are the two main reliever drugs and how do they act on the autonomic nervous system controlling the lungs?
Anti-muscarinics inhibit the parasympathetic nervous system, B2 agonists stimulate the sympathetic nervous system causing bronchodilation and reduced secretions.
Three types of ß2 agonists and their acting time?
Rimiterol 2hrs
Salbutamol 4-5hrs
Salmeterol 12-24 hrs
Side effects of salbutamol?
Skeletal muscle tremor
Hypokalaemia
Arrhythmia
How do Salmeterol and formoterol became long acting ß2 agonists?
Salmeterol - binds to an exposed site via a flexible tail and repeatedly stimulates the receptor
Formoterol - Dissolves into the plasma and then dissolves out to stimulate the receptor.
What are methyxanthines, and what is their mechanism of action?
Bronchodilator used in asthma. They inhibit PDE which is am enzyme involved in turning cAMP to AMP, which is produced after ß-2 stimulation. there is then more cAMP which causes bronchodilation.
Two Methyxanthines?
Theophylline
Aminophylline
Features of theophylline?
Oral administration only
Variable gut absorption and hepatic metabolism.
Narrow therapeutic index.
Three main anti-muscarinic asthma drugs?
Ipratropium
Oxitropium
Tiotropium
Features of anti-muscarinic drugs?
Inhaled M1/3 antagonists
Block the parasympathetic nervous system
Few side effects as they are poorly absorbed from the lungs.
Main drugs used to prevent asthma by treating underlying airways inflammation?
Corticosteroids.
Ways in which corticosteroids reduce the symptoms of asthma?
Reduce the numbers of inflammatory cells such as mast cells and eosinophils
Reduces the cytokine secretion of T-lymphocytes and macrophages
Decrease mucus secretion
Increase ß2 receptors on epithelium.
Some Corticosteroids used in the treatment of asthma?
Fluticasone most common oral inhaler
Oral prednisolone in severe asthma
In status asthmaticus, IV hydrocortisone can be used.
How are side-effects of inhaled corticosteroids reduced?
Giving the lowest possible dose, effective inhaler technique, using drugs such as fluticasone that are inactivated by first-pass metabolism.
What are the receptors for Ach at skeletal muscle fibres and at smooth muscle fibres?
Skeletal: N2
Smooth: Muscarinic
How is the action of suxamethonium and of vecronium terminated?
Suxamethonium: plasma cholinesterases
Vecronium: Through redistribution and metabolism
Side effects of Vecronium and suxamethonium?
Suxamethonium: Post-op muscle pain
Vecronium: no after-effects
Side effects of neostigmine?
Nausea, increased salivation, sweating, nystagmus, due to stimulation of both somatic and autonomic nervous system.
How could you reverse the effects of neostigmine?
Atropine (Ach antagonist)
What drugs are used to treat organophosphate poisoning?
Pralidoxime and atropine later
What would a drug such as edrophonium be used for?
Diagnosis of myasthenia gravis.
True/False: suxamethonium is two molecules of Ach joined together.
False it is three.
Is the duration of action of suxamethonium longer or shorter than vecronium?
Shorter.
What are the main types of adverse drug reactions?
Type A - Augmented, dose related, due to known pharmacological action of the drug.
Type B - unpredicatable dose related reactions
Three type A adverse drug reaction mechanisms?
- exaggerated therapeutic response at target site
- desired pharmacological effect at another site
- additional pharmacological action
Two main types of Type B drug reactions?
Type I - IgE effects on mast cells, and basophil reactions.
Type IV - Lymphocyte mediated.
What kind of effects can Type B, I reactions cause?
Asthma, angiodema
Examples of effects of Type B II reactions?
Skin effects, Topical epidermal necrolysis.
How can ADR’s be diagnosed?
History of administered drugs
Clinical and histological examination
In vivo and in vitro lab tests.
How can ADR’s be managed?
Withdrawing of the drug may be enough
Steroids can be helpful
What are cromones?
Dry powder inhaler used as prophylaxis for asthmatics.
What is the method of action of anti-leukotrienes?
Antagonist of Cys-LT receptor on smooth muscle and eosinophils.
Bronchodilator
Anti-inflammatory
What is anti-IgE used to treat and how does it work?
Used to treat moderate-severe asthma, works by bonding to IgE in plasma and doesn’t cause mast cell degranulation.
How do you treat status asthmaticus?
- oxygen
- nebulised β₂-agonist
- Oral prednisolone or Hydrocortisone
If no improvement in 20 minutes:
- Continued oxygen and β₂-agonist
- Ipratropium
- Mg²+
- admit to hospital
Steps of asthma therapy?
Mild - Short acting β₂ agonist
Mild persistent - Low-dose inhaled GCS
Moderate persistent - High dose inhaled GCS and salmeterol/Anti LT/Ipratropium/theophylline/cromone.
Severe persistent - Oral GCS
Main reasons asthma treatment fails?
Not asthma.
Non-adhereance
Poor inhaler technique/drug interaction.
Main two methods of pathogenesis of COPD?
1.
- oxidative stress can lead to inactivation of α₁-antitrypsin
- increase in proteases and breakdown of elastin.
2.
- Smoke as an irritant increases mucus production
- leads to neutrophils being recruited/infection
- Neutrophils release elastase
Pharmacological treatment of COPD?
Anti-muscarinics
β₂ agonists
Methylxanthines
Steroids
Reasons for intentional non-adhereance?
Patient feels better and stops taking the drug
Patient experiences side-effects and stops taking the drug
Patient doesn’t feel the drug is working
Cost
How can the contractility of heart be regulated in the short and long term?
Short term - Sympathetic drive
Long Term - Hypertrophy
How is sympathetic down-regulation of the heart achieved?
Reduction in number of β₁ adrenoceptors
What receptors on the heart can dopamine affect at different therapeutic levels?
What DA₁ and DA₂
With increased dosage it can affect β1 and α receptors
What receptors on the heart can Dobutamine affect?
β₁ adrenoceptors.
What is the mechanism of action of Digoxin?
Na and Ca exchangers blocked increasing intracellular levels of Na and Ca.
Leads to increased storage of Ca in SR, leading to increased contractility.
What is Digoxin used to treat?
Heart arrhythmias e.g. Atrial fibrillation and flutter.
What are the Neurohormonal effects of Digoxin?
Decreased sympathetic nervous system activity
Decreased RAAS (renin system) activity
Increased Vagal tone
What are the haemodynamic effects of digoxin?
Increased Cardiac output
Increased LV diastolic pressure
Increased secretion of sodium in the kidneys (natriuresis)
Long-term effects of Digoxin in heart failure?
Survival similar to placebo
Less hospital admissions
Improved exercise tolerance
More serious arrhythmias
More MI’s
Effects of increased vagal tone caused by digoxin?
Slows SA node discharge
Slows AV node conduction, increases refractory period
What is the half life for Digoxin and what does this mean for administration?
Half Life of 36 Hours
Long meaning a loading dose is normally required.
Unwanted effects of Digoxin?
Narrow Therapeutic Index:
Anorexia
Fatigue
Arrhythmias or heart block
When would you expect to use Digoxin?
In Atrial Fibrillation, with rapid ventricular response
Short term in heart failure with sinus rhythm.
What is heart failure?
Any condition in which the heart cannot maintain sufficient blood flow around the body to meet the bodies needs.
How do ACE inhibitors work and what are their effects?
Block the Conversion of Angiotensin I to II, blocking the RAAS pathway. They improve exercise tolerance and reduce symptoms.
What are Angiotensin Receptor blockers and how do they work?
Block AT1 receptors, which bind to angiotensin II and are probably equivalent to ACE inhibitors
Effects of Digitalis Glycosides, in heart failure?
Reduces symptoms
Increases exercise tolerance
Decreases risk of HF progression
Does not improve survival
Differences in thrombosis in arteries and in veins?
In arteries it is a streamlined shape with mostly platelets.
In veins it is mostly fibrin due to a long fibrin tail.
Antidote to heparin?
Protamine (fish protein)
What are platelets?
Non-nucleated fragments of megakaryocytes, with a lifespan of 5-9 days
What activates platelets?
Von Willibrand Factor Collagen Thrombin ADP Thromboxane
What inhibits platelets?
NO
ADPase
Prostacyclin (PGI₂)
How does LOW dose aspirin work to inhibit platelet aggregation?
Low dose aspirin inhibits COX-1.
In platelets COX-1 goes on to produce thromboxane, which promotes aggregation. Because platelets are non-nucleated this is irreversible
In the endothelium COX-1 produces PGI₂, which is anti-aggregatory, a low dose will not permanently inhibit this.
When would you prescribe low-dose aspirin?
After an MI or angina
No-prven benefits for patients without atheromatous disease
Risks associated with low-dose aspirin?
Risk of GI bleed.
What is clopidogrel?
A pro-drug, non-competitive antagonist of platelet ADP receptors, this reduces expression of gpIIb/IIIa and reduces aggregation.
When would you clinically use clopidogrel?
Prevention of MI or stroke in symptomatic patients
After MI, and if patient is intolerant of low-dose aspirin
Side effects of clopidogrel?
Severe neutropenia
GI bleeds
An example of a gpIIb/IIIa antagonist? What is it?
Abciximab, immunoglobulin against gp IIb/IIIa, short plasma half-life, Given intravenously
When would you use Abciximab?
In an angioplasty procedure.
Pharmacological treatment of acute MI?
Angelsia: Oxygen, GTN, Heroin,
Reperfusion: Clopidogrel, streptokinase (thrombolytic), Heparin
Protect myocardium: Beta blocker, ACE inhibitor,
Prevention: low does aspirin, Statin.
Mechanism of action of statins?
Inhibit HMG Co A reductase
Blocks cholesterol synthesis
Causes an increase in Hepatic LDL receptors
Less LDL in periphery as it is reuptaken by the kidney
Possible side effects of statins?
Myalgia (Muscle Pain)
Rhabdomyolysis (muscle break down)
How do Fibrates work?
Decrease synthesis of VLDL, Stimulate Lipoprotein Lipase.
Reduce Plasma TG by 20-50%
LDL decreased and HDL increased.
How does nicotinic acid work?
Reduces VLDL release leading to reduced Plasma TG and LDL.
What causes Corneal arcus and xanthelesmata?
Hypercholesterolaemia
Why is GTN taken sublingually?
Because it is inactivated in First-pass metabolism.
What is diamorphine and why is it given with cyclizine?
Heroin, cyclizine is an anti-emitic and will stop him throwing up due to the diamorphine.
Normal tests for MI?
Blood Troponin I and ECG.
What cells are present in Chronic and `Acute inflammation?
Neutrophils in acute
Macrophages in Chronic
Where is the DVT if the whole leg is swollen?
At the bottom.
What is the SOB in an Mi due to?
Pulmonary Oedema
What’s a mural thrombus?
Thrombus in actual heart
What’s Empyema?
Pus in the pleural cavity.
What’s the difference in an obstructive and restrictive lung condition?
Restrictive - Cannot fully fill their lungs.
Obstructive - Can’t get air through the bronchi.
Is emphysema Obstructive or restrictive?
Obstructive.
How do most anti-anginal drugs act?
Reducing myocardial oxygen demand.
What drug is often given at the time of an acute anginal attack? how does it work?
GTN, given sublingually, it works by mostly reducing preload, through vasodilation of the capacitance veins, can also improve collateral coronary circulation.
Prophylactic treatment of Angina?
Long acting form of GTN e.g. Isosorbide
β-Blocker e.g. atenolol, to reduce cardiac work
Non-Dihydropyridine Ca+ Channel Blocker
Dihydropyridine Ca+ Channel Blocker
K+ channel opener, will dilate arterioles.
What’s the difference in Non and Normal Dihydropyridine Ca+ channel antagonists.
A Dihydropyridine Ca+ channel antagonist will have effects on the peripheral circulation, causing arterial vasodilation.
A non-Dihydropyridine Ca+ channel antagonist will supplement these effects with actions on the cardiac muscle decreasing contractility, and on the SA/AV node slowing conduction.
Difference in angina and myocardial infarction?
Angina is due to ischaemia for a short period (20-30mins
How does aspirin work to reduce thrombosis?
It works to inhibit COX-1 in both the endothelial cells and in the platelets.
This inhibits production of thromboxane in platelets, and inhibit production of prostacylin in the endothelium.
Thromboxane: prothrombosis
Prostacyclin: platelet inhibiting (anti-thrombosis)
Platelets cannot produce anymore as they have no nucleus, however endothelial cells can produce more. if the dose is low.
Uses for diuretics?
Diabetes insipidus
Kidney stones
Polycystic ovary syndrome
Osteoporosis
Hugh blood pressure
Heart failure
Where do the CA inhibitor diuretics work?
upper PCT
Where do Osmotic Diuretics work?
PCT, thin descending limb
Where do loop diuretics work?
Thick ascending limb
Where do thiazide diuretics work?
DCT
Where do potassium sparing diuretics work?
start of the collecting tubule
How do loop diuretics work?
Inhibit the Na+/K+/Cl- resorption in the thick ascending limb of the loop of henle
When would you use a loop diuretic?
Peripheral and pulmonary oedema
Congestive heart failure.
S/E of a loop diuretic?
Osteoporosis calcium loss
Hypokalaemia
When would you use a thiazide diuretic?
Mild Heart failure
Hypertension
Oedema
may protect against osteoporosis
How do thiazide diuretics work?
Inhibit the Na+/Cl- transporter in the DCT.
S/E of thiazide diuretics?
Hypokalaemia
Hyperuricaemia (uric acid in joints - gout)
S/E of potassium sparing diuretics?
Hyperkalaemia
Hyponatraemia
How do potassium sparing diuretics work?
Aldosterone antagonists: Inhibits aldosterone and so less Na+/K+ transports on the basolateral membrane in the collecting tubule.
Potassium sparing: blocks the Na+ channels in the collecting tubule
Why do loop and thiazide diuretics cause hypokalaemia?
They block transporters that pump K+ into the interstitium.
How do carbonic anhydrase inhibitors work?
Block the H+/Na+ transporters in the proximal convoluted tubule so there is more Na+ in the lumen and less H+
How do osmotic diuretics work?
e.g. Mannitol is a non-metabolised sugar which is filtered but not reabsorbed and therefore increases the osmotic concentration of the fluid in the lumen an so increase H2O diffusion into the lumen.
