11 Renal - Done Flashcards
What is GFR?
The amount of a substance secreted into the urine/plasma conc. of the substance
What regulates GFR?
Regulated by two pathways: Intrinsic & extrinsic
What is the mean arterial pressure for the glomerulus?
70-100 mmHg to ensure safe organ perfusion
What is the equation for mean arterial blood pressure?
MAP= DP –
[1/3(SP-DP)]
What is the net pressure of the glomerulus?
10 mmHg
What are the two parts of the intrinsic pathway?
Myogenic response & tubulogloerular feedback
What is the myogenic response?
- blood pressure increases
- afferent artery stretches due to high blood flow
- activates stretch-activated sodium intracellular influx
- causes vasoconstriction of AFFERENT arterioles
What is the benefit of the intrinsic pathway?
The vasoconstriction opposes the high perfusion and reduce the damage of the glomerular capillaries which could lead to kidney disease
What is the tubuloglomerular feedback?
- increase perfusion causes increase salt perfusion (NaCl)
- NaCl is perfused into the macula densa cells through NKCC2 transporters
- once at a high intracellular conc. ATP is released from pannexin channels
- release ATP –> AMP –> adenosine
- adenosine binds to A1 receptor of extraglomerular mesangial cells
- calcium is then released to smooth muscles
- vasodialation
What are the routes of the extrinsic pathway?
Neural and hormonal
Describe the neural extrinsic pathway
- blood volume reduced
- blood perfusion reduction sensed by juxtaglomerular cells
- sympathetic nervous system activated to release NA
- constriction of afferent and efferent arterioles
- enhancing perfusion, reducing filtration and fluid loss
When GFR drops, how does the hormonal extrinsic pathway compensate?
- macula densa cells are stimulated
- they stimulate granular cells of the juxtaglomerular complex
- they release renin that activate RAAS
- vasoconstriction and reduction of blood flow occurs
- enhances perfusion
How much of the cardiac output enters the kidneys?
20%
What is the role of the intrinsic pressure?
To protect the blood vessel from high pressure
What is the process when there is high blood pressure? (Myogenic response)
High blood pressure strectched wall which will trigger sodium channels (mechanoreceptors).
Once activated they will activate voltage gated calcium channels so calcium influx.
This causes constriction, reducing blood flow
What are the two processes of the extrinsic pathway?
Neural and hormonal
What is the extrinsic response?
Outside the kidney response to high BP
Explain the neural response in the extrinsic pathway
- when the blood volume is reduced the juxtaglomerular cells sense the reduction
- sympathetic nervous system is triggered to release NA
- this constricts the afferent and efferent arteriolar
- enhancing perfusion, reducing filtration and fluid loss
What is released in the neural extrinsic pathway?
NA: noradrenaline
What are the two processes in the hormonal extrinsic pathway?
RAAS (sympathetic neural system) & arterial natriuretic peptide (ANP)
Describe the hormonal extrinsic pathway - RAAS
- GFR drops (due to bleeding or dehydration
- stimulate macular densar cells
- release of renin to initial RAAS pathway
- leads to vasoconstriction
- reduces blood flow and enhances perfusion
Describe the hormonal extrinsic pathway - atrial natriuretic peptide (ANP)
- ANP is released when there is an increase in blood volume
- this causes vasodialiation of AFFERENT arterioles, increasing renal blood flow and GFR
- filtration SA increases
- increases salt and water excretion
What does the sympathetic nervous system do for the kidneys?
Supplies renal arteries, afferent and efferent arterioles and granular cells
Reduces blood supply to kidney during stress
Explain how the sympathetic nervous system carries out its effects in the kidneys
Releases noradrenalin
- Binds to b-1 cells of granular cells causing renin release
- Also binds to a-1 receptor on blood vessels causing constriction
Explain the RAAS
Sympathetic nervous system release NA, binds to granular cells which release renin
Renin will degrade angiotensinogen into angiotensin I
It will then be converted into angiotensin II by ACE (found in pulmonary circulation or epithelial cells)
Angiotensin II will then carry out effects
What are the effects of angiotensin II?
- Adrenal glands - binds to it to induce the release of aldosterone
- When it binds to receptors on blood vessels causing vasoconstriction which will increase BP
What is the role of aldesterone?
It will go the kidneys to reduce the secretion of sodium and water, retaining it to increase blood pressure
What would the targets be in the RAAS for drugs to manage blood pressure?
1.block the conversion enzyme (ACE)
2. Block receptor of aldersterone
3. Block receptor on blood vessels via -sartans
What is the process of the hormonal pathway: ANP?
- released from atria as pro-ANP
- converted to ANP
- causes reduce sodium water excretion and cause vasodilation
- reduces blood pressure
What would cause the atria to release ANP?
expanding heart would simulate it such as overload
Explain the first step of urine formation
Glomerular filtration:
- occurs in the renal corpuscle
- filtration of unbound small molecules
What does glomerular filtration determine?
How well the kidney is functioning
Give examples of small unbound molecules
- electrolytes
- amino acids
- glucose
- metabolic waste
- some drugs
- metabolites
What can be used to measure filtration?
Creatinine clearance calculation
Square root of (weight (kg) x height (cm))/3600
Where do most of the drugs work?
At tubular reabsorption
Describe the proximal tubule reabsorption
Na is reabsorbed through NaPi channels, sodium glucose channels (mainly SGLT 2), ENaC and NaS1 into the urothelial cells
Enters blood through Na-K-ATPase
Water will follow
What occurs at the proximal tubule?
Na and water reabsorption
Explain the process of reabsorption in the Loop of Henle
NKCC2- specialised
Sodium, potassium, potassium will be reaborbed
Na-K-ATPase will be activated
Water will be reabsorbed
What diuretic will be used at the LOH and what will be the goal?
Loop diuretic - used for heart failure and resistant hypertension
Blocks the reuptake of sodium and water to prevent oedema
Describe the reabsorption of DCT?
NCC - specialised for the absorption of sodium and chloride
Water, chloride and sodium will return to blood
In the DCT, what is the importance of NHE2?
This is important to monitor due to its involvement with blood pH
What diuretic is used to at the DCT?
Thiazide like diuretics - block reabsorbed of sodium and chloride ions
What happens at the collecting duct
Mainly controls sodium and water to be reabsorbed
Sodium through ENaC channels
Water through aquaporins
What is the mnemonic for the site of action for diuretics?
MALTS
M - mannitol - PT
A - acetazolamine - PT
L - loop diuretics - LOH
T - thiazide-like diuretics - DCT
S - spironalactone/ potassium sparing - collecting duct
Describe the aldosterone effect on the collecting duct
Binds to the mineralocortoid receptor
got to neuclus
Gene expression will occur
Over expression of ENaC and influx of sodium and potassium —> reabsorbed
Water would be reaborbed too
Where is aldosterone found?
Zona glomerulosa - outermost layer of the adrenal cortex
What does aldosterone bind to once released?
Mineralocaorcoidal receptor which is a cytoplasmic receptor which takes it to the nucleus
Describe protein reabsorption in the proximal tubule
Small amounts of protein pass into the filtrate via glomerulus
- reabsorbed by pinoytosis
What does it mean if protein is found in the urine?
A sign of glomerular damage and impending renal failure
What is pinocytosis of proteins?
Vesicles transported into cell
Degraded by lysosomes
Amino acids returned to blood
Only limit is transport capacity (low Tm)
Is the reabsorption of protein dependant on Na+ reabsorption via NA-K-APTase?
No
Describe what secretion is in reference to urine formation
Removal of some protein bound drugs and metabolites, toxic and waste products etc.
What is secreted at the proximal tubule?
H+, ammonia, urea and creatinine
What would be secreted at the LOH?
Urea
What would be secreted at the distal convulated tubule and the collecting duct?
H+ and K+
What is the function of specialised pumps in the PT?
Can transport compounds from the plasma into the nephron for excretion
What are the two kinds of pumps found in the PT for excretion?
- Pumps for organic acids or acids drugs
- Pumps for organic bases or alkaline drugs
What is urine osmolarity?
Used to measure the number of roof dissolved protein per unit volume of water in the urine
What is a benefit of urine osmolarity?
It can be used in diagnosing renal disorders and assessing hydration status
What are the three methods of concentrating urine?
- Countercurrent multiplier
- Urea recycling
- Concentration via hormonal effect ADH
Explain the mechanisms of concentrating urine through hormonal effect - ADH when the body is overhydrated
- extracellular fluid osmolality decreases
- ADH secretion from the posterior pituitary gland is reduced
- increases water excretion —> increased water in urine
Explain the mechanism of concentrating urine through hormonal effect - when body the body is dehydrated
- posterior pituitary releases large quantities of ADH
- induces water reabsorption
- increases urine concentration of filtrates with less water
What can cause an increase in conc. of urine?
- dehydration
- SIADH
- adrenal insufficiency
- glycosuria
- hypernatremia
What can cause a decrease in conc. of urine?
- diabetes insipidus
- excessive fluid intake
- acute renal insufficiency
- glomerulonephritis
What causes ADH to be released?
Osmoreceptors in the hypothalamus detect an increase in the blood osmotic pressure
This initiates the release of ADH
Where is ADH secreted from?
Posterior pituitary
What is the function of ADH?
To make principle cells of the collecting duct more permeable to water by triggering the process of aquaporins to be inserted into their apical membrane
Describe the effect of ADH on the collecting duct?
- ADH will bind with V2R receptor on collecting duct
- this receptor is a G-coupled receptor so will convert ATP to cAMP
- it will activate PKA
- PKA will enter cell and initiate expression of aquaporins
- water will then enter blood making urine conc.
How does the kidneys regulate plasma pH?
Controlling H+ and HCO3- filtration in urine
What is neutral pH for plasma?
6.8-7.8
What does the kidneys do in response to to acidosis in the PCT?
- kidney wants to secrete H+ ions but maintain HCO3
- in the lumen H+ + HCO3 —> H2CO3
- luminal carbonic anhydrase (IV) converts H2CO3 into H2O and CO2 in tubular cells
- through carbonic anhydrase, it will be converted back into HCO3 and H+
- HCO3 id reabsorbed via HCO3/Cl- exchanger
- the H+ be exchanged with Na+ through Na+/H+ exchanger and H+ ATPase pumps to be secreted into urine
What does the kidneys do in response to to acidosis in the DCT?
- H+ and HCO3 are filtered through Glomerular
filtration in distal convoluted tubule, and freely react
to form H2CO3 - Luminal carbonic anhydrase type (IV) converts H2CO3
into H2O and CO2 which are generated in tubular
intercalated cells type (A) - HCO3 is reabsorbed in the blood through HCO3/Cl-
exchanger - H+ secreted in urine through Na+/H+ exchanger and
H+ ATPase pumps - H+ secreted in urine through K+/H+ ATPase pumps
What does the kidneys do in response to to alkalosis in the DCT?
Renal casePY511 Renal case
1. H+ and HCO3 are filtered through Glomerular
filtration in distal convoluted tubule, and freely react
to form H2CO3
2. Luminal carbonic anhydrase type (IV) converts H2CO3
into H2O and CO2 which are generated in tubular
intercalated cells type (B)
3. HCO3 is reabsorbed is secreted through HCO3/Cl-
exchanger
4. H+ is reabsorbed through Na+/H+ exchanger and H+
ATPase pumps and K+/H+ ATPase pumps
In uncontrolled diabetes what would be the mechanism to compensate for metabolic acidosis?
Stimulating chemoreceptors and hence
inducing hyperventilation to exhale CO2
The kidneys will excrete H+ ions, while
reabsorbing HCO3-
In severe exercise, what would be the compensating mechanism for metabolic acidosis due to lactic acidosis?
Stimulating chemoreceptors and hence
inducing hyperventilation to exhale CO2
The kidneys will excrete H+ ions, while
reabsorbing HCO3-
Why should we measure renal function?
- identification of renal impairment
- modification of dosages of drugs which are cleared by the kidneys
Who are the patients at risk of renal failure? (Will be in exam)
- extremes of age
- polypharmacy
- specific disease states
- patients receiving large amounts of long term analgesia
- transplant patients
- drug herald
- patient undergoing imaging procedures
What are the ways you can monitor a patient’s renal function?
- patient’s clinical condition (clinical assessment or use of bedside clinical data)
- modern imaging techniques (macroscopic views of renal flow, filtration and excretory function)
- biochemical data
What does biochemical data allow you to do in reference to monitoring a patient’s renal function?
Allow evaluation of the ability of the kidneys to handle water and solutes
Give examples of medication you would need to consider renal function when dosing?
- metformin
- ACE inhibitors (hyperkaleamia - leading to cardiac arrest due to high potassium)
- NSAIDs
What would be the clinical sign if vitamin D function is affected?
Osteomalacia - symptoms of bone pain
Give examples of things you would would look at when collecting bedside clinical data
- weight charts
- fluid balance charts
- degree of oedema
- results of urine dipstick testing
What is renography?
Nuclear medicine imaging test that uses small amounts of radioactivity to evaluate the function of kidneys and bladder
Why do patients with oedema complain of breathlessness?
Due to fluid buildup in lungs and may require drainage
Symptoms of low sodium?
- confusion
- stomach upset
- ECG abnormalities - palpitations
What are the blood (plasma or serum) markers of renal function?
- plasma or serum creatinine (sCr)
- plasma or serum urea or blood urea nitrogen (BUN)
What makes up plasma?
Serum + clotting proteins (e.g. fibrinogen)
What is plasma urea an indicator for?
Renal function (and failure)
Where is urea produced?
In the liver in the urea cycle as a waste product of protein digestion
Where is urea filtered?
At the glomerulus and is also secreted and reabsorbed in the tubule
A plasma urea value of > 2 mmol/L indicates what?
Moderate to severe renal function
What does BUN stand for?
Blood urea nitrogen
What increases plasma urea?
- high protein diet
- hypercatabolic conditions
- GI bleeding
- muscle injury
- drugs
What is creatinine?
The breakdown product of creatine phosphate in muscle
Describe the rate that creatinine is produced?
At a constant rate
Where is creatinine filtered?
Filtered at the glomerulus but also some secrete into the proximal tubule
What can increase plasma or serum creatine?
- large muscle mass, dietary intake
- drugs that interfere with analysis
- drugs which inhibit tubular secretion
- ketoacidosis
- ethnicity
What can decrease plasma or serum creatinine?
- reduce muscle mass
- cachexia/starvation
- immobility
- pregnancy due to increase plasma volume in the mother
- severe liver disease
What is biochemical data useful for?
- identifying renal impairment
- evaluation of the ability of the kidneys to handle water and solutes
- modifying dosages of drugs which are cleared by the kidneys
What are the requirements for an ideal maker of kidney function?
- a naturally occurring molecule
- not metabolised
- only excreted by the kidneys
- filtered by not secreted or reabsorbed by the kidneys
Describe the renal clearance for inulin
Freely filtered but not reabsorbed or secreted
Excretion rate = rate it was filtered
What is clearance?
The volume of plasma completely cleared of a given substance in a unit time
What does renal clearance compare with each other?
It compares the rate at which glomeruli filter a substance with the rate at which the kidneys excrete it into the urine
What does the measurement of the difference in the amount filtered and excreted allow in reference to renal clearance?
Allows estimation of the net amount reabsorbed or secreted by the renal tubules
Renal clearance provides information about what 3 basic functions of the kidneys?
- glomerular filtration
- tubular reabsorption
- tubular secretion
What is the ‘clearance’ of a solute?
the virtual volume of blood that would be totally cleared of a solute in a given time (ml/min)
Where do solutes come from?
Blood perfusing kidneys
What is the drawback of measuring renal clearance?
- by measuring clearance means measurement of overall nephron function
- this gives sum of all transport processes occurring along nephrons
- but no information about precise tubular steps or mechanisms of process
What is GFR?
The rate at which filtrate is produced in the kidneys (180 L/day)
What can GFR be used for?
Can be measured clincally and used as an indicator of renal function
How can GFR be estimated?
By measurement of clearance of CREATININE ie. Creatinine clearance
What is the limitation of using creatinine clearance to measure GFR?
It is filtered and secreted into the tubule thus not an accurate estimation
What would be a more accurate estimation of GFR rather than creatinine and why?
Inulin:
filtered but not secreted into tubule
What is inulin?
A plant polysaccharide
If a substance has a clearance greater than inulin, then it must be ____
Secreted
If a substance has a clearance less than inulin, then it must be being _____
Reabsorbed or not littered freely at the glomerulus
Why do we not use inulin to calculate GFR?
It has to be administered via IV
Difficult to analyse due to being technically demanding
What is the limitation with the colorimetry methods used to measure creatinine?
Underestimates creatinine conc. by abut 20%
What is the advantages of creating clearance?
- cheap, easy, reliable
- used clinically
- avoids IV infusions (requires venous blood and urine sample)
What must you take into account when analysing creatinine clearance?
- if he person has muscle disease/damage
- has had large quantities of meat to eat
How long do you measure creatinine clearance over to get reliable results?
Over 24 hours period
When can creatinine clearance be adjusted?
It can be adjusted to take into account body surface area which produces a corrected CrCl (GFR) in ml/min/1.73m2
What does estimation of GFR using plasma creatinine only allow?
Allows estimation of GFR without having to collect urine samples
What is the kidney function at stage 1 of kidney disease?
Normal kidney function
What is the kidney function at stage 2 of kidney disease?
Mildly reduced kidney function
What is the kidney function at stage 3 of kidney disease?
Moderately reduced kidney function
What is the kidney function at stage 4 of kidney disease?
Severely reduced kidney function
What is the kidney function at stage 5 of kidney disease?
Very severely reduced kidney function
What condition can produced a measurement of serum creatinine which is higher than the normal expected baseline?
Ketoacidosis
What is hyperkalemia?
High potassium levels in blood
What occurs at the distal convulated tubule?
SECRETION of ions, drugs, metabolites, acids and toxins
REABSORPTION of water, na+ and Ca2+ (hormone controlled)
What occurs at the Bowman’s capsule?
Production of filtrate?
Where do carbonic anhydrase diuretics work?
Mild diuretic that works in the proximal convoluted tubule?
Where would you find NCC and what do they do?
They are found in the DCT and transport Na and Cl
Upregulation of NCC can cause what?
Hypertension which makes it a viable target for hypertensive medication
What channel does thiazide diuretic target?
The NCC channel as it is the main channel in the DCT leading less Na in the urothelial cells
Why would you not target other channels in the DCT when tackling hypertension?
Because you want to bring function back to baseline
Explain how thiazides carry out their function
- inhibit NCC channels
- causes the intracellular conc. of Na in the urothelial cell to decrease
- as a result the cell activates calcium-sodium exchange between the blood/interstitial fluid and urothelial cell
- bringing in sodium from the blood to compensate the lack of ions
How does thiazide diuretics cause hypokaleamia?
- Na+ will be filtered and go through different points it can be reabsorbed but when it reaches the DCT where it is mainly reabsorbed, the process has been inhibited
- it will then go to the collecting duct and the urothelial cells will detect high level in urine
- it will start a conc. gradient to reabsorbed as much sodium as it can via Na-K-ATPase
- however we have a limited amount of ENaC therefore it an not all be reabsorbed and the patient has hyponatremia, hpokalemia and and less water
What are the cautions of thiazide diuretics?
- risk of gout (uric acid increase)
- risk of diabetes
What need to be monitored when taking thiazide like diuretics?
Monitor electrolytes
What are the side effects of thiazide diuretics?
Electrolyte imbalance
Hyperglycaemia
Hyperuricaemia
Postural hypotension
Why is there a risk of diabetes with thiazide diuretics?
In the pancreas there are beta cells
We are loosing potassium from the interstitial fluid surrounding the beta cells
The cells start leaking potassium lowering the action potential
They will then not be stimulated to release insulin use to not meeting threshold to release calcium
Thus diabetes
What are the indicators of thiazide like diuretics?
Oedema and hypertension
In heart failure and/or hypertension what happens to the level of NKCC2?
Increased making them viable targets for Loop diuretics
Why is there a risk of hypokalaemia when taking Loop diuretics?
We are blocking sodium, chloride and potassium
We are loosing potassium via two ways
What is the mode of action of Loop diuretics?
K, Cl and Na will not be reabsorbed by NKCC2
Water will not be taken up either
- sodium will remain in the urine
- it will then go to the collecting duct and the urothelial cells will detect high level in urine
- it will start a conc. gradient to reabsorbed as much sodium as it can via Na-K-ATPase
- potassium will leave urothelial cells via ROMK
- however we have a limited amount of ENaC therefore it an not all be reabsorbed and the patient has hyponatremia, hpokalemia and and less water
What are the cautions of loop diuretics?
- risk of gout
- diabetes
- hyokalaemia
What must you monitor when taking loo diuretics?
Eletrolytes
What are the common side effects of loop diuretics?
- electrolyte imbalance
- metabolic alkalosis
- muscle spasms
Why are potassium sparing diuretics given the name?
They are given alongside other diuretics to inhibit ENaC or ATPase to keep potassium in the urothelial cells preventing hypokalaemia and preventing the loss of potassium in the urine
What are the two subclasses of potassium sparing diuretics?
Aldosterone antagonist and Na+ channel blockers (NCB)
Give an example of aldosterone antagonist diuretics (potassium sparring)?
spironolactone
-one suffix
What happens if you block aldersterone receptor?
- aldosterone can still be released but it will not have anywhere to bind to
- mineralcotocoid receptor is free thus nothing will be expressed
- this will keep the Na+ in the tubule dragging water by osmosis
- It will spare the Na+ in the blood avoid cardiovascular risk of arrhythmia because of hyperkaleamia
Explain the mode of action of NCB (Na+ channel blockers)
- they let aldosterone bind with mineralcoticoid receptors and carry out expression of ENaC channels
- HOWEVER, it will then inhibit the ENaC channels preventing the intake of Na preventing the risk of hypokaleamia
What are the indicators of potassium sparring diuretics?
- oedema
- hypertension
- primary aldosterone
- nephrotic syndrome
- in combination with other diuretics
What are the cautions of potassium sparing diuretics?
- diabetes mellitus
- gout
- may cause blue fluorescence of urine
What must you monitor with potassium sparing diuretics?
Electrolytes
What are the side effects of potassium sparing diuretics?
- diarrhoea
- hyperkalaemia
- gynaecomastia
Why would potassium sparing diuretics result in hyperkalaemia?
it prevents sodium secretion resulting in a build up thus taken in conjunction with another diuretic
Where does potassium sparing diuretics work?
In the distal convoluted tubule
Sodium glucose co-transport inhibitors induce what and why?
Induce diuresis due to inhibiting one of the minor sodium reabsorbing transporter but major glucose transporter - SGLT2
Where does Sodium glucose co-transport inhibitors carry out their function?
Proximal tubule and loop of Henle
How does SGLT2 inhibitors works?
If we block the SGLT2 (major for glucose reabsorption), glucose has osmotic effect and will have an effect on water keeping it in urine as it is not being reabsorbed.
Why is SLGT2 inhibitors inconvenient for diabetic patients?
- if they take it after 3pm, they cannot sleep as the drug conc. will peak in the night causing them to need to urinate often so advise them to take it in the morning
What are the indications of SGLT2 inhibitors?
Diabetes
Heart failure
CKD
What are the contraindications of SGLT2 inhibitors?
- diabetic ketoacidosis
- T2D
Give an example of a loop diuretics?
Furosemide
What are the cautions of SGLT2 inhibitors?
- UTI
- Hypovolemia
What must you monitor when taking SGLT2 inhibitors?
- Ketones
- Kidney function
What are the side effects of SGLT2 inhibitors?
- balanoposthitis - inflammation of the glans penis
- constipation
- hypoglycaemia
- hypovolaemia
- increased risk of infection
- thirst
why is there an increase risk of UTI when taking SGLT2 inhibitors?
Increase in glucose
When is osmotic diuretic used?
Emergency cases of oedema eg. Cerebral oedema in haemorrhage
Explain the mechanism of osmotic diuretics
- actively filtered (freely)
- stays in nephron and is highly osmotic
- thus it will drag water via osmosis
- it prevents fluid reabsorption from the glomerular filtrate + interstitial fluid and produced diuresis
Give an example of osmotic diuretic
Mannitol
Why would osmotic diuretics be useful in situations where a patients is at risk of onset of acute renal failure or in situations of oliguria/anuria ?
It promotes urine flow
What are the indications of mannitol?
- oedema (cerbral)
- intraocular pressure (glaucoma)
- cystic fibrosis (inhaler)
What are the contra indicators of mannitol?
Anuria (IV)
What should you monitor when taking Mannitol?
Electrolytes
What are the side effects of mannitol
- cough
- headache
- vomiting
What is the function of carbonic anhydrase?
It will control and regulate pH in the proximal convulated tubule
How does carbon anhydrase inhibitors work? Mode of action
If we inhibit carbonic anhydrase, we keep sodium in the lumen and water will follow.
What are the indicators of carbonic anhydrase inhibitors?
Glaucoma
Epilepsy
What are the contra indicators of carbonic anhydrase inhibitors?
Andrenocortical insufficiency
Hyperchloraemic acidosis
Hypokalaemia
Hyponatraemia
What are the cautions of carbonic anhydrase inhibitors?
- diabetes mellitus
- renal calculi
What must you monitor when taking carbonic anhydrase inhibitors?
Electrolytes and blood count
What are the side effects of carbonic anhydrase inhibitors?
- metabolic acidosis
- nephrolithiasis
What can be used to treat glaucoma?
Carbonic anhydrase inhibitors & osmotic diuretics (old fashioned)
What is glaucoma ?
Raise in intraoccular pressure
What glands can you find in the eyelids?
- Meibomian glands
- Glands of Zeis
- Glands of Moll
What does the Meibomian glands secrete?
Sebaceous gland secreting the outer lipid layer if the precorneal tear film, preventing evaporation
What does the glands of Zeis secrete?
Modified sebaceous glands producing an oily substance that lubricates the hair follicle of the eye lashes
What does the glands of Moll secrete?
Secretions provide defensive roles through its bacteriolytic enzyme lysozyme, mucin 1 and immunoglobulin A
What is the function of spontaneous blinking?
It ensures the distribution of the tear film
What is the role of the tear film and what 4 things does it provide?
To maintain constant lubriction of the lid margin and provide:
1. Maintenance of an optically uniform corneal surface
2. Cleaning and lubrication via flushing the cornea and conjunctiva
3. Providing oxygen and nutrients to the cornea
Providing antibacterial protection
Where is drainage from the tear chambers done?
Via the superior and inferior punctuation lacrimal and canaliculi
The lacrimal gland is part of what?
The upper part of the nasolacrimal duct (tear duct)
Tears flow down the nasolacrimal duct due to what?
Gravity
Although, blinking also has a pumping effect
How is reflux of tears prevented?
Internal valve system
What is the conjunctiva?
A thin transparent mucous membrane covering the front portion of the eye (except the cornea)
Is the conjunctiva vascular?
Yes but the vessels are constricted and not apparent but they dilate when there is inflammation or irritation
The conjunctiva contains numerous 1. _______ cells which secrete the 2. _____ _____ of the tear film to add 3. _________
- Goblet
- Mucoid layer
- Lubrication
Where does the lymphoid tissue lie in reference to the conjunctiva?
They lie immediately under the conjunctival epithelium
What is the sclera?
The whites of the eye
- tough, collagenous layer BENEATH the conjunctiva
What is the function of the sclera?
Provides rigidity and normal optical function
What does the sclera blend with?
With the cornea at the limbus
The blood supply of the sclera is provided by?
- Blood vessels from the choroid (internally)
- Blood vessels from he conjunctiva (externally)
What is the episclera?
A thin membrane that lies between the conjunctiva and the sclera
What is the cornea?
It is a curved epithelial multilayer, transparent and a vascular tissue rich in collagen (tough) and extracellular matrix
What does the cornea allow to happen (function)?
Allows light rays to enter the eye and become focused as an image on the retina
How is the cornea kept healthy?
Substrates ad oxygen are provided through?
1. Lumbar blood vessels beside sclera
2. From the front of the cornea from tears
3. From behind the cornea via aqueous humour
Why is the cornea sensitive to touch?
Because of the ophthalmic fibres of the trigeminal nerve
Where in the eye does a glaucoma take place
In the anterior chamber - aqueous humour
What does the anterior chamber of the eye contain?
Crystal clear fluid called the aqueous humour
What is the function of the aqueous humour?
- Maintain intraocular pressure to retain the corneal optical shape
- Nourished the lens and cornea
Where does aqueous humour drain through?
- Canal of Schlemm
- Trabecular mesh work and the episceral veins
- Smaller portion via the uveoscleral pathway
What does the iris consist largely of?
Connective tissue containing smooth muscle fibres, blood vessels and pigment cells
Why does the iris control the light entry into the eyes?
It can:
1. expand to contract the pupil - MIOSIS
2. Contract to dilate the pupil - MYDRIASIS
What is miosis of the eye?
Expansion of the iris to constrict the pupil
What is mydriasis?
Contraction of the iris to dilate the pupil
What is mydriasis?
Contraction of the iris to dilate the pupil
What is the normal intraocular pressure of the eye?
10-21 mmHg
Glaucoma is the leading cause of what?
Irreversible vision loss
Explain how glaucoma can cause vision loss
- increased intraocular pressure can cause mechanical stress and strain on the posterior structures
- this leads to damage of axonal transport in the optic nerve fibres
- thus degeneration of the optic nerve and loss of vision
What are the two main types of glaucoma?
- Open angle glaucoma
- Closed angle glaucoma
What is the problem with glaucoma? What is it caused by?
There is an imbalance between secretion of aqueous humour by the ciliary body and its drainage mainly through the canal of Shlemm and trabecular mesh work.
What is the difference between open and closed angled glaucoma?
In open angle glaucoma, the eye drainage is clogged while in close-angle glaucoma, the eye drainage is blocked by the iris
Both result in an increase in intraocular pressure.
Open-angle glaucoma is gradual which close-angle glaucoma causes a sudden spike in pressure
What are the two routes to treat glaucoma?
Either decrease aqueous humour synthesis or increase aqueous humour drainage
How would you decrease aqueous humour synthesis to treat glaucoma?
Using:
- beta blockers (sympathetic)
- alpha-2 agonists (sympathomimetic)
- carbonic anhydrase inhibitors
How does carbonic anhydrase inhibitors reduce aqueous humour synthesis to treat glaucoma?
- Inhibit the formation of bicarbonate
- Which will reduce the sodium (and chloride) influx into the ciliary body
- Therefore, reducing sodium secretion into the anterior chamber
- Hence reducing the water flow - by reducing osmotic effect of sodium - and reducing aqueous humour formation
How is aqueous humour formed using carbonic anhydrase?
- H2CO3 converted to H2O + CO2 by CA (IV)
- it is then converted to HCO3- and H+ ions
- Sodium- hydrogen exchanger sends H+ ions into the stroma and Na+ enters the pigmented epithelium
- Chloride-carbonate exchanger moves Cl- into the pigmented epithelium and HCO3- into the stroma
- there is now a gradient between the pigmented and non-pigmented epithelium and Na+ moves across
- this then activates Na-K-ATPase, sodium will move into the aqueous humour dragging water with it
- building up the aqueous humour
Where is aqueous humour synthesised?
Ciliary body
What switches on aqueous humour synthesis
Noradrenaline
What switches on aqueous humour synthesis
Noradrenaline
Explain the process of noradrenaline when activating aqueous humour synthesis
- noradrenaline binds to beta receptor (B2)
- the beta-2 receptor becomes activated and activates an alpha subunit
- the alpha subunit activates adenylyl cyclase which will then activate protein kinase (PKA)
- PKA will go on to to activate Na-K-ATPase
- Sodium will enter the anterior chamber, dragging water to form the aqueous humour
If the aqueous humour fluid has increased, how do you turn on its synthesis?
- noadrenaline also bind to the A2 receptor which will turn this process off
-It does this by inactivating adenylyl cyclase which means protein kinase is not active, no more exchange and no more sodium transported to the anterior chamber
What is timolol in regard to glaucoma treatment?
Non-selective beta antagonist that reduces the synthesis of aqueous humour
How does beta blockers work in the treatment out glaucoma?
It works by blocking the B2 receptor preventing noradrenaline from binding, stopping the synthesis of aqueous humour
What is bromonidine in the treatment of glaucoma?
An A2 agonist that reduces the synthesis of aquaous humour.
How would A2 agonists treat glaucoma (mode of action)?
Binds to A2 receptors to turn off adenylyl cyclase which means the synthesis of aqueous humour would stop
How would you increase drainage to treat open angle glaucoma?
- mannitol (osmotic diuretic)
- prostaglandins analogues (-Prost suffix)
- mitotic drugs
How does mannitol treat gluaucoma?
Increases the blood plasma toxicity
- this draws water out of the eye’s vitreous humour and into the intravascular space
How would you treat closed angle glaucoma?
Surgery
Closed and open angle glaucoma refer to ______ issues of the aqueous humour
Drainage
What are prostaglandins F2a analogues?
They are selective agonists for prostanoid FP receptors located on the UVSC and canal of Schlemm
What is the mode of action of prostaglandin F2a analogues?
- they bind to prostanoid FP receptors
- in response they widen the canals
- this increases the outflow of aqueous humour
What would be the expected symptoms of using prostaglandins?
- Blood pressure changes
- impact on kidney function
- stomach pain
Give an example of a mitotic drugs used in the treatment of glaucoma
Pilocarpine 1,2 and 4% - a topical mitotic drugs used
How does Pilocarpine 1,2 and 4% work to treat glaucoma?
induces ciliary muscle contraction by binding to the muscurinic receptor (M3) and hence pupil constriction and miosis that increase the outflow of aqueous humour
What receptor does Pilocarpine bind to to carry out its effect?
M3 - muscarinic recept
What is the limitation of pilocarpine?
Patient wont be able to see far due to lens becoming thick =
What is the definition of bactriuria?
Presence of bacteria in urine > 10 to the power of 5 cfu/mL
What is asymptomatic bacteria?
Bacteriuria in apparently healthy people with no associated symptoms
Bacteriuria is common in what groups?
> 65 years old
People with urinary catheters
Does bacteruria alone get treated in asymptomatic patients?
No, except pregnant woman
What are the risk factors for Bacteriuria?
- increased prevalence in women
- sexual activity
- older age
- co-morbidities
- residence in nursing or care homes
- urinary catheter
- pregnancy
What are the types of UTI?
Lower and Upper
Why is the term used for upper UTI?
Pyelonephritis
Why would you not treat bacteruria in patients with catheters?
Because it is an opening so you would expect bacteria present
Why are women more susceptible to Bacteriuria?
Because they have shorter urethra than men
How else can UTIs be classified?
Uncomplicated and complicated
How long is the treatment for men for UTIs and why?
7 days which is longer than women because urethra is longer so the bacteria can travel longer causing more severe infection
Describe uncomplicated UTIs
The anatomy of the urinary tract is normal and there is no underlying condition contributing to infection
Less likely to result in serious kidney damage
Compare uncomplicated and complicated UTIs
- Uncomplicated UTIs have NORMAL anatomy of urinary tract while in complicate the anatomy is NOT STRUCTURALLY NORMAL, or may a have a metabolic or functional problem
- Uncomplicated UTIs are more common in WOMEN while complicated is more common in MEN due to long urethra
Are most lower UTIs complicated or uncomplicated?
Uncomplicated
Why would kidney stones result in a complicated UTI?
Kidney stones block the flow of urine in the urethra, and an cause damage leading to scars which lead to infection
What is the key issue of complicated UTIs?
The increase risk of treatment failure
Describe UTI pathogens
Almost always bacterial - commonly commensal bacteria of the GI tract or genitalia
Fungal UTI infections are possible especially with immunosuppressed patients
What is the most likely pathogen cause of a UTI?
E.coli - gram -ve bacteria (>70%)
What are the common signs and symptoms of LUTI? (Lower urinary tract infections)
- dysuria (pain)
- frequency
- urgency
- polyuria
- fever
- haematuria (blood)
- offensive smell
- elderly: behavioural changes, confusion
What are the common signs and symptoms of upper urinary tract infections?
Loin pain (very severe) MAIN SYMPTOM TO DIFFERENTIATE BETWEEN UPPER AND LOWER UTI
Abdominal tenderness
Often unwell and require hospital treatment
What are the three main ways we diagnose UTIs?
- Urine dipstick - initial screen simple
- Mid-stream Urine (MSU) - increased likelihood of obtaining pure culture
- Signs and symptoms
In a dipstick test, what would you be looking at to be present do diagnose a UTI?
The presence of leukocytes, nitrites and blood which is indicative of a UTI
What are the advantages of a urine dipstick test?
- cheap
- easy to use/conduct
- non invasive
- simple initial test
- easy to interpret
- doesn’t require technical skill
What does the presence of nitrites in a urine dipstick indicate?
The presence of gram -ve bacteria
What are the disadvantages of a urine dipstick test?
- very crude
- non specific
- patient may be unable to urinate
- need further testing to confirm
What is the caution about using a urine dipstick test?
It cannot be used in isolation and you will need further testing to confirm diagnosis e.g MC&S test
How would a clean catch MSU test be conducted?
- you would let urine flow at first, hold for a second before resuming the stream in a cut of sample bottle.
- ensure that there is no contamination from normal flora around the genitals
What does ‘clean catch’ refer to in a clean catch MSU and how can you make sure that it is done right?
You avoid contamination of the sample from the normal flora around the genitals and this can be done by cleaning extensively the genitals with a wipe before urinating
What is the benefit of clean catch MSU?
It obtains a purer culture
What is the relevance of signs and symptoms when diagnosing a patient with a UTI?
It is essential when diagnosing an infection as it allows other clinical markers to be checked (eg. Fever and FBC)
And helps paint better clinical picture
What are the principles of UTI treatment?
- only treat if symptomatic or pregnant use to risk of miscarriage
When might you switch antibiotics?
Per microbiology results if bacteria are resistant using narrow spectrum antibiotic if possible
What is the usual treatment duration for LUTIs for men, pregnant women and non-pregnant women?
Men: 7 days
Pregnant women: 7 days
Non-pregnant women: 3 days (unless complicated)
What are the steps in treating infections?
- Look @ the local empirical guidelines
- Look @ first-line recommended treatment ensuring it is appropriate
- Select the best drug(s), route, dose and duration
- Monitor
- Review when MC&S results are available
What are the mot common drugs used to treat UTIs?
Nitrofurantoin (LUTI) - first line
Trimethoprim (LUTI) - used to be but now there is resistance
Pivmecillinam (penicillin) narrow spectrum for gram -ve
Methanamine hippurate
cephalosporins
Give an example of a UTI drug that is narrow spectrum for gram negative bacteria
Pivmecillinam
What common drugs used to treat UTIs should you avoid for a patient with penicillin allergies?
Cephalosporins (cross reaction) and pivemcillinam
What is the first line treatment for LUTIs?
Nitrofurantoin- broad spectrum, bactericidal and is active against E.coli and many other likely gram -ve bacteria
How does Nitrofurantoin work?
interferes with bacterial RNA/DNA synthesis
What is Nitrofurantoin not effective against?
Pseudomonas - resistant
Describe the bioavailability of nitrofurantoin
Absorbed from GIT
Bioavailability is not great but the drug conc. very well in urine
40% excreted unchanged in urine
When would you avoid using Nitrofurantoin and why?
When eGFR <45 mL/min because of peripheral neuropathy & antibacterial efficacy depends on renal secretin urinary tract
May be used with caution if eGFR 30-44 mL/min as a short-course only (3-7 days) for uncomplication LUTI caused by suspected or proven multidrug resistant bacteria and only if potential benefit outweighs risk.
When you’re on long-term therapy of nitrofurantoin what must you monitor?
- liver function
- pulmonary symptoms
Especially elderly
What are the two main reasons why you cannot give Nitrofurantoin to patients with an eGFR of <45 mL/min? (3 marks)
- because eGFR is below 45 mL/min
- risk of peripheral neuropathy
- antibacterial efficacy depends on renal secretion into urinary tract
What is trimethoprim?
Broad spectrum, bacteriostatic
- used to treat LUTI
How does trimethoprim work against LUTIs?
Interferes with bacterial folic synthesis
- inhibits dihydrofolate reductace enzyme
- this blocks the reduction of dihydrofolic acid to tetrahydrofolic acid
What drugs for UTIs are pseudomonas resistant against?
Trimethoprim & Nitrofurantoin
Why is trimethoprim limited in use against LUTIs?
Due to increasing resistance and you would avoid or reduce dose in renal impairment where eGFR is less than 30 mL/min
What is meant by bactericidal?
kills the bacteria
What is meant by bacteriostatic?
Stop it from producing so immune system has to get rid of them
What would you monitor in patients who are taking trimethoprim for LUTIs?
- blood counts (long term use or risk of folate deficiency)
- serum electrolytes
- renal function
- plasma trimethoprim conc. in long term use
What are the second line options for LUTIs?
- beta-lactams (co-amoxiclav)
- aminogycosides (gentamicin)
- quinolones (ciprofloxacin)
Also used in UUTI in combination with
What must you make sure when patients take pivecillinam?
It is irritating to the stomach so make sure they sit up right or stand up and take it with water
Caution if they have history or stomach ulcer.
What is Pivmecillinam and how does it work?
Bactericidal which interferes with eh biosynthesis of the bacterial cell wall
-penicillin type
- gram negative narrow spectrum
- for LUTI
What must you monitor when taking Pivmecillinam?
Liver and renal function when in long term use
What is the mechanism of fosfomycin?
expected response - inhibits the production of peptidoglycan
Bactericidal
- inhibits enzyme phosphoenolpyruvate transferease and formation of N-acetylmuric acid
What is fosfomycin used for?
Broad spectrum for LUTIs
What is N-acetylmuramic acid essential for?
For making peptidoglycan which a necessary component of the bacterial cell wall
If you give fosfomycin via IV, what must you do?
Monitor electrolyte and fluid balance
What advise should you give when taking fosfomycin?
Take at night or when emptying bowls.
Granules should be taken on an empty stomach
Once granules are dissolved into a glass of water, they should be taken immediately
When might you prescribe Methenamine hippurate?
in patients who have long term prophylaxis or treatment of chronic or recurrent LUTIs
But otherwise less suitable for prescribing
What is the limitations of methenamine hippurate?
Requires an acidic urine for its antimicrobial activity but it is ineffective for UTIs
UTI in pregnancy is considered as a _______ infection
Complicated
Why would you treat UTIs in pregnancy even if they are asymptomatic?
- high risk of developing pyelonephritis
- risk of complications as a result so it is advised to eradicate Bacteriuria to reduce it
A catheterised man present with a positive urine dipstick test with no symptoms.
Would you treat this patient?
No
Catheterised patients are expected to have bacteria, so you would not treat them unless they had symptoms.
What are the forms and doses of nitrofurantoin?
Immediate release and modified release
MR dose: 100mg BD
IR dose: 50mg QDS
What is micturition?
The process of emptying the bladder
What initiates the micturition reflex?
Initiated upon the stretch of the bladder
What is dysuria?
Painful (usually burning pain) and/or associated in urination which is associated with urges and pollakisuria
What are urges in reference to micturition?
The strong sudden need to urinate which is difficult to delay as a result of the micturition reflex
What is pollakuria?
Increased frequency of micturition as in UTI
Where is the micturition reflex integrated in infants and adults?
Infants: integrated in the spinal cord
Adults: integrated in the brainstem and become voluntary at the age 2-3 years old
When is urine is a useful sample?
for basic diagnosis such as:
- infection
- substance misuse
- doping
- PK studies
- assessing kidney function
What does the bladder store?
The accumulating urine
What is the initiation of voiding influenced by?
The perceived sense of bladder fullness
A conscious decision
What are the 3 major areas in the CNS controlling micturition?
- The sacral micturition centre
- The pontine micturition centre
- The cerebral cortex
What is the role of the sacral micturition centre in controlling micturition?
Coordinates bladder and sphincter activity
What is the role of the pontine micturition centre in controlling micturition?
Acts as a relay and switches the bladder between storage ad voiding modes
What is the role of the cerebral cortex in controlling micturition?
- inhibits the sacral centre
- provides conscious input to the pontine centre, activating the micturition reflex when required
What are the two main phases of bladder function?
- Urine storage phase
- The voiding phase
Describe the Pathway of filling of the bladder (muscle walls)
- when we have an empty bladder, it gives signals to brain to tell it that is empty
- the brain send instructions to the bladder to close the sphincter and relax the muscle walls.
-The brain via presynaptic neurones will release ACh which will bind to a nicotinic receptor
The nicotinic receptor will activate the postsynaptic adrenergic neurones - they will release noradrenaline which ill bind to B3 receptors
- this will inhibit contraction and relax the smooth muscles in the bladder
Describe the Pathway of filling of the bladder (closing the internal sphincter)
- when we have an empty bladder, it gives signals to brain to tell it that is empty
- the brain send instructions to the bladder to close the sphincter and relax the muscle walls.
- ACh is released and will bind with the nicotinic receptor of the postsynaptic receptor
- that will activate the adrenergic receptor
- it would then release noradrenaline which will bind to A1 receptors which would cause constriction of the internal sphincter
What are the two muscles of the sphincter?
Internal and external muscles
What controls the internal muscle of the sphincter?
Adrenergic sympathetic nervous system
What type of muscle is the external urethral sphincter?
A voluntary skeletal muscle and has a M3 receptor
M3 receptor for the external sphincter is activated by many neurotransmitters.
Give examples and what neurone do they activate?
- noradrenaline
- seratonin
- glutamate
And they activate the on-off neurone
How is the external sphincter activated?
- neurotransmitters, such as noradrenaline, activate the on-off neurone
- it will release ACh which will bind onto M3 which is found on the external wall of the sphincter
- this will aid the internal sphincter to close the bladder by constricting
When the bladder is filled, what receptor will be activated?
Stretch
What is the process of emptying the bladder in reference to GABA?
- stretch receptors will be activated once bladder is full —> activate neurones going to the CNS telling brain it is full
- interneurones in spinal cord will get activated by CNS
- GABA will be released and will bind to GABA-B receptor which will EFLUX potassium positive ions
-this will bring the membrane potential down
-repolarise and hyper polarise the membrane - this will inhibit the nucleus, preventing signalling
- no constriction of the external sphincter
- when GABA binds with GABA-A receptors on the adrenergic neurone, influx chloride ions, reducing membrane potential, leading to passive relaxation of the internal sphincter
How does the detrusor muscle aid emptying the bladder?
- the brain will realease ACh
This will activate the nicotinic receptor of the parasympathetic pathway
-this will release ACh which would bind onto the muscarinic receptor, M3 - this will cause constriction of the muscle emptying the bladder
What is GABA?
An inhibitory transmitter
What are the two aims to treat an overactive bladder?
- to block the M3 receptors OR agonise B3 receptor
- this will increase capacity of the bladder for urine and prevent constriction of the bladder wall muscles
What are some of the non-pharmacological treatments of overactive bladder?
- reduce caffeine intack
- losing weight
- bladder training
- pelvic floor muscle training - Kegel exercises
What are the pharmacological treatments of an overactive bladder?
- antimuscarinc drugs (anticholinergic)
- B3 agonist
Give examples of antimuscarinc drugs for the treatment of an overactive bladder?
-fenacine
Darifenacine, fesofenacine, solifenacine
Oxybutynin
What is mirabegon?
A B3 agonist used in the treatment of an overactive bladder
How do antimuscarinc drugs work to treat an overactive bladder?
They bind to B3 receptors as a M3 antagonist preventing ACh from binding and stimulating contraction of the detrusor muscle
This will abuse passive relaxation and prolong the filling phase
How does a B3 agonist work to treat an over active bladder?
We don’t have enough neurones to release enough noradrenaline to bind to B3 receptors
Mirabegron acts as noradrenaline, binding to B3 receptors
Which has a better effect and affinity and will induce relaxation to the detrusor
What must you consider when treating a patient with an overactive bladder?
Patient’s Age
Because of ACB (anticholinergic burden) caused when there is anticholinergic activity of multiple drugs that add up the ACB
If you antagonise ACh, this can lead to increase risk of cognitive impairment
> 67 years may not be the preferred group for anticholinergic drugs
Why are the elderly at risk of ACB (anticholinergic burden)?
- Increased permeability of the BBB
- Age related deficits in central cholinergic transmission
- Decreased drug metabolism and elimination
What does a score of 3 on the ACB calculator mean?
There is a high likelihood of the patient having complications if put on anticholinergic drugs
What is a caution of taking anti muscarinic drugs?
Anticholinergic burden - ACB
What effects would first generation antihistamines/TCA?
Have anticholinergic effect
- patient would complain of difficulty peeing and emptying bladder as muscarinic receptors M3 would be blocked, there is no contraction of the bladder
What is the effect of benzodiazepines of the bladder?
Mimic GABA
Leads to urinary incontinence
What forms a major pathway for renal elimination of small hydrophilic cationic drugs/
hOCT2 and hMATE1/2-k
What is hOCT2?
An organic cation transporter
Explain the mechanism of organic cations removal?
- in blood then enters urothelial cells via hOCT2
- enters urine from urothelial cells via hMATE which is an exchanger, exchanging it with H+ ions
Give an example of an organic cation
Metformin
Where is metformin eliminated?
Eliminated unchanged by the kidneys
What is Pyrimethamine?
A selective inhibitor of hMATE1/2-k with slight inhibition of hOCT2
What would happen to metformin in blood is hMATE1/2-k or hOCT2 was inhibited? (Drug-Drug interaction)
- build up of conc. of metformin in blood as it is not being secreted
Leading to overdose
Thus you would not take malaria drugs and some anti-HIV medication
What drug-drug interaction should you be cautious of when taking metformin?
Malaria medication and some anti-HIV medication due to their ability to inhibit hOCT2 and hMATE1/2-k transporters which are important in the elimination of metformin. It can lead to overdose and toxic effects
Is methotrexate a cation or anion?
Anion
What transporters are used to eliminate methotrexate?
hOAT 1 & 3 and MRP 2 & 4
What are MRPs?
Multi-drug resistant- associated proteins are membranes proteins involved in transporting rugs outside of the cell
What are the drug-drug interactions you should be caution of when taking methotrexate?
Avoid NSAIDs and penicillin
Blocks/inhibits the hOAT1 & 3 and MRP2 & 4 transports
Methotrexate cannot be eliminated so it builds up conc. in the blood leading to toxicity
What is digoxin used for
Heart failure & arrhythmias
What transporters are used to eliminate/secrete digoxin?
P-gp (activated by ATP) and hOAT
What is P-gp?
P-glycoprotein (P-gp) is an effluent pump that actively exports hydrophobic drugs int the urine
What drug-drug interactions should you be cautions of with digoxin?
Quinine, verapamil, clarithomyocin & herbs such as curcumin
- inhibit P-gp, Leading to Digoxin toxicity
What do NSAIDs do?
Block COX pathway, reduce prostaglandin release
Prostaglandins are inflammatory mediators causing vasodialation
As a result, NSAIDs reduce blood flow
Prostaglandins stimulate 1. ___ release which then stimulates 2. ___ release
- Renin
- Aldosterone
Why would a patient on digioxin and NSAIDs have hyponataemia ?
We are blocking aldosterone pathways via NSAIDs resulting in sodium to be secreted
What is the concern when taking lithium with thaizides?
In DCT:
Lithium excretion is influenced by changes in sodium this high excretion of sodium (via thiazides for example) may increase lithium reabsorption causing serious efffects
How dies caffeine induce diuresis?
- blocks Adenosine1 receptors in the afferent neurone, keeping the afferent arterioles dilated so more blood is filtered leading to frequent urination
What are the three classifications of drug-induced renal failure?
- Pre-renal (NSAIDs, diuretics)
- Intra-renal (Thiazides, Allopurinol)
- Post-renal ( analgesics causing nephropathy, anticoagulants)
What is the first line-treatment for a patient with a GFR of 15mL/min who requires diuretic
therapy?
Bumetanide 5mg PO; OD
What 3 things must you consider when prescribing the right drug for a patient?
- does the drug work = efficacy
- can the patient tolerate the drug = safety
- how does the drug fit the lifestyle of the patient
It is important to diagnose CKD early. Why?
- prevention or slowing down of progression to renal failure
- adequate time to prepare patient for dialysis/ treatment
- better and earlier management of complications
- better medicines management
CKD is a marker for increased _____
cardiovascular risk
- target patients for CV risk reduction interventions
why is it important for early referral to nephrology?
- late referral increases morbidity and mortality, and cost
- gives patient choice as to modality of ESRF treatment
- gives time to prepare patient for dialysis/transplantation
- avoidance of venous catheters and associated bacteraemia
Who are the patients at risk of developing renal failure?
- extremes of age
- polypharmacy
- specific disease states
- patients receiving large amounts. long term analgesia
- transplant patients
- drug therapy: nephrotoxic drugs, dosage adjustments
What is the degree of renal impairment at stage 1& 2 of CKD?
normal GFR with other evidence of kidney damage
What is the degree of renal impairment at stage 3 of CKD?
Moderate
What is the degree of renal impairment at stage 4 of CKD?
severe
What is the degree of renal impairment at stage 5 of CKD?
established renal failure (or on dialysis or transplant)
What is prevalence?
the total number of cases of a disease in a given population at a specific time
What is the relationship of plasma creatinine to true GFR?
Non-linear relationship with GFR
What determines plasma creatine?
muscle mass as well as renal function
What would increase serum creatinine?
- Large muscle mass, dietary intake
- Drugs
- Ketoacidosis
How does drugs increase serum creatinine?
interfering with analysis (jaffe reaction) or inhibit tubular secretion
What would decrease serum creatine?
- Reduced muscle mass (elderly)
- Cachexia / starvation
- Immobility
- Pregnancy
What are some of the triggers of an AKI?
- ischaemia
- nephrotoxins
- radiocontrast
- bacterial endotoxins
What are endotoxins?
Part of the outer membrane of the cell wall of gram -ve bacteria
Invariably associated with gram -ve bacteria whether the organisms are pathogenic or not
sCr (serum creatinine) does not change until ___% of kidney function is lost
50%
What does RIFLE stand for?
Risk, injury, Failure, Lost of kidney function and End-stage kidney disease
Used to define and stratify the severity of acute kidney injury
Describe the pathophysiology of AKI
- triggers induce the release of inflammatory mediators from both endothelial and tubular cells in the kidneys
- neutrophils and other leucocytes migrate to the site of inflammation and marginate along the peritubular capillary wall very early after the insult
- endothelial inflammatory injury -> increased vascular permeability -> migration of neutrophils into kidney intistitium and tubular lumen
- Neutrophils release pro-inflammatory cytokines that further aggravate the tubular injury
- loss of cytoskeletal integrity leading to desquamation of viable cells and also apoptosis and necrosis.
Why do NGAL have the potential to be a renal biomarker?
NGAL is expressed in multiple molecular forms in the
urine – dimeric from neutrophils and monomeric from kidney tubular cells
What is KIM-1?
A cell membrane glycoprotein, plays a
role in the regeneration process after injury. It is not detected in a normal kidney but instead is elevated in clinical renal damage
What is urea?
Urea is the final degradation product of protein and amino acid metabolism
What is the significance of proteinuria?
Indicative of glomerular disease
Proteinuria itself is nephrotoxic (causes renal tubular cell damage)
Marker for increased risk of progression of renal disease
Proteinuria is reduced with ACE inhibitors/ARBs
what are the properties for the ideal drug used in renal impairment?
- < 25% renal excretion
- Largely hepatic/biliary elimination
- Unaffected by protein binding or fluid balance
- not nephrotoxic
Absorption altered because of renal impairment is related to the consequences of what?
- pathology of renal disease
- underlying disease
- drug interactions
what distribution changes would you see because of renal impairment?
- changes in functional compartment
- alterations in protein binding
- tissue binding
Metabolism alterations have limited importance in renal impairment but give a example where it is
Metabolism of insulin - insulin requirements in diabetic is reduced in renal impairment
Alterations in elimination due to renal impairment is significant when?
Highly significant for drugs (or metabolites) where renal function is the main organ of clearance for example aminoglycosides, digoxin and ciclosporin
What is nephrotic syndrome?
Kidney disorder that causes protein to enter urine.
what are the clinical signs of nephrotic syndrome?
Proteinuria
Hypoalbuminaemia
Generalised Oedema
Hyperlipidaemia
What are the presenting signs and symptoms of nephrotic syndrome?
- weight gain
- fatigue
- foamy urine
- loss of appetite
4 drugs that cause the nephrotic syndrome?
Gold,
NSAIDs,
penicillamine
Heroin taken via IV
What are the 4 treatment options of nephrotic syndrome?
- Treatment of causative disorder - like stopping the drugs causing the condition
- Angiotensin inhibition ( so using ace inhibitors or ARBs)
- Reduce sodium intake
- Diuretics
which two classifications of drug induce renal failure are intra renal?
direct toxicity
immunological damage
Why do drugs cause renal failure?
- as the kidney is exposed to 35% of cardiac output, it is also exposed to a high conc. of drug so any drug that compromises the circulation may induce acute renal failure
- it could worsen pre-existing renal failure
- drug could damage the large endothelial surface
what are the 4 different classifications of Drug Induced Renal Failure
- Pre-renal
- Direct Toxicity (intra-renal)
- Immunological Damage (intra-renal)
- Obstructive uropathy (post renal)
what are the 2 different mechanisms that can lead to pre-renal failure and what are examples of drugs that can cause them?
Volume depletion - diuretics
prostaglandin inhibition - NSAIDS
what condition can be caused if ACE inhibitors are given to a patient with bilateral renal artery stenosis and why?
acute renal impairment as this would lead to ischemia in the kidneys
NSAIDs induce renal impairment. What patients are at risk?
age >60 years
Sex F>M
Underlying renal disease
Concurrent medication esp. if nephrotoxic
Decrease om effective circulating blood volume
What is ATN (acute tubular necrosis)?
Direct chemical insult to proximal tubule e.g. Aminoglycosides, amphotericin, acyclovir, cyclosporin and cisplatin
what are the two mechanisms that lead to direct toxicity renal failure and name drugs that can cause this?
- Acute Tubular Necrosis (ATN): Often caused by nephrotoxic drugs like antibiotics and ciclosporin
- Interstitial damage - caused by chronic exposure to analgesics
what are the three mechanisms of immunological damage
- Acute Interstitial Nephritis (AIN): kidney inflammation caused by allergic reactions to drugs like antibiotics and NSAIDs,
- Immunological damage - caused by a generalised allergic reaction caused by penicillamine
- Glomerular damage - caused by an immune response that can be induced by drugs like NSAIDs and penicillamine
what causes obstructive uropathy?
This results from obstruction of urine flow, leading to increased pressure in the urinary tract and damage to the kidneys.
- retroperitoneal haemorrhage
- retroperitoneal fibrosis
- ureteric obstruction
- tubular blockage
how can drugs causes obstructive uropathy and give one example of a drug that causes this?
Drugs can cause this by forming crystals that precipitate in the urine.
example: sulphonamides
what complications may arise when attempting to treat renal disease?
- Hypertension
- Fluid retention
- Electrolyte control
- Aneamia
Renal disease is both a cause and consequence of 1._____.
Reduction of 2._____ reduces risk of developing both renal and cardiovascular disease.
- hypertension
- blood pressure
what are the blood pressure targets in chronic kidney disease?
if the protein-creatine ratio is below 100mg/mol. - less than 130/80
if the protein-creatine ratio is above 100mg/mol - less than 125/75
What is the effect of blood pressure reduction on the preservation of renal function?
The lower the systolic blood pressure, the lower the annual GFR reduction so the longer it takes to lose 40 ml/min GFR
What are the consequences of renal damage in HTN?
Functional: decrease in GFR, proteinuria
Structural: glomular basement membrane changes, expanded mesangial matrix, glomerulosclerosis, tubulo-intestinal fibrosis
What are the non-pharmacological measures you can take to treat hypertension?
- weight reduction
- reduce salt intake
- limit alcohol consumption
- dynamic exercise
- increase fruit and veg intake
what are the 4 treatment options for fluid retention?
Fluid restriction
reduce salt intake
avoid potassium-sparing diuretics as the patient is at high risk of hyperkalaemia.
Loop diuretics
what are normal potassium serum levels?
3.5-5.0 mmol/L
When is hyperkalaemia life threatening?
Life-threatening condition when serum conc > 7 mmol/L
cardiac arrhythmias (peaked T-waves)
what are the 3 Treatment options of hyperkalaemia
- avoid foods with high potassium (bananas, chocolate)
- avoid nephrotoxic drugs and K+-sparing drugs
- If potassium is between 5.0-6.5 mmol/L use calcium resonium
what do you do when potassium is over 6.5 mmol/L?
10,10,10,10, 50:50
10 ml of 10% calcium gluconate over 10 mins plus 10 units of soluble insulin
Give in 50 mls of 50% dextrose
what are normal serum levels of calcium?
2.2-2.6 mmol/l
what are normal serum phosphate levels?
0.8-1.2 mmol/L
what causes hypocalcaemia in patients with CKD?
reduced vitamin D synthesis
What happens to red blood cells when there is reduced kidney function?
- Kidney is unable to send as much of the EPO hormone to the bone marrow
- Bone marrow produces fewer blood cells which causes anaemia
- Fewer red blood cells carry less oxygen through the blood stream
- Less oxygen is made available to the organs which can lead to several complications
How does EPO lead to iron deficiency?
EPO stimulates erythropoiesis to > normal levels, leads to functional iron deficiency
How do you prevent/treat iron deficiency in patients with CKD?
Oral iron cannot maintain adequate iron stores in haemodialysis patients receiving EPO thus functional iron deficiency is prevented by regular use of intravenous (IV) iron
Give synthetic EPO
_________(TSAT) is the best indicator of iron availability (20 to 50%).
Transferrin saturation
Serum ferritin (100 – 800 mcg/L) is the best indicator of ______
tissue iron stores
What are some of the contents of urine?
- water
- urea
- electrolytes
- chloride
- creatinine
- urobilin (colour)
What should you not find in urine and what could it indicate?
- blood, bilirubin
- glucose, ketone bodies
- betanin
Raise flags for conditions such as diabetes, AKI
What is does SPE cartridges do?
Act as a filter to clean out mater.
What is happens in sample clean up?
Remove interfering species (matrix components)
OR
Remove species of interest
What are the approaches of ion measurement?
- simple ion-chromatography
- simple ion-selective electrode
- capillary electrophoresis (based of mass to charge ratio)
- atomic spectroscopy (the best technique)
- gel electrophoresis
What are the three types of calibration plots?
- simple calibration plot
- standard addition
- internal standard ‘spiking’
Describe a simple calibration plot
you have a y axis and x axis - independent and dependant variable
R squared value should be close to 1
What is the use of standard addition (type of calibration plot)?
To counter matrix effects and is often seen in complex sample such as urine
Based that you +1 or multiple aliquots (fixed added volume) of a standard included
What is the use of internal standard ‘spiking’?
Used as a counter to sampling inconsistency which causes high error
You add known quantity of similar analyte e.g. methanol for ethanol, copper for iron
Properties of atom defined by associated ___________
non-bonded electrons
non bonded- electrons are promoted or demoted dependant on what?
these are promoted from the ground state or demoted from the excited state depending on absorption or emission of (a quantum of) energy
What is the line spectrum of atom?
series related to occupancy of specific energy states by
electrons
What are resonance lines?
Emitted radiation - specific y light generated by outer electrons on their FALL from various elevated excited
states
Describe Atomic emission spectroscopy
we take a compound in solid form - MX(s)
turn it into gas molecule in a flame - MX (g)
gas molecule splits into two: metal gas M(g) + non-metal gas X(g)
absorption of energy promotes the electrons of metal ions
When they fall from this excited state they give off light
What are the requirements of atomic emission spectrometer?
Small uniform sized droplets <20 mm - so they can fit
Constant feed rate - otherwise signal is feeble and you underestimate
“Clean” samples
What is the benefit of Microwave plasma?
- Dramatically reduce operating (analysis) cost
- Superior detection limits and larger linear
dynamic range compared to flame AA - Unattended; no flames/expensive gas supply
and handling of dangerous gas cylinders
Describe atomic absorption spectroscopy
VERY specific
- Electronic excitation of volatilised dissociated atoms
- Excitation achieved: electric glow discharge of hollow
cathode (ray) lamp (HCL)
- Sample specific cathode element
What is the equation of Beer-Lambert Law?
A = ecl
absorbance = path length (cm) x conc. (mod.dm-3) x molar extinction
absorbance is related to conc.
You must do a blank for the graph!!
Give examples of atomic spectroscopy
Mass spectrometry - ICP-MS
X-ray fluorescence spectrometry – XRF
What are the interferents in test sample for absorbance tests?
Alumino-silicates
Phosphates
Pharmaceutical tablets and products can contain: starch, polysorbates, Mg stearate,
celluloses, lactose, silicon dioxide, titanium dioxide, iron oxide, talc
these can act as interferents causing refractory oxides
Why is copper used for X-ray generation for one type of
spectroscopy based on fluorescence? [5 marks].
- KLM outer shell electrons and pure and large source
- XRF - x ray fluorescence spectroscopy
- detects all elements in the periodic table except halide with great sensitivity and selectivity
- very expensive
- perfect analytical technique for alloys and mixed of elements
Describe Continuum source correction
Absorbance of materials in the flame which are energised by the deuterium lamp and generate a signal, this background can be then removed electronically
What are examples of spectral interferences?
-Overlap of emission and absorption
lines (broad and narrow)
-Combustion products
- Sample matrix
-Ti, Zr, W, V, Mo and B - form
refractory oxides. Common
chemical interference agents e.g.
Oxides
Silicates
Aluminates
Complex salts
How do we prevent interferences causing refractory oxides?
To avoid aluminium (Al) or silicon (Si) binding with strontium (Sr; analyte) we can add a
preferential binding agent such as lanthanum (La). Also works for phosphate interference
What can atomic spectroscopy look for in quality control?
- Metal salts of drugs
- Highly toxic metals†* in consumed matter
- Metals catalysts of oxidative changes: pro-oxidants for drugs and organics
- Metals used for pigments in pharmaceutical products
- Electrolytes (flame photometry), kidney function tests
Simple pharmaceutical salts and excipients (flame photometry) lithium carbonate, calcium
carbonate, sodium bicarbonate, sodium phosphate, etc
What else is atomic spectroscopy used for?
-Analysis of body fluids, maybe part of
nutritional investigations e.g. selenium,
copper, zinc
* Clinical studies involving e.g. skin, hair,
bones, teeth
* Analysis of medical materials (e.g. stent?)
What are the limitations of spectroscopy?
- cost of equipment
- detection limit
- additional corrections may need to be possible
What does the acronym ICP represent?
inductively-coupled plasma
