block E - renal and hepatic Flashcards
1
Q
what are the functions of the kidneys?
A
- regulation of H2O and inorganic ion balance
- removal of metabolic waste products from blood and excretion in urine
- removal of forign chemicals in the blood and excretion in unrine
- gluconeogenisis
- endocrine functions
2
Q
what is the functional unit of the kidney?
A
the nephron
3
Q
how many nephron are there in the 2 kidneys?
A
about 2.5 million
4
Q
what does each nephron consist of?
A
- the tubular component - contains what will eventually be urine
- the vascular component - blood supply
5
Q
what do the mechanisms by which the kidneys perform their functions depend on?
A
they depend on the relationship between the tubular component and the vascular component
6
Q
what does the glomuler filtrate drain into?
A
bowman’s space then into the proximal convoluted tubule
7
Q
what do the endothelium pores allow through?
A
small molecules
8
Q
why do podocytes have a negative charge?
and what are they?
A
- it to stop proteins getting through into the tubular fluid, the basement membrane also helps with this job
- they wrap around capillaries and neighbour cells of the bowman’s capsule, they make the epithelial lining of the bowman’s capsule
9
Q
what does macula densa sense GFR via?
A
[Na+]
10
Q
what does the juxaglomuter (JG) apparatus do?
A
it helps regulate renal blood flow, GFR and indirectly modulates Na+ balance and systemic BP
it also has cells that secrete renin
11
Q
what is GFR (glomerular filtration) controlled by?
A
its controlled by diameters of afferent and efferent arterioles
12
Q
what is high hydrostatic pressure at golomutar capillaries due to?
A
short, wide afferent arteriole (low R to flow) and the long, narrow efferent arteriole (high R)
13
Q
how do the kidneys control long term blood pressure?
A
by controlling blood volume
14
Q
how do the kidneys reduce renal pressure?
A
they control the intrarenal redistribution of pressure and increased absorption of salt and water
15
Q
what does angiotensin II do?
A
- causes direct constriction of renal arterioles
- stimulation of aldosterone synthesis - sodium absorption and increase in intravascular blood volume
16
Q
what does decreased pressure in renal arterioles and sympathetic activity cause?
A
renin production and angiotensin II production
17
Q
name some common liver disease conditions?
A
hepatitis A, B, C, D and E
18
Q
what is hepatitis A?
A
its typically spread through contact with contaminated food and water
symptoms may clear up without treatment and recovery is a few weeks
19
Q
what is hepatitis B?
A
it can be acute (short term) or chronic (long-term)
spread through bodily fluids
its treatable but theres no cure
20
Q
what is Hepatitis C?
A
can be acute or chronic
often spread through bodily fluids with someone with hepatitius C
it often doesnt show symptoms in the early stages but it can lead to permenant liver damage
21
Q
what is Hepatitis D?
A
its a serious form of hep that only develops in people with hep B
22
Q
what is Hepatitis E?
A
its usually caused by drinking contaminated water
generally clears up in a few weeks on its own without any lasting complications
23
Q
what is the early treatment of acute hep C?
A
interferon alpha may reduce the risk of chronic infection
24
Q
what do interferons do?
A
they don’t directly kill viral or cancerous cells but they do bbost the immune system response stimulating T cells and other immune system cells to attack
25
what are some names of anti-viral drugs?
Ombitasvir with paritaprevir and ritonavir (inhibits a wide range of DNA and RNA viruses)
26
what does sofosbuvir do?
it inhibits the hep C virus NS5B protein
27
what does NAFLD stand for?
non-alcoholic fatty liver disease
28
what is alcoholic fatty liver disease caused by?
heavy alcohol consumption
29
what is NAFLD caused by?
factors other than alcohol that theyre still trying to understand
30
if left unmanaged, what can both types of liver disease lead to?
they can both cause liver damage, leading to cirrhosis and liver failure
31
what can improve symptoms and reduce your risk of complications of both types of liver disease?
diet and lifestyle changes
32
what can lead to fatty liver disease?
fat build-up in the liver
33
what does non-reversible damage of the liver cause?
- metabolism
- bile production
- cholesterol
- haematological implications
34
what is pioglitazone/ vit E used for?
its used by adults with advanced liver fibrosis
35
what does pioglitazone do?
it improves the sensitivity of hepatic tissue to insulin
theyre synthetic ligands for peroxiome proliferator-activated receptors (PPARs)
they ater the transcription of genes influencing carbohydrate and lipid metabolism resulting in changed amounts of protein synthesis and therefore metabolic changes
36
what vitamin is a potent antioxidant?
vit E
37
what are some of the autoimmune conditions involving your immune system attacking cells and your liver?
autoimmune hepatitis
primary biliary cirrhosis
primary sclerosing cholangitis
38
what does autoimmune hepatitus involve?
it causes your immune system to attack your liver, resulting in inflammation
if its left untreated, it can lead to cirrhosis and liver failure
39
what is primary billiary cirrhosis and what can it lead to if left untreatec?
it results from damage to the bile ducts in your liver and causes a build up of bile
it can lead to eventual cirrhosis and liver failure
40
what is Primary sclerosing cholangitis and what can it lead to?
its an inflammatory condition which causes gradual damage to your bile ducts, they eventually become blocked and cause bile to build up in your liver
can lead to cirrhosis or liver failure
41
what are the two treatments used to treat autoimmune liver conditons?
prenisolone and azathioprine
42
what is presisolone?
it increases the conc of neutrophils and decreases the levels of T and B lymphocytes, monocytes, eosinophils and basophils. it also causes a decrease in cytokine release, including decreasing in IL-2 and TNF alpha
43
what does azathioprine do?
its an immunosuppressant agent which acts through its effects as an antagonist of purine metabolism, resulting in the inhibition of DNA, RNA and protein synthesis
44
if a cancer develops somewhere else and then spreads to the liver, what is it called?
its called secondary liver cancer
45
what is the most common type of liver cancer?
hepatocellular carcinoma
46
how does hepatocellular carcinoma develop?
it tends to develop as several small spots of cancer in your liver, but it can also start as a single tumour
47
what other factors may contribute to the development of other cancers?
complications from other liver diseases
48
how do you treat liver cancer?
through surgery, chemotherapy and pharmacotherapy
49
what are the mechanisms of action for immune checkpoint inhibitors?
two signals are required to initiate the activaton of T cells
the first signal involves the binding of a MHC to a TCR on T-cells
the second signal arises with the binding of APC ligands, CD80 or CD86, to CD28 on t-cells
50
what are the names of some MABs that have been extensively studied for the treatment of cancer?
ipilimumab, tremelimumab, nivolumab, atezolizumab, durvalumab and avelumab
51
what is prenisolone used to treat?
a lot of autoimmune conditions
52
what is everrlimus?
its the brand name for mTOR (mammalian target of rapamycin) inhibitor
53
what is cholesostais commonly associated with?
liver cancer
54
what is choleostasis?
its an impairment of bile formation and/or bile flow, which may clinically present with fatigue, pruitus, dark urine, pale stools and jaundice and fat soluble vitamin deficiencies
55
what is cholestyramine?
its a bile acid sequestrant
56
what is sertraline? and what is it used to treat?
its a selecive serotonin reuptake inhibitor (SSRIs) , used as a treatment for pruritus
57
what are lipoprotein packages?
its lipoprotein thats in blood
58
what are things that build-up and contribute to liver function and cardiovascular disease?
cholesterol and lipoproteins
atherogenesis- this is the build up of plaque which leads to cardiovascular disease
sterol
59
where does cholesterol synthesis happen?
its synthesised primarily in the liver
occurs in the cytoplasm and ER
60
what is the rate limiting step of cholesterol synthesis?
the HMG-CoA reductase raction is rate limiting and highly regulated
61
what is the target of pharmacological intervention in cholesterol synthesis?
the HMG-CoA reductase reaction step, this enzyme os a gate keeper as it has to be active to synthesise new cholesterol, the 75% of cholesterol which is just resynthesized isn't made this way though
62
what does tiparanol do?
it inhibits the last step of the choesterol synthesis pathway, it was introduces into clinical use in the mid 60s but was withdrawn from the market because of side effects, the side effects were attributed to tissue accumulation of demoterol, a substrate for the enzyme it affected
63
why is it important for many people to take drugs which reduce cholesterol formation?
because many of the intermediates in the pathway have biological concequences and are equally hazerdous as choleserol so if you block the pathway then you also block these intermediates from being produced
64
how do statins interfere with cholesterol
they interfere with the HMG-CoA reductase enzyme and as a result, the pathway downstream is blocked
65
why are patients at high risk of cardiovasular disease often prescribed statins?
becuase its cheaper in the long run to reduce the chances of people developing it rather than waiting until they have it then having to pay for expensive treatments to make them better, theyre prescribed them from it getting any worse
66
what are the functions of cholesterol?
cell membranes
sex hormones
hromones relased by the adrenal glands
production of bile acids
vitamin D
67
how does cholesterol play a role in cell membrane permeability?
the -OH interacts with the polar head groups of the membrane phosphilipids and sphingolipids while the bulky steroid and the hydrocarbon chain are embedded in the membrane - this increases membrane packing and reduces membrane fluidity to things like neutral solutes, protons and sodium ions
68
how does cholesterol help in the production of sex hormones?
its involved in the production of pregesterone, estrogen and testosterone
69
what is essential for the production of hormones released by the adrenal glands such as cortisol and aldosterone?
cholesterol
70
what does cortisol do?
it increases blood sugar through glucogenesis and aids in fat, protein and carbohydrate metabolism
71
what is aldosterone important for?
its helps control blood pressure by regulating sodium and potassium levels
72
what do bile acids help to do?
they help to digest food in the intestines
73
what vitamin requires cholesterol during its synthesis?
vitamin D needs cholesterol when synthesised from sunlight
74
what are risks of having high cholesterol?
atherosclerosis
stroke
peripheral vascular disease
75
what is atherosclerosis?
its an increased coronary heart disease risk and a narrowing of blood vessels
can lead to:
-heart attack
- angina
76
what is coronory heart disease?
its an abnormality of the arteries that supply blood and oxygen to the heart
77
what is angina?
chest pain/ discomfort that occurs when your heart muscle doesn't get enough blood
78
what is a heart attack?
it occurs when the supply of blood and oxygen to an area of the heart muscle is blocked, usually by a clot in the coronary artery
this causes your heart muscle to diw
79
what are 'other cardiovascular conditions'?
diseases of the heart and blood vessels
80
what are strokes and mini-strokes?
they occur when a blood clot blocks an artery or vein, interupting the flow to an area of the brain
can also occur when a blood vessel breaks
brain cells begin to die
81
what have plaques got to do with strokes and heart attacks?
they can build up in the arteries and rupture and travel through the bloodstream. if they get stuck in the coronary artery, this can result in a heart attack. if they get stuck in a carotid artery, this can result in a stroke
82
how does cholesterol travel round the body if its insoluble?
its transported in the circulatory system within lipoproteins
83
why cant cholesterol not just travel freely around the body on its own?
because lipids are oil based and blood is water based so they dont mix
if cholesterol was dumped into the bloodstream, it would congeal into unusalble globs
84
how does the body get around the problem of cholesterol not being able to travel freely around the body?
the body packages cholesterol and other fats into miniscule protein-covered particles called lipoproteins (lipid and protein) that DO mix well with blood
85
what are the proteins used in lipoproteins?
apolipoproteins
86
what does LDL mean?
low density lipoprotein
this is sometimes known as bad cholesterol
it carries cholesterol frim the liver to cells, of oo much is carried, and theres too much for the cells to use, there can be a harmful build up og LDL
this lipoprotein can increase the risk of arterial disease, if the levels rise too much.
most human blood contains aprox 70% LDL- this may vary depending on the person
87
what does HDL stand for? and what is it?
it stands for high density lipoprotein
often referred to as good cholesterol
experts say that HDL prevents arterial disease and it does the opposite of LDL- it takes the cholesterol away fromt he cells and back to the liver, in the liver, its either broken down or expelled from the body as waste
88
what do chylomicrons carry?
they carry triglycerides fromt he instines to the liver, to the skeltal muscle and to adipose tissue
89
what do VLDLs carry?
they carry newly synthesised triglycerides from the liver to adipose tissue
90
what are IDLs intermediates between? also what does IDL stand for?
stands for intermediate-density lipoproteins and they're the intermediates between VLDL and LDL and aren't usually detectable in the blood
91
what are the risk factors for cholesterol?
- diet
- medical conditions like diabetes and hypertension
- genetics
- sex
- age
- smoking - this damages the endothelial and changes the oxidative stress level
- inactivity and obesity
92
what arer the drugs therapy of hyperlipidemia?
- stains
- bile-acis sequestrrants
- niacin (nicotinic acid)
- fibric acid derivatives
- ezetimibe and the inhibition of dietary cholesterol
93
how do bile-acid sequestrants reduce cholesterol levels?
they cause the body to make more bile and one of the main components is cholesterol so it reduces the amount in the body
94
how does fibric acid derivatives help to reduce cholesterol levels?
the fibre binds to the cholesterol
95
what is the mechanism of action for statins?
they inhibit an early rate-limiting step of cholesterol biosynthesis
inhibiting hepatic cholesterol synthesis results in increased expression of the LDL receptor gene
it also reduces the degradation of LDL receptors
96
why is it good to have decreased levels of free cholesterol in the blood?
its good becuase this causes membrane-bound regulatory proteins to be cleaved and translocated to the nucelus to binf the sterol reponsive element of the LDL receptor gene
this enhances transcription and increases the synthesis of LDL receptors
97
what is triparanol?
its a drug which inhibits the late step int hre pathway of cholesterol synthesis and was introduced into clinical use in the 1960s
but it was withdrawn from the market shortly after because of the development of cataracts and various cutaneous side effects
they're attributable to tissue accumulation of desmosterol, the substrate for the inhibited enzyme
98
what are Rho and Rac?
theyre monomeric g-proteins important in self-signalling
99
what is the role of Rac in the self-signalling pathway?
it pulls together the 5 subunits of NAD(P)H-ox
100
what do the 5 subunits of NAD(P)H-ox do?
they are bad monomeric g proteins that are associated with cardiovascular disease - by reducing the activity of these, we confer a benefit
this is the off-target benefit of statins
101
what is the proper name for statins? (the unshortened name)
competitive inhibitors of HMG-CoA reductase
102
what do stains do?
they decrease levels of cholesterol synthesis and increase levels of expression of the LDL receptor gene
103
what have statins been documented to have effects on?
documented in reducing fatal and non-fatal coronary heart disease, strokes and total mortality
104
what type of inhibitor are statins?
theyre reversible competitive inhibitors of HGM-CoA's natural substrate
105
what step do statins inhibit?
they inhibit an early and rate limiting step in cholesterol biosynthesis
106
how do hepatocytes respond to the drcreased production of cholesterol?
they synthesise LDL receptors to draw cholesterol out of circulation
membrane bound SREBPs are cleaved and translocated to the nucelus to increade production of LDL receptors, these receptors then take up LDL and VDL into the liver from the circulation and can reprocess it into bile salts
107
what does a greater number of LDL receptors on the surface of hapatocytes result in?
they result in the removal of LDL from the blood and thereby lowering LDL-C levels
108
how do some studies suggest statins cam reduce LDL levels by?
by enhancing the removal of LDL precursors and by decreasing hepatic VLDL production
because VLDL remnants and IDL are enriched in apoE, a statin-induced increase in the number of LDL receptors, which recognise both apoB-100 and apoE, enhances the clearance of these LDL precursors
109
what are the non-lipid lowering effects?
- endothelial function (enhances production of nitric oxide)
- anti-inflammatory
- reduces venous thromboembolic events (43%)
110
how much do statins decrease triglycerides and lipoprotein levels?
35-45%
111
how much do statins reduce HDL-C in normal patients and low patients?
normal- 5-10%
low- 15-20%
112
how much do statins rediuce LDL-C levels?
20-55%
113
what are the adverse effects of statins?
hapatoxicity and myopathy
114
what is hepatotoxicity?
- its an elevated haptic transaminase value
one cause of liver failure per million persons-per-year so its a very rare side effect
115
what is myopathy?
its another word for muscle pain and is a muscular disease in which the muscle fibres dont function
it causes one death per million prescriptiosn caused by rhabdomyolysis
116
what are transaminase values?
theyre an indicator of livre damage, synthesize and break down amino acids to convert energy storage molecules, in the case of liver damage hepatocyte membranes become more permeable and some of the enzymes leak out into the blood
117
what is rhabdomyolysis?
its the breakdown of muscle fibres that lead to the release of muscle fibres contents (myoglobin) into the blood stream
myoglobin is harmful to the kidney and often causes kidney damage
118
what os rhabdomyoysis?
its usually caused by drug interactions with fibrates or other drugs that affect statin catabolism or uptake into hepatocytes
119
what are the pleiotrophic effects of HMG-CoA reductase inhibitors?
reduced the incidence of recurrent ischemic events
120
why are statins associated with type 2 diabetes?
they can sometimes be the final straw in the development of type 2 diabetes but in a lot of these cases they were always going to get it, the statins just fast tracked the process slightly
121
are there any problems with taking statins?
rarely, some people taking statins have developed abnormal muscle breakdown, which can lead to kidney problems and can be life-threateneing
the UK independant safety regulater said that for every 100,000 people who take stains, over a year, 1 or 2 of them will expericence this type of muscle damage
122
what is andromeda?
its a reduction in hsCPR in patients with baseline CPR >/= 2mg/L
123
how are the kidneys controlled long term?
liver produces angiotensin and renicleaves peptide to make angiotensin I then ACE converts this to angiotensin II
this then stimulates the adrenal gland to produce more aldosterone, thsi produces an increase in sodium which then increases the water level
124
what is the macula densa part of?
the distal tube
125
what are the 2 primary hormones involved in the kidneys?
angiotensin II and alsosterone
126
what does RAAS stand for?
renin-angiotensin-aldosterone system
127
what is RAAS activated in response to?
its activated in response to reduced blood flow to the kidneys
128
what is the principle factor for controlling Ang II levels?
renin release
129
how does decreased circulating volume stimulate renin release? (what is it via)
via:
-decreased BP (symp effects on JGA)
- decreased [NaCl] at macula densa (NaCl sensor]
- decreased renal perfusion pressure
130
what are the important actions of angiotensin II?
Stimulation of aldosterone release from adrenal cortex.
Vasoconstriction of renal and other systemic vessels.
Enhanced tubuloglomerular feedback – makes macula densa more sensitive.
Enhance Na-H exchanger and Na channel function to promote Na reabsorption.
Renal hypertrophy.
Stimulates thirst and ADH release by acting upon hypothalamus.
131
what does aldosterone do?
- it stimulates Na+ reabsorption and K+ excretion by the renal tube
- it also exerts indirect negative feedback on RAAS by increaseing ECV and lowering plasma K+
132
what is aldosterone really good at?
Really important in conserving Na+ and water, but also really good at preventing massive swings in K+ levels.
133
how is effectove circulating volume controlled?
negative feedback control of effective circulating volume
a low effective circulating volume triggers 4 parallel effector pathways that act on the kidney
- either changes haemodynamics or changes Na+ transport by renal tubule cells
134
what do sympatholytics do?
they oppose the downstream effects of post-ganglionic nerve firing in effector organs innervated by the sympathetic nervous system (SNS)
they're indicated for various functions i.e. may be used as hypertensives
135
what are the different types of diuretics?
sympatholytics
act on RAAS
calcium channel blockers
direct-acting vasodilators
136
what do all diuretics indirectly do?
they all indirectly prevent the reabsorption of water in the kidneys - most of them do this by preventing the reabsorption of sodium
137
what are loop diuretics?
furosemide supplemented with spironolactone or amiloride
138
what is the proper name of drug classified under thiazides?
bendroflumethiazide
139
what are potassium sparing diuretics?
they dont directly act on sodium channels, they tend to have an effect on potassium and other chloride ions in the blood
140
what type of diuretic has the biggest effect and why is this?
furosemide has the biggest effect since its at the start of the tubule so it prevents sodium reabsorption in the rest of the tubule
141
where in the tubule are the different types of diurects found?
furosemide- proximal convoluted tubule
thiazides- early distal convoluted tubule
potassium sparing- tubule and collecting duct
142
what are diurects' mechanism of action?
loop diuretics act principally by inhibiting the Na+/K+/2Cl-co-transporter
143
what is the lumen?
its where the filtrate is
144
how do thiazide diuretics work?
theyre the most commonly used diurectic and inhibit the sodium-chloride transporter in the distal tubule
145
why are thiazide diuretics less effective than loop diurectics in producing diuresis and natriuresis?
because the sodium-chloride transporter normally only reabsorbs about 5% of filtered sodium
146
how does aldosterone promote reabsorption?
it does this by upregulating the sodium channels
147
what does ACE stand for?
angiotensin-converting enzymes
148
what is angiotensinogen and where is it synthesised?
its synthesised in the liver and is the substrate for renin, an arterial ezyme
149
what does renin act upon to make angiotensin II?
it acts upon angiotensinogen
150
why may hypertension be involved in drugs acting on RAAS?
it may be due, in part, to increased levels of angiotensinogen, since it circulates at about the same Km (binding affinity), for renin, small changes would markedly affect the generation of angiotensin I
151
what does ACE stand for?
angiotensin converting enzyme
its a glycoprotein found in lung, endothelial cells and plasma, removes 2-carboxy-terminal amino acids from angiotensin I to form angiotensin II
152
what's my name
oreo
153
what is used to treat renin-dependant hypertension?
Various antagonistic peptide analogues of angiotensin II and drugs like Captopril (a suicide substrate that inhibits ACE)
154
what does angiotensin II do?
it increases blood pressure by causing vasoconstriction of the arterioles and is the most potent vasocatve substance known
it also inhibits renin release for a short feedback loop and is a potent simulator of aldosterone production
155
what does aldosterone do?
it increases Na+ and H2O retention
156
what stimulates renin release?
any combination of factors that decrease fluid volume (dehydration, decreases blood pressure or blood loss) or decreases in NaCl conc (low Na+ intake)`
157
what drugs inhibit renin?
aliskiren
B1 antagonists
158
what are the names of aldosterone antagonists?
spironolactone
eplerenone
159
what do alsosterone antagonists do?
theyre potassium sparing diuretics and competitively bind to the aldosterone receptor and promote Na+ and H2O excretion in the collecting tubule and duct
160
THIS IS JUST A SUMMARY OF THE RENAL 3RD LECTURE
Kidney function GFR important
Kidney modulation of RAAS system relevant
Direct renin inhibitors
Diuretics
ACE inhibitors (indirect effect on kidneys)
