Week 5 Flashcards
Causes of hepatitis?
Viral (Hep A-E) Non-viral Drugs e.g. paracetamol Alcohol Poisons e.g. Aflatoxins Other e.g. pregnancy, circulatory insufficiency
What do hepatitis viruses A-E all have in common?
All are hepatotropic i.e. are able to infect hepatocytes (liver cells). However are all part of different virus families
6 stages of viral replication?
Adsorption Penetration Uncoating Replication of nucleic acid Maturation/ assembly Release
Hep A Virus: Viral features? Transmission? Shellfish as a source of infection? Stages of infection?
Viral features:
• Picornaviridae family
• Single-stranded RNA virus
• Non-enveloped virus (naked) • Only 1 serotype
Transmission:
– Faecal-oral route
– Poor hand hygiene
– Contaminated food or water
Shellfish as a source of infection:
If water is contaminated with sewage when shellfish filter water, the virus concentrations in flesh. Eating raw or partly cooked shellfish leads to infection
Stages of infection:
• Incubation period of 2-4 weeks leads into prodromal phase (a.k.a pre-icteric stage)
• Virus excreted in faeces for 1-2 weeks before symptoms
• Translocation from GI tract to blood
• Infection of liver cells
• Passage to biliary tract and back to GI tract
• Excretion in faeces
HAV:
Clinical features?
Treatment?
Prevention?
Clinical features: • Fever, anorexia • Nausea, vomiting • Jaundice • Dark urine, pale stools • No chronic carriage • Presence of anti-HAV IgM
Treatment?
• No specific treatment
• Maintain comfort and nutritional balance
• Fluid and electrolyte replacement
Prevention: • Vaccine • Good hygiene • Resistant to chlorination • Killed by boiling for 10 mins
Hep B Virus:
Viral features?
Antigens?
Viral features:
• Hepadnaviridae
• Double-stranded DNA virus
• Enveloped virus
Antigens:
- HBsAg= Surface antigen. Indicates high transmissibility and provide immunity
- HBcAg= Core antigen
- HBeAg= Envelope antigen. Indicates high infectivity
HBV:
Transmission?
Transmission:
• Sexual intercourse
• Intra-uterine, peri- and post-natal infection
• Blood or blood products
• Contaminated needles and equipment used by intravenous drug users
• In association with tattooing, body piercing and acupuncture
• Contaminated haemodialysis equipment
HBV: Stages of infection?
• Incubation period of 2-4 months
• 50% patients develop chronic active hepatitis
–> 20% of these proceed to cirrhosis
–> 1-4% of these risk developing liver cancer
HBV, difference between an acute and chronic infection?
- HBsAg and HBeAg appear during incubation period
- Viral DNA becomes detectable
- Antibodies to core antigen (HBcAg) appear concomitantly with rise in liver transaminases
- Antibodies to HBeAg and HBsAg only appear during convalescence
- Continued presence of HBsAg and absence of antibodies to it indicate that infection has become chronic
Chronic: No antibody for surface antigen. Surface antigen levels don’t drop down. Leads to infection
Stages of an acute HBV?
- Incubation period of 45 – 120 days
- Pre-icteric period of 1 – 7 days
- Icteric period of 1 – 2 months
- Convalescent period of 2 – 3 months in 80-90% of adult cases
Clinical features of icteric period of HBV? Cause?
Yellowish pigmentation: Skin, sclerae, other mucous membranes
Caused by hyperbilirubaemia
What does fulminant mean?
Severe and sudden in onset
Clinical outcomes of acute HBV infection?
• Fulminant hepatitis
• Chronic hepatitis or asymptomatic carrier
state
• Resolution of infection
HBV treatment and prevention?
Treatment:
• Pegylated interferon (peginterferon): superior
compared to α-interferon alone
• Nucleoside analogues such as oral lamivudine
Prevention: • Vaccination: 3 injections over 6 months. Against the surface antigen • HBV immunoglobulin • Blood screening • Needle exchange programmes • Sexual health education
Hep C Virus:
Viral features?
Clinical features?
Viral features: • 6 virus types (from nucleotide sequences) • Flaviviridae • Single-stranded RNA • Enveloped virus
Clinical features: • Usually asymptomatic • Fatigue • Nausea • Weight loss • May rarely progresses to cirrhosis • Small proportion of patients may develop hepatocellular carcinoma many years after primary infection
HCV:
Transmission?
Stages of infection?
Transmission: • Blood and blood products • Blood contaminated needles • Tattooing, body piercing, acupuncture • Haemodialysis
Stages of infection:
• Virus replicates mainly in hepatocytes
• Incubation period 2 weeks to 6 months
HCV: Prevention and treatment?
Prevention:
- Screening: Blood test based on NAAT
- No vaccine
Treatment:
- Ribavirin + pegylated alpha-interferon.
- Combination therapy(HAART) : Sofosbuvir, boceprevir, telaprivir, daclatasvir
HBV: Clinical Features of Pre-icteric Period?
- Malaise
- Anorexia
- Nausea
- Pain in right upper quadrant (tender liver)
Hep D Virus:
Viral features?
Viral features:
• Small (35nm) circular single-stranded RNA virus
• Defective virus
• HDV picks up HBsAg as it buds from liver cell (i.e. only comes in co infection with HBV)
HDV: What is function of HBV? Transmission? What increases risk for HDV infection? Treatment?
What is relevance of HBV:
• Found as co-infection with HBV
• HBV serves as helper virus for infectious HDV production
Transmission: Percutaneously, sexually, from infected blood
What increases risk for HDV infection: Chronic HBV carriers are at risk for infection with HDV
Treatment: None
Hep E Virus: Viral features? Incidence? Transmission and symptoms? Prevention?
Viral features:
• Caliciviridae
• Single-stranded RNA
• Non-enveloped virus
Incidence: Young adults. Can be life-threatening in pregnant woman
Transmission and symptoms: • Waterborne disease • Incubation period 3-8 weeks • Usually self-limiting • Signs and symptoms are similar to other acute forms of hepatitis
Prevention:
• Good sanitation & hygiene
• Vaccine (Hecolin)
6 other causes for viral hepatitis?
- Epstein-Barr virus
- Cytomegalovirus
- Yellow fever virus
- Adenoviruses
- Bunyaviruses
- Flaviviruses
- List the causes of release of erythropoietin by the kidneys.
High altitudes
Haemorrhage
Red blood cell destruction
Increased tissue oxygen demands
The ability of RBCs to carry O2 determines the release of erythropoietin
- List the functions of erythropoietin.
Sustains red blood cell production
Stimulates bone marrow cell that are committed to becoming red blood cells.
- Describe how chronic renal failure affects the release of erythropoietin and what the consequence of this is.
As chronic renal failure progresses, the scarring that occurs leads to a decrease in functioning cells and a drop in the release of erythropoietin.
As a consequence, there is a reduced capacity of the blood to carry oxygen and the patient may present with lethargy as a result of anaemia.
- Describe how low levels of erythropoietin are treated in chronic renal failure.
Synthetic erythropoietin is now used in therapy to counter these effects.
- List the main actions of calcitriol (1,25-dihydroxycholecalciferol).
- Stimulate the absorption of ingested Ca by increasing expression of Ca channels used to transport Ca across the cell membrane at the intestinal mucosa.
- Increases phosphate absorption
- Calcification of bone matrix by stimulation of osteoblasts and osteoclasts, facilitating the remodelling of bone
- Describe the effects of chronic renal failure on calcitriol production.
In renal failure, 25-hydroxycholecalciferol is not converted to 1,25-dihydroxycholecalciferol.
The kidneys add a hydroxyl group in this conversion
- Describe the effects of chronic renal failure on bone.
Leads to osteomalacia (softening of the bones) and osteoporosis (loss of bone tissue leading to brittle bones)
What structure becomes the posterior abdominal wall?
The mesoderm by lateral folding that enclose intra-embryonic coelom (The peritoneal cavity)
How does the mesoderm form the peritoneal cavity and posterior abdominal wall in development?
- The mesoderm forms somites adjacent to the notochord and developing neural tube.
- These form intermediate and lateral plate mesoderm
- The lateral plate mesoderm cavitates to form the coelom
- Folding moves the intermediate mesoderm to the posterior abdominal wall while the coelom becomes the peritoneal cavity
What are the two points from which urinary and reproductive systems begin development?
- Mesoderm and coelomic epithelium of the posterior abdominal wall
- Endodermally derived cloaca (divided by the urorectal septum) and the allantois
What does the renal primordia in the mesoderml form sequentially 3 times to form?
The renal primordia form sequentially 3 times within the mesoderm of the posterior abdominal and pelvic walls.
Forms the pronephros, mesonephros and metanephros.
Where do the mesonephric ducts open into?
The cloaca
The cloaca is being divided by the urorectal septum into:
Anteriorly: Urogenital sinus and allantois
Posterioly: Recto-anal region posteriorly
By the 5th week, what stages is the urogenital system in development?
The ureteric bud (on each side) extends from the mesonephric (Wolffian) duct and induces the metanephros that is forming in the pelvis.
The metanephros will become the definitive kidney
The metanephric blastema lie adjacent to each other
The ureteric bud gives rise to the _____ and ______ ducts
The metanephros becomes the renal tissue i.e. glomeruli and loops of _____
The kidney is functional by about __ weeks
If the collecting ducts do not meet the nephric vesicles, ____ form within the kidney
The ureteric bud gives rise to the ureter and collecting ducts
The metanephros becomes the renal tissue i.e. glomeruli and loops of Henle
The kidney is functional by about 10 weeks
If the collecting ducts do not meet the nephric vesicles, cysts form within the kidney
What 2 abnormalities can occur when the kidney ascend from the pelvis up the posterior abdominal wall?
- Pelvic kidney (1 risen, 1 in pelvic)
2. Horseshoe kidney (1 fused kidney in the pelvis
What is the consequence of abnormal branching of the ureteric bud before it reaches the metanephric blastema?
Bifid ureter
If the ureteric bud fail to branch at all within the metanephros, then there will be no induction of kidney development. Condition?
Renal agenesis
1 ureter may end up going to bladder, 1to vagina
Ureteric bud extends from the…
Mesonephritic (Wolffian) duct
The urogenital sinus will eventually form the..
Bladder and urethra
Relationship between the urogenital sinus and mesonephric ducts and ureteric buds?
The urogenital sinus (bladder and urethra) grows and the mesonephric ducts and ureteric buds (ureters) become incorporated within its walls
Ureteric buds eventually form the..
Ureters
Eventually what happens to the mesonephric ducts?
The mesonephric ducts move caudally to open in to the urethra as the vas deferens and ejaculatory ducts
From weeks 4-6 what 4 major changes to the urogenital system development occur?
- The cloacal membrane “sinks” into a pit of ectoderm as the underlying mesoderm proliferates
- The urorectal septum (mesoderm) completely separates the cloaca and becomes the perineal body
- The cloacal membrane ruptures leaving the anal canal and UG sinus open to the exterior
- The roof of the UG sinus is the urethral plate
The proximal part of the UG sinus ____ ____ _____, while the allantois closes to become the ______, which may remain patent
The pelvic part of the UG sinus becomes the prostatic and membranous ____
The distal part of the endodermal UG sinus or ______ UG sinus is drawn along the floor of the extending genital tubercle as the ______ ______
The proximal part of the UG sinus becomes the bladder, while the allantois closes to become the urachus, which may remain patent
The pelvic part of the UG sinus becomes the prostatic and membranous urethrae
The distal part of the endodermal UG sinus or definitive UG sinus is drawn along the floor of the extending genital tubercle as the urethral plate
Which 4 main embryological structures for the urinary system
The metanephros, ureteric bud, urogenital sinus and allantois
During week 6, the ___mesonephric duct develops lateral to the mesonephric duct as an invagination from a cord of coelomic _____l cells
The mesonephric and ____mesonephric ducts form the reproductive ducts and structures, while the ____ is formed in the mesoderm of the genital ridge, which is developed from the overlying coelomic epithelium; and ____ ____ that have migrated from the yolk sac endoderm
During week 6, the paramesonephric duct develops lateral to the mesonephric duct as an invagination from a cord of coelomic epithelial cells
The mesonephric and paramesonephric ducts form the reproductive ducts and structures, while the gonad is formed in the mesoderm of the genital ridge, which is developed from the overlying coelomic epithelium; and germ cells that have migrated from the yolk sac endoderm
Which cells become the cells that produce ova and sperm
Germ cells
How does female and male genital development begin to differentiate?
Males from mesonephric
Females from paramesonephric
Absence of the Y chromosome and the SRY gene leads to female development from the paramesonephric ducts, while the mesonephric ducts degenerate (due to lack of testosterone)
At week 8!
Mesonephric remnants found near vagina and ovary?
Mesonephric remnants: Gartner’s cysts near vagina or epoophoron and paroophoron near ovary
In male genital development, the appendix epididymis is a remnant of the proximal end of?
The mesonephric duct
Whilst paramesonephric ducts degenerate but remain as the appendix testis and the prostatic utricle
Female genital development:
The two __________ (Mullerian) ducts meet in the midline and fuse with each other and with the sino-____ ___ that is derived from the posterior aspect of the urogenital sinus
During months 3 to 5, the ducts zip together in a cranial direction to form the proximal vagina and the ____
Further cranially, the ducts stay separate as the ___ and ____ uterine tubes, with fimbriated ends that are open to the coelomic (peritoneal) cavity
As the ducts lift off the posterior abdominal wall they lift peritoneum as the ____ _______
The uterus and vagina may be septate and even double.
The two paramesonephric (Mullerian) ducts meet in the midline and fuse with each other and with the sino-vaginal bulb that is derived from the posterior aspect of the urogenital sinus
During months 3 to 5, the ducts zip together in a cranial direction to form the proximal vagina and the uterus
Further cranially, the ducts stay separate as the left and right uterine tubes, with fimbriated ends that are open to the coelomic (peritoneal) cavity
As the ducts lift off the posterior abdominal wall they lift peritoneum as the broad ligament
The uterus and vagina may be septate and even double.
6 uterine abnormalities during development
- Double uterus + double vagina (due to incorrect fusion of paramesonephric fusion)
- Double uterus
- Bicornate uterus
- Separated uterus
- Unicornate uterus
- Cervical atresia
As the gonads become more differentiated from the surrounding mesoderm, they remain “tethered”, cranially and caudally by what?
The suspensory ligament and the gubernaculum that extends to the labioscrotal folds
How do the testis migrate from the abdominal wall to the scrum?
Name a congenital condition that results in incomplete descent?
The gubernaculum shrinks to draw the testis down the posterior abdominal wall to the inguinal canal, then through the canal during the 8th and 9th months, so the testis should be in the scrotum by birth
Cryptorchidism: Failure of complete descent
What is the process in vaginalis?
If it stays open?
The loop of parietal peritoneum that the testis takes into the scrum.
If it stays open = Indirect inguinal hernia, hydrocele will form
The urogenital sinus gives rise to an endodermal urethral plate (between the adjacent ectodermal plates or ridges raised by underlying mesoderm) to form the _______ _____.
In males = growing into the penis, penile ______ and scrotum
In females= Remaining as the _____, and the separate labia minora and majora
The urogenital sinus gives rise to an endodermal urethral plate (between the adjacent ectodermal plates or ridges raised by underlying mesoderm) to form the external genitalia.
In males = growing into the penis, penile urethra and scrotum
In females= Remaining as the clitoris, and the separate labia minora and majora
In the male, during week 6 the urethral folds that form on either side of the urethral _____, fuse with the genital tubercle to grow with it, and create the urethral ______ between
The folds and groove stop short of the end of the ______ ______ (glans penis), but the urethral plate continues distally as a solid cord of (endodermal) cells
In the male, during week 6 the urethral folds that form on either side of the urethral plate, fuse with the genital tubercle to grow with it, and create the urethral groove between
The folds and groove stop short of the end of the genital tubercle (glans penis), but the urethral plate continues distally as a solid cord of (endodermal) cells
As the penis elongates, the edges of the urethral folds move towards each other and fuse in the midline to create the penile ______
The ______ “zips-up” from proximal to distal
The solid cellular cord in the glans ______, joins the penile urethra, and also forms the external ____
-As the penis elongates, the edges of the urethral folds move towards each other and fuse in the midline to create the penile urethra
The urethra “zips-up” from proximal to distal
The solid cellular cord in the glans ______, joins the penile urethra, and also forms the external _____
Male genetalia congenital abnormalities:
- Glans hypospadias?
- Penile hydrospadias?
Abnormal canalisation of the urethra in the glans causes glans hypospadias
Failure of the urethral folds to form, or to extend along the penis and fuse throughout its full length causes penile hypospadias
What feature of the urogenital system and anal canal predisposes them to fistulae formation?
Their common origin
6 functions of the renal system?
- Regulation of ECF volume and bp
- Regulation of osmolarity
- Maintenance of ion balance
- Regulation of pH
- Excretion of waste
- Production of hormones
Kidney structure
Outer cortex (contains superficial glomeruli 90% and the remaining glomeruli are Juxtamedullary) Inner medulla (divided into renal medulla pyramids with interlobular arteries/veins inbetween). Pyramid contain duct of Bellini that drain into the renal pelvis --> ureter
5 stages that occur in the nephron from glomerulus to collecting duct
- Filtration by glomerulus
- Obligatory absorption (most of water and ions) and secretion (toxins etc) by proximal tubule
- Generation of osmotic gradient by loop of Henle
- Regulated absorption and secretion by distal tubule
- Regulation of water uptake by collecting ducts
Structures present within the glomerulus?
Bowman’s space with the capillary tuft with fenestrated walls sitting within it
During the formation of filtrate, what triple barrier does it occur across?
What are the limitations of passage due to the “triple barrier”?
- Endothelial lining of the capillaries
- Basement membrane of the capillaries as it has a negative charge
- Foot processes of epithelial cells (podocytes) form filtration slit diaphragm inbetween
Limitations :
- Allows free passage of solutes up to about 60kDa
- Opposes movement of cells and large protein
- Negatively charged molecules are filtered less easily
What are podocytes?
Podocytes are cells in the Bowman’s capsule in the kidneys that wrap around capillaries of the glomerulus.
As values of glomerular filtration, what does RBF and RPF stand for?
RPF equation?
R.B.F - Renal blood flow. Total amount of blood that traverses renal artery or vein per unit time = 1100ml/min
R.P.F. - Renal plasma flow. Total amount of plasma that traverses renal artery or vein per unit time.
RPF= (100-haematocrit) x RBF
What are the factors favouring and opposing movement into the tubule?
Favouring movement INTO tubule:
- hydrostatic pressure of the blood (+55 mmHg)
- oncotic pressure of the tubule (0 mmHg)
Opposing movement into tubule:
- hydrostatic pressure of tubule (-15 mmHg)
- oncotic pressure of blood (-30 mmHg) due to proteins remaining in blood as they aren’t filtered into capsule
Balance: +10 mmHg
What is GFR?
Glomerular filtration rate (i.e. rate of filtrate production)
Normally 125-130ml/min
What are the auto regulation mechanisms of glomerular filtration?
Intrinsic and local control:
- Myogenic mechanism: Mediated by stretch receptors in the arterioles.
- Tubuloglomerular feedback (nephrogenic)
What are the 4 outcomes of myogenic auto regulation of glomerular filtration?
Afferent arteriole:
- Constriction = Reduces filtration pressure so GFR falls
- Dilation = Increases the pressure driving ultrafiltration so GFR increases
Efferent arteriole:
- Constriction = Pressure build up within the capillary, GFR increases
- Dilation = Allows blood to easily escape the capillary and pressure falls so GFR decreases
Afferent respond to increased bp by constricting, results in a relatively consistent GFR and RBF
What is the mechanism of Tubuloglomerular feedback?
A function of the juxtamedullary nephron
Flow in the DCT is indirectly monitored and high flow information fed back to the arterioles
Which ion concentrations increase when the filtrate flow is high in glomerulus?
Na+ and Ca+
What cells monitor Na and Ca levels?
The macula densa cells adjacent to the DCT monitor Na+ and Ca+ levels and signal to the afferent arteriole which causes it to constrict via adenosine release if levels are too high.
This lowers flow rate to normal limits
What are the extrinsic hormonal factors that affect RBF and GFR?
DECREASED afferent blood flow - vasoconstriction
- Sympathetic nerves release norepinephrine
- Circulating epinephrine
- Angiotensin II
INCREASED afferent blood flow- vasodilatation
- Renal prostaglandins
- Atrial natriuretic peptide
Functional unit of kidneys?
Nephron
Function of juxtamedullary glomerulus?
pumps NaCl, urea and ammonia into interstitium. This allows water to be reabsorbed into blood stream
Structure of the nephron
Cortex, outer medulla, inner medulla
Glomerulus -> Bowmans capsule -> TAL -> tDLH -> tALH -> CCT -> CNT -> ICT -> Outer medullary collection duct (OMCD) -> IMCD
Describe the classification of helminths
- Nematodes (roundworm)
- Blood and tissue
- Intestinal - Cestodes (tapeworms)
- Taenia (human host)
- Echinococcus (human is an accidental host) - Trematodes (flukes)
- Lungs
- Liver
- Blood
4 main pathological mechanisms of helminths
Inflammation
Competition for nutrients
Space occupying lesions
Stimulation of fibrosis
Name 4 Nemotode helminths found in the intestines
Ascaris
Hookworm
Enterobius
Trichiuris
Name 2 Yaenia cestode classified helminths
E. granulosus
E. multilocularis
Name 2 Echinococcus cestode classified helminths
Taenia solium
Taenia saginata
Name 2 Echinococcus cestode classified helminths
Taenia solium
Taenia saginata
Name 1 trematode found in the lung?
Paragonomiasis
Name 3 trematodes found in the blood?
S. mansoni
S. haematobium
S. japonicum
Name 2 trematodes found in the liver?
Opisthorcis
Fasciola
Name 2 trematodes found in the liver?
Opisthorcis
Fasciola
Transmission of helminths?
Faecal-oral
Vector
Direct invasion
4 types of host?
Definitive
Intermediate
Accidental
Parathenic
4 examples of helminth vector?
Flies, Aedes mosquito, crysops and snails
What is the consequence of repeated cycles of inflammation and bacterial infection in acute lymphoedema?
Elephantiasis
Clinical features of trichiuris?
• Vague abdominal symptoms • Trichiuris dysentery syndrome • Growth retardation • Intellectual compromise -micronutrient deficiency -mucosal integrity
Clinical features of hookworm?
Anaemia due to blood usage
Vague abdominal pain
Ascaris clinical features?
Vague abdominal pain
Intestinal obstruction
Hepatobiliary obstruction and jaundice
Competition for nutrients, name 4 helminthis in which this is their main pathological mechanism?
- Hookworms
- Ascaris
- Tapeworms
- Trichiuristrichiura
Space occupying lesions?
- Eggs in the wrong place
- Cysticercosis causing CSF obstruction
- Ascaris causing intestinal obstruction
What pathology’s are caused by parasites being in the liver, brain and CSF
Cysticercus causing CSF block
Hydatid cyst in the liver
Cerebral cysticercosis in the brain (leading to seizures)
What is the consequence of schistosomiasis?
In schistosomiasis, eggs trapped in the tissues produce granulomatous inflammatory reactions, fibrosis, and obstruction.
What is the result of fibrosis associated with tissue schistosomes?
Leas to inflammation and fibrosis….
Lung fibrosis –> Right HF
Liver fibrosis –> Portal hypetension
Bladder fibrosis –> Bladder cancer
What is the general treatment for helminth infections associated with the following pathogenesis: • Inflammation • Competition for nutrients • Space occupying lesions • Stimulation of fibrosis
Inflammation
• Anti-inflammatory eg., steroids
Competition for nutrients
• Reduce worm burden and support nutrition
Space occupying lesions
• Surgery, decompression
Stimulation of fibrosis
• Helminth eradication and treatment of secondary effects
Treatment of cestode classified helminths?
Praziquantel
Due to the problems of the cysticercosis, what must be combined with anti-helminthic treatment of cestodes?
Continue anti-epileptic drugs
+ Steroids
Treatment of nematodes classified helminths?
Albendazole mainly
[Levamisole and piperazine are rarely used]
Praziquantel: Mechanism? Treats which diseases? Properties? Side effects on neuro, GI, Liver and skin? Drug interactions?
Mechanism: Probably increases calcium permeability of membranes depolarising them. May interfere with purine synthesis
Treats: • Hydatid disease • Cysticercosis • Schistosomiasis • Clonorchis, Fascioliasis and Paragnomiasis infection
Properties:
- Well absorbed orally
- Low systemic conc
- Excreted in the kidneys
- Short half life
Side effects:
Neural: Dizziness, headache, drowsiness and somnolescence
GI: Abdominal cramps and nausea. Diarrhoea
Liver: Transient asymptomatic rise in transaminases
Skin: Urticaria, rash and pruritis
Drug interactions:
Interacts with rifampicin (decreased concentrations), carbamazine, phenytoin (reducing praziquantel bioavailability)
Albendazole: Classification? Used for treatment of which nematode? Used for treatment of which protozoa? Used for treatment of which Cestoda infections? Mode of action? Where is it concentrated? Side effects?
Classification: A benzimidazole
Treatment of nematode infections: trichiuriasis, filariasis, Enterobius infection, ascariasis, hookworm, toxocariasis, strongyloidiasis
Treatment of some protozoa: giardia
Treatment of some cestode infections: Neurocysticercosis
and hydatid disease
Mode of action:
- Binds to colchicine sensitive receptor or tubulin. Prevents polymerisation into microtubules.
- Impaired glucose uptake and depleted glycogen stores
- Degenerative changes appear in the worm
Concentrated in semen and may be teratogenic
Side effects: • Persistent sore throat • Headaches dizziness and seizures • Acute liver failure • Aplastic anaemia and marrow suppression
Piperazine as a treatment for helminths?
- Agonist activity against the gamma butyric acid receptor paralysing muscular activity
- Orally active
- Metabolism in liver
- Variable half life
- Used to treat ascariasis and enterobius infection
- SE include GI tract upset and rarely hypersensitivity, dizziness
What drug replaces levamisole and pyrantel
Albendazole as it’s less toxic
Helpful use of diethyl carbamazine?
Causes worms to come to skin surface for diagnosis by biopsy.
Features:
• A piperazine derivative
• WHO essential medicine list
• Inhibits arachidonic acid making parasites more susceptible to immune attack
• Filaria infection
• Associated with increase in inflammation: caution Mazzotti reaction, loss of site in onchocerciasis
Ivermectin: Mode of action? Active against? Complicated by? How is absorption increased pass the BBB?
- Ivermectin binds glutamate-gated chloride increase in the permeability of the cell membrane to chloride ions with hyperpolarization of the nerve or muscle cell resulting in paralsysis and death of the parasite either directly or by causing the worms to starve.
- Active against fliarial worms, lice, scabies and bed bugs
- Complicated by CNS depression
- Increased risk of absorption past the blood brain barrier of HIV protease inhibitors, calcium channel blockers and glucocorticoids
Niclosamide:
Mechanism?
Treats?
Side effects?
Mechanism: Inhibits glucose uptake, oxidative phosphorylation and anaerobic metabolism
Treats: Used for the treatment of tape worm infections only
Side effects: Causes dizziness, skin rashes, drowsiness and perianal itching.
Prevention and control of intestinal helminths
- Vector control for filariasis
- Meat inspection for cysticercosis
- Sanitation and hygiene for intestinal nematodes
Functions of the proximal tubule
Recovery of ions, sugars, amino acids, peptides and a considerable amount of total water
Secretes components for urinary excretion
Metabolises amino acids
What are the two pathways molecules and ions might take across the proximal tubule epithelium?
- Transcellular route (through the cell body)
2. Paracellular route ( through the leaky ‘tight’ junctions between cell bodies
What are the forces involved in obligatory reabsorption from the proximal tubule?
- ION GRADIENTS across the basolateral membrane – active transport 3Na out 2K in
- This sets up an ELECTROCHEMICAL GRADIENT of about -3mV (tubule lumen negative; causes paracellular efflux of cations)
- OSMOTIC GRADIENT set up by pumping Na out of the cell into the interstitial space
- Water moving along the paracellular path due to osmotic pressure drags solutes along with it. Known as SOLVENT DRAG
- Chemical concentration of solutes left behind when water leaves the tubule facilitates a CHEMICAL GRADIENT
Different transport mechanisms at the proximal convoluted tubule cell?
Sodium pump: Sets up Na+ concentration gradient. Gradient used by cell to transport other substances Co-transport: Moves substances with Na into the cell Counter transport (exchange): Moves substances with sodium out of tubule
Movements of components occurring at the proximal convoluted tubule?
- The sodium pump decreases [Na+]i
- Sodium conc. gradient is used by the Na+/H+ exchanger to transport H+ OUT of the cell (against its conc. gradient)
- H+ combines with filtered bicarbonate to produce carbonic acid which breaks down to H2O and CO2
- H2O and CO2 diffuse into the cell
- H2O and CO2 produce H+ and bicarbonate
- H+ leaves cell (see note 2) into tubule lumen
- On basolateral membrane chloride, bicarbonate and potassium leave down their concentration gradients
- On basolateral membrane Ca2+ is exchanged for Na+. Ca2+ leaves the cell against its conc. Gradient
- On apical membrane, Ca2+ enters through a Ca2+ channel. Also via paracellular route
- Entry of other solutes: coupled to Na+ entry on apical membrane; facilitated diffusion on the basolateral membrane.
- Solvent drag: Due to osmotic gradient from lumen to ISF. Movement of water (solvent) drags other ions through the paracellular route
What is “transport maximum”?
The limit of how much solute can be moved across the proximal convoluted tubule.
A.k.a. Tm or Tmax
Measured in mg/min or mmol/min (rate)
How does exceeding Tmax affect reabsorption and excretion?
Ion/component remains in fluid in tubule and is excreted in urine
Amount filtered (mg/min) =
plasma conc (mg/ml) x GFR (ml/min)
Threshold is the point at which the amount filtered is equivalent to ____
Threshold is the point at which the amount filtered is equivalent to Tmax.
Above threshold, substance appears in the urine. E.g. in diabetes the conc of glucose in urine is proportional to the plasma concentration
Amount of solute filtered is proportional to the amount present in the ______
Amount of solute filtered is proportional to the amount present in the plasma
The amount of solute appearing in the urine is the amount filtered from glomerulus plus ???
The amount secreted
What happens to the following solutes in the proximal convoluted tubule after they have been filtered in the glomerulus: Urea? Lipid soluble substances? Phosphate? Protein?
Urea: simple diffusion reabsorbs 50-60% (rest lost)
Lipid-soluble substances: simple diffusion
Phosphate: sodium-linked transport. Activity of carriers changed by parathyroid hormone
Protein: small amount digested to amino acids within the tubule cells
What substances are obligatorily reabsorped in the proximal convoluted tubule?
100%: glucose, amino acids, lactate 90%: bicarbonate 65%: water and sodium 55%: potassium 50%: chloride
What is clearance?
Range?
The volume of plasma which is cleared of substance per unit time (ml/min)
Theoretical value
Range:
Zero (i.e. fully reabsorbed e.g. glucose, or never filtered e.g. protein)
—->
Equivalent of RPF (all substances filtered ends in urine)
What 3 renal processes determine and modify composition of urine?
How are this values used to calculate the amount secreted?
Glomerular filtration
Tubular reabsorption
Tubular secretion
Amount secreted= Amounted filtered - amount reabsorbed + amounts secreted
Filtration fraction =
F.F. = GFR/RPF
What qualities must a substance have to have it’s GFR measured?
Ideal substance?
To measure GFR the substance must be:
- Freely filtered at the glomerulus
- Neither secreted or reabsorbed
- Not metabolised
- Not toxic
Inulin – ideal substance but is a plant sugar
and needs to be infused to establish constant
plasma concentrations
What is the of the clearance ratios of {substance] and inulin?
Clearance [substance]/ clearance ilulin
If ratio = 1. Neither secreted or reabsorbed
If ratio> 1. Substance secreted
If ratio < 1. Substance reabsorbed
Use of clearance ratios?
Determine renal transport mechanism (ie. net absorption and net secretion)
Clearance =
Clearance = (urine concentration of X x urine flow rate)/ plasma concentration of X
3 modes of transmission of helminths?
Faecal oral (Ascaris) Vector (filariasis) Direct invasion (Schistosomiasis)
Examples where inflammation
is the main pathogenic mechanism
- Filariasis
- Onchocerciasis ( in eye leading to blindness)
- Toxocariasis (generalised inflammation all over body)
- Cysticercosis
- Schistosomiasis
- Enterobius
How many lobes should a neutrophil have? Pathology leading to excess lobes?
Should have 4
If more, sign on anaemia
Cells in the stomach involved in gastric acid production
The stomach has a mucus cell lining, parietal glands an pyloric glands.
The parietal cells secrete HCl, pepsinogen, IF, mucus.
Whilst pyloric glands secrete mucus for protection and gastrin which stimulates ECL cells.
Describe the pathogenesis of Helicobacter infection
Produces urease which raises the gastric pH allowing H pylori to colonise
–>
Mucosal damage by bacterial mucinase etc
Inflammation by gastric acid, proteases and effector molecules
Mucosal cell death by cytotoxins and ammonia
Inhibition of gastric secretion
• Food in the small intestine stimulates a reverse enterogastric reflex
• Reflex can also be initiated by
- distention of the small bowel
- acid in the upper intesting
- presence of protein breakdown products - irritation of the mucosa
• Secretin also opposes gastric secrtion
Inhibition of gastric secretion
• Food in the small intestine stimulates a reverse enterogastric reflex
• Reflex can also be initiated by
- distention of the small bowel
- acid in the upper intesting
- presence of protein breakdown products - irritation of the mucosa
• Secretin also opposes gastric secrtion
H pylori infection consequences
Peptic ulcer disease
Gastric carcinoma
MALT lymphoma
Also: Dyspepsia, atrophic gastritis, iron deficiency anaemia, idiopathic thrombocytopaenic purport
Role of helicobacter in peptic ulceration:
Acute infection?
Chronic infection?
Acute infection:
• Can cause acute infection with symptoms that include nausea, dyspepsia, malaise and halitosis
• Acute infection tends to last about two weeks
• Gastric mucosa is inflamed with neutrophils and inflammatory cells with marked persistent lymphocyte penetration
• Stomach acid production falls
Chronic infection: • Local inflammation and gastritis • Outcome depends on: - pattern of inflammation - host response - bacterial virulence - environmental factors - patient age
Tests for diagnosis of H. pylori infection
Urea breath test
Stool antigen
Biopsy: Histology, rapid urease test, culture
3 approaches to managing peptic ulcer disease?
1. Reducing the damage to the mucosal surfaces • dietary advice • antacids • bismuth 2. Killing H. pylori 3. Reducing gastric ascid • proton pump inhibitors • H2 blockers
What drugs are used in killing H, pylori?
PPI
Ampicillin
PLUS either clarithromycin or metronidazole
(If penicillin allergic then clarithromycin AND metronidazole)
How are histamine blocked drugs used to reduce gastric acid in H. pylori treatment?
• Reduce gastric acid by reducing the stimulation of oxyntic cells via the histamine pathway
• Reduces gastric acid and permits ulcer healing
• Cimetidine was the first drug to show the value of this
approach
• Ranitidine followed and had a better safety profile
What is the use of cimetidine in H pylori treatment?
H2 blocker so reduce gastric acid secretion
Oral
Renal excretion
Adverse event response:
-Causes dizziness
-Use P450 inhibitor. Affects hormone metabolism
What is the use of Ranitidine in H pylori treatment?
H2 blocker
Oral
Renal excretion
Causes: Malaise and dizziness, liver toxicity, increased risk of GI infection
Omeprazole use in H pylori:
Action?
Side effects?
Action:
Inhibits H+K+ATPase by binding irreversibly as the apical membrane. Hence K+ isn’t pumped into parietal cell and the H+ isn’t pumped out.
HCl can therefore not be formed.
Side effects: Headaches, dizziness, abdominal pain, diarrhoea, nausea, vomitting, rash
If there is previous exposure to and penicillin allergy, what drugs are used in H pylori?
- Proton pump inhibitor
- bismuth
- metronidazole
- tetracycline
If treatment of H pylori fails, what is the second line treatment?
Occurs 1/5
2nd line Tx:
- either an alternative regimen
- quadruple Tx (PPI+bismuth+2 antibx)
Describe the epidemiology of liver disease in the Scottish population
Obese
Females
Hep B/C
Time: Increased deaths due to alcoholic liver disease
Person: All age groups at risk. More females
Place: Scotland high in comparison with other European/ UK countries
Outline the political, economic, behavioural and organisational barriers to reducing alcoholic liver disease in Scotland
Political:
- To be in power you need to be accepted by society
- Economic + culture factors = Political barriers
Economic:
- Alcohol industry
- Secondary alcohol enterprises
Behavioural:
- Stigma to not drinking
- Form of celebration
- Culture
- Social lubricant
Organisational:
- Scottish government
- Alcohol industry
- Retailers
- NHS
- Police
- Local authorities
Define the Ottawa Charter for health promotion
Explain the Tannahill Model of Health Promotion
- Developing Personal Skills
- Strengthening Community Action
- Reorientation Health Services
- Building Healthy Public Policy
- Creating Supportive Environments
Explain the concepts of population and risk approaches to disease prevention
Population Approach:
• Seeks to reduce disease/risk factor in everybody in the population
• Useful when:
– The disease/risk factor is distributed among large
proportions of the population
– The results of not intervening to prevent the disease even in one person are very severe
Risk Approach:
• Seeks to reduce disease/risk factor in a target group
• Useful when:
• It may be difficult to change behaviour at population level
• Wherethereis concentrated risk within the population
Impacts of excessive alcohol intake?
Health intake Violence Crime Domestic violence Economical productivity Family/social impacts
Population approach to reducing alcohol liver disease, examples?
Adding folic acid to flour
Water fluoridation in the UK
Population approach to reducing alcohol liver disease, 2 examples?
Adding folic acid to flour
Water fluoridation in the UK
Risk approach to reducing alcohol liver disease, 2 examples?
Bowel cancer screening to over 50s
Preventative surgery for women at risk of breast and ovarian cancer
How does the “Changing Scotland’s Relationship with alcohol: A Framework for Action” encourage a supportive environment?
- Support expansion of diversionary initiatives for young people e.g sports, culture and arts
- Promote implementation of workplace alcohol policies
- Work with retailers and producers to develop a code of practice for responsible promotion of alcohol
How does the “Changing Scotland’s Relationship with alcohol: A Framework for Action” promotes a healthy public policy?
- Prevent the sale of alcohol as a loss-leader
- Introduction of a minimum price per unit of alcohol
- 125 ml glasses of wine to be available and the default
How does the “Changing Scotland’s Relationship with alcohol: A Framework for Action” promote personal skill development?
- Work with partners to improve substance misuse education in schools
- Promote awareness and understanding or alcohol misuse and responsible drinking
- Support measures to improve alcohol product labelling
How does the “Changing Scotland’s Relationship with alcohol: A Framework for Action” work to re-orientate health services?
- Appropriate use of screening tools improves the detection and treatment of alcohol problem
- Provide a national training programme for staff involved in Brief interventions to reduce alcohol consumption
- Introduction of new NHS target to delivery Brief interventions to reduce alcohol consumption
How does the “Changing Scotland’s Relationship with alcohol: A Framework for Action” work to strengthen community?
- Support for early intervention such as the Community Initiative to Reduce Violence
- Establishment of a youth commission on alcohol and young people
