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Case 4 notes

Physiology and pharmacology of hormonal contraception


Length of a normal menstrual cycle is 21 to 40 days
Hypothalamus produces
gonadotropin releasing
hormone (GnRH) in
pulses every 1/2 hrs.

GnRH stimulates the


pituitary gland to
produce FSH and LH
(positive feedback of
GnRH on FSH and LH)

Oestrogen released by ovaries increases


LH and decreases FSH
HORMONES OF THE MENSTRUAL CYCLE Progesterone and oestrogen released
 Both had direct effect on ovaries, not together by ovaries (after ovulation)
endometrium decreases LH and FSH
 FSH is responsible for follicle development
o Helps recruit 10-15 follicles. However, it needs to decrease to prevent ovaries from
maturing multiple follicles (therefore leading to multiple eggs being released) and keep only
one leading follicle
o Peak in FSH helps detach the egg from inside the follicle
 LH helps in egg maturation and provides hormonal for ovulation and release of eggs from the ovary
o Follicle releases oestrogen, high levels of oestrogen -> triggers LH peak -> leads to ovulation
o Increase in oestrogen and inhibin leads to the decrease in FSH, therefore preventing
multiple follicles from developing
o Oestrogen is responsible for the development and growth of the endometrium and cervical
mucous
 This helps the sperm survive for up to 5 days and move towards the egg
 Ovulation happens 36 hours after LH starts to rise and 18 hours after LH peak

 AFTER OVULATION: corpus luteum releases progesterone


o Progesterone is responsible for growth and maturation of the endometrial lining
o Cervical mucous becomes dried and less nutritious – this prevents fertilisation and other
eggs from being released
 If no fertilisation – oestrogen and progesterone fall and trigger menses
 If fertilisation – oestrogen and progesterone continue to increase
o Keeps FSH and LH low
FOLLICULAR PHASE =
development of follicle
OVULATION = mature egg
released from follicle
LUTEAL PHASE = corpus
luteum releases
progesterone

COMBINED PILL

 Oestrogen + progestogen (synthetic version of progesterone)


 3 main types
o 21 day pills (monophasic)
 Each pill has the same dosage
 Pills taken for 21 days, then 7 days with no pills
o 21 day pills (phasic)
 Different dosage within each packet
 Needs to be taken in order
 Mimics more natural increase in hormones
o Every day pills (could be monophasic or phasic)
 21 pills contain hormones
 7 pills are placebo
 Taken for 28 days without a break
 Causes high levels of oestrogen and progesterone from the start of cycle
o This prevents rise in FSH and LH – so not follicle recruitment and no ovulation
 Progesterone and oestrogen still affect the endometrium the same way -> it thickens -> prevents
sperm from surviving
 When pill is stopped (or dummy pill taken for 7 days), withdrawal bleed occurs
o Hormone levels drop and endometrium bleeds due to withdrawal from the pill (not due to
ovaries)
 Pill dampens effect of FSH and LH (not completely 0)
 SIDE EFFECTS – loss of libido and poor lubrication, hypertension, DVT, heart attack, stroke, PE, liver
tumours
 OESTROGEN BASED PILLS CONTRAINDICATED FOR:
o Blood clots
o Heart disease
o Liver tumours
o Oestrogen/ progesterone sensitive cancers
o Smokers and above 35
 Protective against – ovarian + endometrial cancer, ovarian retention cysts, pelvic inflammatory
disease

PROGESTERONE ONLY PILL

 ‘mini-pill’. Needs to be taken at the same time everyday because it stops working as soon as you
miss one and it doesn’t prevent ovulation as effectively
o This means NO WITHDRAWAL BLEED
o Works by thickening the cervical mucous, reduce fallopian tube’s cilia activity to prevent egg
from travelling from the ovary
o If pill is stopped, mucous changes are quickly reversed -> not very efficient
 3 hour pill
o Levonorgestrel or norethisterone
o If one is missed, needs to be taken within 3 hours
 12 hour pill
o Desogestrel
o If one is missed, needs to be taken within 12 hours
 Prescribed to people who have just given birth or are breastfeeding
 Used to delay menstruation – especially in women who have irregular periods due to menopause
EMERGENCY CONTRACEPTION

 Levonorgestrel – POP, ‘morning after pill’


o High dose of progesterone to thicken mucous and prevent ovulation
o Efficacy depends on the phase of the menstrual cycle
 More effective when taken close enough to the LH surge to suppress it
o Needs to be taken within 3 days of unprotective sex
 Ulipristal acetate – progesterone receptor modulator
o Prevents progesterone from binding to its receptor -> reduces endometrial thickness
o Animal studies – possibly embryotoxic
o Needs to be taken within 5 days of unprotected sex

PREGANACY TERMINATION AND MISCARRIAGE MANAGEMENT

 Mifepristone ‘abortion pill’ – also a progesterone receptor antagonist


o Taken in hospital setting
 1-2 days later, patient takes Misoprostol (synthetic prostaglandin E1 analog)
o Works by softening the cervix and causing uterine contractions

INTRAUTERINE DEVICES

 Copper IUD is the most effective emergency contraception


 COPPER IUD – slowly releases copper ions which prevent sperm from fertilising egg
o Might increase flow
o Works straight away
o Can be placed at any time during the menstrual cycle
o Reversible as soon as it is removed
o Protection for up to 10 years
o Inserted and removed by medical professional
o Slight risk of infection
 Hormonal intrauterine system (IUS)
o Releases progesterone, similar to POP
o Similar side effects to POP
o Might reduce flow and cramps

OTHER PHARMACOLOGICAL CONTRACEPTIONS

 Combined
o Patch – 1 patch a week, 3 patches then break. Might fall off and cause skin irritation
o Vaginal ring – lasts 21 days, works in diarrhoea, can come out but easily reinserted, works
straight away if started witing day 5 of cycle
 Progesterone only
o Subdermal implant – under the skin and lasts 3 years, CONTRAINDICATED – liver disease,
heart disease, stroke or breast cancer
o Injection – lasts 8-13 weeks, might take up to a year for menstrual cycle to return to normal
after stopping, not affected by other medicine
BARRIER METHODS

 Male and female condoms


o Male – 98% effective, female – 95% effective
o Protect from STI, including HIV
o Female are less commonly available and more expensive
o Male condoms with spermicide increase risk of UTIs

STERILISATION

 Male – vasectomies, Female – tubal ligation (laparoscopic procedure)


o Cut and tied with heat or closed with clips/ silicon rings
o Small chance that vas deferens or fallopian tubes can re-join
o Usually difficult to revert or permanently sterile

Microbiology of the genitourinary tract


UTIs PRESENTING SYMPTOMS
 Cystitis (bladder) Uncomplicated UTI risk factors
o Increased urinary urgency and frequency - female
o Dysuria – painful urination
o Lower abdo pain - older and younger age (extremities)
o WBC and bacteria in urine
o Raised temp
Complicated UTI risk factors
 Pyelonephritis (kidney)
o As above - indwelling catheters
o Flank pain
- immunosuppression
o High fever
o Malaise - urinary tract abnormalities
o Confusion - antibiotic exposure
o Nausea

Uropathogenic E.coli (UPEC)


most commonly causes UTI
HIV
Recommended
antiretroviral therapy
contains:
- Two nucleoside
reverse transcriptase
inhibitor (NRTI) –
tenofovir and
emtricitabine
- Plus one of the
following: (ritonavir)
boosted protease
inhibitor/ non-
nucleoside reverse transcriptase inhibitor (NNRTI)/ integrase inhibitor (INI)
HIV PrEP
Pre exposure prophylaxis – prevent HIV by taking a pill everyday
Brand name TRUVUDA, contains tenofovir and emtricitabine (NRTIs)
89 -99% effective if taken daily.

Pharmacology of antibiotics
Antibiotic – can be used to treat bacterial infection and cancer and sometimes some fungi/ protozoa.
Synthesised in vivo by bacteria or fungi
Chemotherapeutic – used to treat bacterial infection and cancer. Synthesised in a lab
TARGETS FOR ANTIMICROBIALS

 Inhibitors of cell wall synthesis – -Lactams (penicillin and cephalosporins) – mainly for GRAM
POSITIVE infections
o Glycopeptides - Vancomycin – different MOA – treatment for MRSA (gram positive)
 BACTERICIDAL effect
o Cephalosporin – Neisseria Gonorrhoea (gram negative) treatment as Gonorrhoea is
completely resistant to penicillin
o Gonorrhoea and chlamydia tend to have co-infection (together), so cephalosporins and
azithromycin (to treat chlamydia intracellularly) are used in combination
 This is helpful because it helps reduce the chance of gonorrhoea developing
resistance to cephalosporins.
 In addition, some gonorrhoea phagocytosed by neutrophils can also be killed quicker
as azithromycin penetrates cell wall
o Penicillin - BACTERICIDAL effect
 Penicillin binds to penicillin binding proteins (PBP)
 This prevents cross-linking of peptides within the peptidoglycan cell wall

 Inhibitors of protein synthesis – tetracyclines, aminoglycosides, macrolides


o Human ribosomes are 40S and 60S, whereas bacterial ribosomes are 30S and 50S (so it
shouldn’t interfere with human protein synthesis)
o At higher concentrations, it can interfere with mitochondrial function
o Some of these drugs have a narrow therapeutic index
o Macrolides (thromycin) – used to treat chlamydia (intracellular infections). Inhibits liver
enzymes and increases half life of other drugs (warfarin -> leads to bleeding)
 BACTERIOSTATIC AND BACTERICIDAL effects
 They work by inhibiting the translocation events in the bacterial protein synthesis by
binding to 50S subunit of the bacterial ribosome
o Tetracyclines (Doxycycline) – in children can affect bone growth and stains teeth, associated
with superinfection
 BROAD SPECTRUM infections
 BACTERIOSTATIC effect by outcompeting tRNA for the A binding site of bacterial 30S
ribosomes. Therefore they inhibit bacterial synthesis
 CONTRA – in pregnancy as it can affect teeth and bone development
o Aminoglycoside (gentamycin) – mostly for GRAM NEGATIVE infections – associated renal
damage, contraindicated in elderly. Synergism with cell wall inhibitors
 Aminoglycosides block the initiation of bacterial protein synthesis by binding to the
30S ribosomal subunit
 ADR – dose related irreversible ototoxicity
 BACTERICIDAL effects

 Inhibitors of nucleic acid function or synthesis – fluoroquinolones and rifampicin – BROAD


SPECTRUM infections
o Ciprofloxacin/ levoflaxin (fluoroquinolones) – inhibition of topoisomerase 2 – DNA strand
breaks – used in UTI and gonorrhoea
 BACTERIACIDAL – prevent bacteria DNA replication
o Synergism with cell wall inhibitors
o Rifampicin – mRNA synthesis inhibition. Enhances liver function – shorter half-life of
contraceptive pill

o Metronidazole is nitroimidazole antibiotic

 Inhibitors of metabolism – sulphonamides (sulfamethoxazole)


o Dihydrofolate reductase inhibition - Antibiotics target folate synthesis which is important for
protein and DNA synthesis
 BACTERIOSTATIC effects – limit bacterial growth
o Sulphonamides and trimethoprim act synergistically (co-trimoxazole) in toxoplasma
infections
o Useful in UTIs – BUT CONTRAINDICATED IN HEPATIC IMPAIRMENT (e.g. hepatitis)
o These drugs are not used in the presence of pus as dead neutrophils can be useful for
bacteria

 Inhibitors of cell membrane function – isoniazid


COMBINING ANTIBIOTICS

 Prevention of resistance
 In serious infection
 Infection with more than 1 microorganism
 Unknown microorganism
 Enhanced efficacy – SYNERGISM
SYNERGISM - this means the net effect of using the two antibiotics at the same time is bigger than the
additive effect (e.g aminoglycoside (protein synthesis inhibitor) used with penicillin (cell wall synthesis
inhibitor)- penicillin weakens cell wall and allows aminoglycosides to enter an effectively kill bacteria)

Selective toxicity: antimicrobials can affect bacteria without major effects on host mammalian cells.
However, at higher concentrations, the drug can cause side effects by affecting human cells
Therapeutic index: difference between effectiveness and toxicity

WHY CAN BACTERIA BE RESISTANT TO ANTIBIOTICS?

 Mycoplasma/ urea plasma – don’t have a cell wall, so no penicillin binding protein
 Bacteria may have polymorphism – slightly different sequence of penicillin binding protein
 Inaccessible – e.g. chlamydia where the bacteria grows intracellularly
 Bacteria can naturally express Beta lactamase (S. Aureus)
o Beta lactamase can cleave the beta-lactam ring in penicillin and cephalosporins, therefore
making them inactive
o This resistance can be overcome by clavulanic acid – mimics beta lactam antibiotics and
inhibits beta lactamase in bacteria
o Clavulanic acid has no antibiotic activity itself, therefore this is NOT synergism
o Co-amoxiclav – combination of amoxicillin (penicillin) and clavulanic acid
 Acquired – genetic shift – transfer or resistance between strains, acquired beta lactamase
expression

DRUG TYPES AND THEIR DISTRIBUTIONS

 Lipid soluble – body fats, cells, CSF In meningitis, BBB is broken down, so it
o Well absorbed, well distributed is easier for penicillin (hydrophilic) to
 Polar drugs (extracellular – plasma and tissue) enter the CSF and reach therapeutic
o Can’t cross BBB, can’t get into cells levels. Over time uptake of penicillin is
o Low volume of distribution reduced as BBB has recovered
o pH dependent

Intracellular bacteria (chlamydia, legionella, mycobacteria TB) are also


harder to reach. Penicillin can’t penetrate the human cell, so it can’t
be used. Macrolides (clarithromycin and azithromycin – protein
synthesis inhibitors) accumulate in cells, so they are used. They are
lipophilic – very lipid soluble
If person is renally impaired, antibiotics are accumulated and can cause toxicity
I.E in elderly people, gentamycin is contra indicated Pharmacodynamics – what drugs do to
the body
ADVERSE DRUG REACTION IN PATIENTS
Pharmacokinetics – how drugs are
 Type A ADR
absorbed/ metabolised/ excreted in
o Predictable and dose related
the body
 Type B ADR
o Unpredictable, often immune related or allergic reaction
o Not dependent on dose and can be induced at low concentrations

Broad spectrum antibiotics risk killing the commensal flora.


The use of this can allow other pathogens to proliferate (this is SUPERINFECTION). E.g. tetracycline causes
candida (yeast) and thrush (clinical infection)
After use of penicillin -> C. difficile infection -> pseudomembranous colitis (all caused by killing of the
commensal flora)
Treatment for imbalance of commensal flora is faecal transplant – poo from a healthy commensal gut
transplanted

POLYPHARMACY

 Competition for metabolic pathway -> shortage of enxymes, slower metabolism, accumulation of
toxic products
 Inhibition of the function of the liver (fluroquinolones, macrolides)
o This is problematic is patient is on warfarin
o If warfarin increases, patient starts bleeding
 Activation of the function of the liver – rifampicin – TB treatment
o Increases metabolism of the oral contraceptive pill -> reduced half life of contraceptive pill ->
increased risk of pregnancy

BACTERIOSTATIC VS BACTERIOCIDAL ANTIBIOTICS

 Bactericidal = actual reduction of the bacteria (used in immunodeficient patients)


 Bacteriostatic = only stops
bacterial growth, when
antibiotic is removed,
bacteria starts growing
again
Bactericidal – used in
immunodeficient, critically
ill patients, areas where
there are not many immune cells (e.g. CSF), endocarditis – where bacteria is trapped in fibrin matrix
and divides slowly

Bacteriostatic – in healthy individuals to allow natural immune response, uncomplicated infections.


Important to finish course for this!

A given agent can be bacteriostatic and bactericidal in different conditions – depends on dosage of drug
and target of bacteria

Applied renal physiology - How does the kidney work?


GFR

 Determined by
o Hydrostatic pressure
o Oncotic pressure
o Properties of the barrier (basement membrane)
 GFR = K(f) x net filtration pressure
o K(f) determined by hydraulic properties and surface area

Inulin is used to measure GFR as it is freely filtered


and unchanged at glomerulus. It is not reabsorbed.
Law = amount of inulin filtered should in theory
equal amount of inulin excreted

CREATININE

 Derived from creatine in skeletal muscle


 Freely filtered at glomerulus, not reabsorbed or metabolised
 If GFR, nephrons, diet and skeletal muscle mass are all constant, then plasma creatinine should also
be constant in theory
o This is not true in excessive exercise -> muscle breakdown etc.
 HOWEVER, some creatinine is secreted in proximal tubule, so it overestimates creatinine levels
MDRD GFR/ eGFR (Age, ethnicity etc.) is not very accurate at higher level of GFR.

VESICO-URETERIC REFLUX (VUR)

 Ureter enters the bladder at angle, so that when the bladder muscle contract, a ‘valve’ is created
and the increased pressure doesn’t cause the urine to back up into the kidneys
o If this is impaired, a pool of urine collects in the bladder/ ureter, increasing risk of infection
 PRIMARY VUR – resolves as patient grows older
o Incompetent ureterovesical junction
o Shortening of intravesical ureter
o Spontaneous resolution of growth
 SECONDARY VUR
o High pressure bladder
o Dysfunctional voiding or neurogenic bladder (e.g. spina bifida)
Radiology tutorial
Ionising radiation – CT and radiographs and urethrogram
No ionising radiation – ultrasound and MRI and barium
Ultrasound

 Air is white
 Fluid is black
 Solid structures are shades of grey

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