Introduction To Pharmacology Flashcards
What do we regulate in blood plasma?
Oxygen
Glucose
Ions
Volume
What do we regulate in interstitial fluid?
Glucose
Ions
What do we regulate in intracellular fluid?
ATP
Glucose
Ions
Volume
What is total body water?
42 L
~ 60%
How much water in blood plasma?
3L
How much water in interstitial fluid?
13L
- liquid surrounding cells
How much water in transcellular fluid?
1L
- CSF, lymph ect
How much water in intracellular fluid?
25L
What is the osmolality?
290 mOsm
What’s the distribution of ions ECF vs ICF?
ECF = more Na+, Cl-, Ca2+
ICF = more K+
What is amphipathic?
Have a region of polar and non-polar.
- Phospholipid bilayer
What is the cell membrane’s permeability?
Impermeable to large & charged.
Permeable to hydrophobic (O2, CO2, steroid hormones)
What are the two types of active transport?
Primary - direct - pumps using a chemical reaction
Secondary - indirect - cotransporters and exchangers - coupled uphill movement of one thing with downhill of another e.g. sodium potassium ATPase.
What is the effect of electrochemical gradients on transport?
Drives passive transport.
Depends on concentration gradient.
For charged molecules - also depends on voltage.
What is simple diffusion?
It is the movement of an uncharged hydrophobic solute through lipid bilayer.
How fast it moves = describes by flux (Jx)
What does flux (Jx) depend on?
- permeability coefficient of X (Px)
- concentration gradient
What is the flux equation?
Jx = Px(conc gradient)
What is a transmembrane protein?
- an integral membrane protein
- composed of membrane-spanning alpha helix domains
- can be single pass or multipass
What defines a protein membranes topology?
Location of sequence
What are the types of transmembrane proteins?
Pore - non-gated channel
Channel - gated pore
Carrier
Pump - requires energy
What is a transmembrane protein?
All have multiple transmembrane segments surrounding a solute permeation pathway.
Allow hydrophilic molecules to pass the membrane.
What is the structure of a transmembrane protein?
- Amphipathic helices - alternating hydrophobic and hydrophilic amino acids - hydrophobic surfaces face the membrane, hydrophilic surfaces create a central pore.
What do pores do?
Always open - facilitated diffusion
Have multiple subunits
e.g. aquaporins
Driving force = electrochemical gradient.
What does each channel have?
1) a moveable gate
2) a sensor: voltage, ligand, mechanical
3) a selectivity filter
4) an open channel pore
What do carriers do?
Never has a continuous path.
Driving force = electrochemical gradient
Slow
Can become saturated
e.g. GLUT
How does carrier diffusion work?
1) The carrier is open to the outside
2) X enters and binds to binding site
3) Outer gate closes - X still bound
4) Inner gate opens
5) X enters cell
Why can carrier diffusion become saturated?
Flux limited by # of carriers and speed of carrier cycle.
Jmax = conc high enough to occupy all carriers.
What carriers use active transport?
Pumps
Cotransporters
Exchangers
How do cotransporters work?
- Requires a solute whose electrochemical gradient provides the energy.
- Move both in (symporters e.g. Na/glucose)
- Can become saturated.
What is osmolality?
Total conc of all particles free in a solution.
mOsm = milliosmoles per kg of water
What does a channel do?
Gated ion channels e.g. potassium channel.
Driving force = electrochemical gradient
How do exchangers work?
Solutes move in opposite directions (antiporters e.g. Na/Ca).
What did Henry Dale do?
He won a Nobel prize for studying acetylcholine as an agent in the chemical transmission of nerve impulses.
What is a mediator?
A chemical, peptide or protein which communicates between cells.
What are the criterias for a mediator?
- released in sufficient amounts to produce a biological action on a specific cell in a time frame.
- applying a sample will have the same biological effect
- interference on synthesis, release or action will stop/control response.
What is the general path for mediators?
They are extracellular signal molecules –> bind to receptors on target cells –> initiates intracellular signals which alter cell behaviour through effector proteins (cell signalling)
What is signal transduction?
Converting extracellular signals to intracellular.
What are the five types of intercellular communication?
- contact-dependant
- autocrine
- synaptic
- paracrine
- endocrine
What is contact dependant signalling?
Shortest type of signalling.
e.g. immune responses and development (delta-notch signalling)
What is paracrine signalling?
Extracellular mediators act locally - stored in vesicles or synthesised on demand.
e.g. histamine, nitric oxide (vessel diameter), prostaglandins.
What is autocrine signalling?
Similar to paracrine but activates itself.
What is neuronal signalling?
Uses synapses - fast - to specific cells.
Mediators - neurotransmitters e.g. ACh (neuromuscular junction &heart), Noradrenaline (on heart)
What is endocrine signalling?
Long distance - uses hormones through the blood.
Slow and non-specific.
Hormones can be protein (insulin), aa derives (adrenaline) or steroid (estradiol).
What two ways are mediators synthesised?
1) small molecular - regulated by specific enzymes.
2) peptides - regulated by transcription - depends what genes are active and cells can produce multiple types of mediator. Vesicles can store more than one.
What are the two groups of mediators?
- preformed and stored in vesicles until released by exocytosis - rapid - includes noradrenaline and insulin –> conc usually mM which is good so we can have high conc for response.
- on demand synthesised and released by diffusion or constitutive secretion - slower to act - e.g. nitric oxide and prostaglandins.
How did we know that neurotransmitters are released in vesicles?
Studies showed quantal nature which suggested packages.
How does neurotransmitter action stop?
Enzymes can stop it e.g. acetylcholinesterase.
The NT can also be taken back into the neuron or supporting cells e.g. glia - this is due to specific transporters in membrane
Who discovered acetylcholine?
Otto Loewi
How are noradrenaline and adrenaline made?
From tyrosine –> dopamine –> noradrenaline —> adrenaline
Enzymes required for each step.
What regulates both types of mediator release?
Calcium
What is a ligand?
Any molecule which binds to a receptor - can be antagonist or agonist
Hydrophilic or hydrophobic
What is an endogenous agonist?
Mediator in the body which binds to a receptor - produces a response
e.g. ACh, noradrenaline, insulin
What is converging cell signalling?
All cells have multiple types of receptors - can integrate information
Receptors can use similar transduction mechanisms = amplify signal
What is diverging cell signalling?
Molecules can act on more than one type of cell type.
Allows coordinated responses.
What are receptors?
Proteins - recognition sites which can bind to a molecule and modulate activity of the cell
What do the first three receptor classes have in common?
- each has transmembrane spanning segments
- each has a ligand binding domain
- ligands here are hydrophilic
What are the four classes of receptors?
1) Ligand-gated ion channels (ionotrophic) - could cause electrical signals - takes milliseconds
2) G protein-coupled receptors (metabotropic) - could contact muscles - takes seconds
3) Kinase-linked receptors - can change enzyme activity - takes hours e.g. insulin receptor
4) Nuclear (intracellular) - more channels in cell membrane - takes hours
What are nuclear receptors?
Polypeptides with multiple domains
Ligands here are hydrophobic
Act as a transcription factor - binds to DNA and regulated gene expression
e.g. oestrogen receptors
Which chemical mediators use which receptors?
Most small mediators = ligand or g protein-coupled
Peptide hormones = g protein-coupled or kinase-linked
Steroid = nuclear
What are ligand-gated ion channels?
- Ion channels
- involved in fast synaptic transmission
- agonists = neurotransmitters
- made of 3-5 subunits
- had central aqueous pore
- channel closes when agonist removed
e.g. NAChR
What is nAChR?
Nicotinic Acetylcholine Receptor
- excitatory ligand gated ion channel
- on every skeletal muscle
- in NMJ and autonomic NS
- has 5 subunits
- agonist = ACh or nicotine - when bind cause depolarisation as ions flow through
What is GABA?
Bind to ligand gated ion channels (GABAa receptors) - causes inhibition as cause hyperpolarisation
What is a G protein-coupled receptor?
- Single transmembrane protein which spans membrane 7 times (7TM)
- > 800 genes code for these
- Interacts with an intracellular G protein (heterotrimeric GTP-binding protein) - has 1 alpha, 1 beta, 1 gamma subunit
e,g, MAChR
What do the heterotrimeric g proteins do?
1) beta and alpha units are bound to the receptor
2) when ligand binds - g protein changes and causes GTP to bind to alpha instead of GDP
3) G protein leaves receptor
4) a-GTP and beta-gamma dissociate
5) they can bind with their effectors
6) when GTP –> GDP again - trimer reassembles
What are examples of effectors that G proteins may control?
- ion channels
- enzymes: adenylyl cyclase, phospholipase C
What are secondary messengers?
Small diffusible molecules that spread a signal
Amplify a signal
How is adenylyl cyclase modulated?
GAs - stimulates - more adenylyl cyclase, more cAMP and more protein kinase A
GAi - inhibits - less adenylyl cyclase, less cAMP, less protein kinase A
cAMP - secondary messenger
How do g proteins increase calcium levels?
Gaq (alpha subunit) activates phospholipase C which breaks down PIP2 into IP3 & DAG. IP3 triggers release of calcium from the ER.
What do specific G proteins do?
Gs - activates adenylyl cyclase - e.g. adrenergic B1/2
Gi - (a) inhibits adenylyl cyclase or (By) activates potassium channels - e.g. adrenergic a2/muscarinic M2
Gq - activates phospholipase C - increases calcium e.g. adrenergic a1/muscarinic M1/M3
What is a drug?
A known chemical substance which, when administered, causes a biological response.
Can interfere with synthesis, storage, release, degradation or receptor-dependent response produced by a mediator.
What is an assay?
Lab test where we investigate the function of mediators, measure toxicity and test phamacological activity.
What are the principles of pharmacology?
- drug action must be explicable
- drug molecules must be bound to cells/tissues to produce an effect
- drug molecules must exert a chemical influence on 1 or more parts of a cell to produce a pharmacological response
What proteins are usually targeted by drugs?
- enzymes
- transporters
- ion channels
- receptors
What is an antagonist?
Drug which inhibits the response of an agonist - competes with agonist and binds instead
DO NOT MAKE A RESPONSE
When are side effects caused?
When drugs lack specificity - drugs will bind to its specific receptor anywhere.
What is therapeutic manipulation of contact-dependant signalling?
e.g. CAR T immunotherapy uses this signalling to kill cancer cells - engineered by altering genome of T cells
How is paracrine signalling affected by drugs?
e.g. mast cells secrete histamine - antihistamines will block histamine receptors
e.g. prostaglandins (a type of eicosanoid) are formed from different enzymes - paracetamol can target these enzymes
e.g. nitric acid relaxes blood vessels - viagra inhibits an enzyme - prolongs NO action
How can drugs target neurotransmission?
e.g. can block voltage gated sodium channels - prevent action potential - used as local anaesthetic - lidocaine
e.g. Botulinum toxin - from bacteria - cleaves proteins needed for synapses
e.g. amphetamines increase noradrenaline by displacing it from vesicles
e.g. fluoxetine blocks 5HT reuptake - antidepressant
What are endocrine cells?
Hormones are secreted from here into blood.
Have close proximity to capillary beds.
Found in endocrine tissues or glands (NO DUCTS)
What is endocrine signalling?
Enables signalling along long distances
Slow
Specific to receptors - not specific organs or tissues
What are the different hormone types?
Protein e.g. Insulin
Amino acid e.g. adrenaline
Steroid e.g. estradiol
What is a peptide hormone?
- from amino acids
- released by exocytosis by secretory granules
- receptors = cell membrane surface
- response - s to min
What are amino acid derived hormones?
- derived from tyrosine (requires specific enzymes)
- released from vesicles via exocytosis (except thyroid hormone)
- receptors = cell membrane surface (except thyroid hormone)
- response = s to min (except thyroid)
What is a steroid hormone?
- metabolite of cholesterol (needs enzymes)
- lipid soluble = diffuses out
- diffuses into cells and binds to nuclear receptors
- response = hours to days
What are the 7 endocrine glands?
- Pituitary
- Thyroid
- Parathyroid
- Adrenals
- Ovaries
- Testes
- Pancreas
What are endocrine tissues?
- hypothalamus
- kidneys
- GI tract
- heart
- liver
- adipose tissue
What is the anterior part of the hypothalamus?
Adenohypophysis
- developed from upward projection of pharynx
- troph cells are stimulated by hormones from hypophyseal portal system from hypothalamic neurons
What is the posterior lobe of pituitary called?
Neurohypophysis
- developed from downward projection of brain
- releases hormones from large diameter neurones into bloodstream
What are the main pituitary hormones?
Tropic hormones - stimulate effects from other hormones - GH, ACTH, TSH, FSH, LH, Prolactin
Posterior - ADH & Oxytocin
How is the thyroid an endocrine gland?
Secretes T3 & T4 (amino acid derived) - these depend on hypothalamic-pituitary hormones and iodine
These transport across cell membranes by facilitated diffusion and bind to nuclear receptors.
This regulated metabolism, development and growth
How is the parathyroid gland endocrine?
Parathyroid hormone (peptide) regulates plasma calcium and phosphate and targets bone, intestine and kidneys.
What is the feedback loop for PTH?
High plasma calcium is sensed by chief cells - lower PTH, lower kidney reabsorption, less bone resorption and low intestinal absorption.
What does adrenal cortex release?
Releases steroid hormones: glucocorticoid (cortisol), mineralcorticoid (aldosterone)
Zona glomerulosa - mineral
Zona fasciculata - gluco
What does the adrenal medulla release?
Chromaffin cells release adrenaline
Noradrenaline is also released
What is the hypothalamic-pituitary-adrenocortical axis?
Hypothalamus releases CRH - this causes the anterior pituitary to release ACTH - causing adrenal cortex to release cortisol.
Cortisol inhibits CRH and ACTH release
What do the ovaries secrete?
Steroid hormones: oestrogen and progesterone
This gland can switch from negative to positive feedback
What do the testes secrete?
Leydig cells secrete steroid hormone - testosterone
What is the somatic NS route?
Somatic NS
Afferent to CNS (brain and spinal cord)
Efferent to somatic NS (voluntary)
Skeletal muscles
What is the visceral nerve route?
Visceral nerves (sensory part of peripheral NS)
Afferent to CNS
Efferent to autonomic NS (involuntray - motor part of peripheral NS)
Smooth muscle, cardiac, glands ect.
What are the parts of the autonomic nervous system?
(part of peripheral)
Sympathetic - fight or flight - coordinated full body or organ specific
Parasympathetic - rest and digest - organ specific
What are examples of sympathetic stimulation?
- eye - dilation
- heart - increase heart rate
- blood vessels - constricting
- lungs - bronchiole dilatione
- liver
- reproductive systems
What are examples of parasympathetic stimulation?
- heart - decrease heart rate
- eyes
- GI tract
- bladder
- reproductive organs
How do parasympathetic and sympathetic work together?
Innervate the same tissues but have opposite effects - work synergistically.
Except for sweat glands, hair, blood vessel sm and adrenal medulla which are mainly sympathetic
What is the structure of the autonomic nervous system?
Preganglionic neuron in CNS
Postganglionic neuron in peripheral ganglion
both symp and parasymp have this organisation
What are preganglionic neurons?
Always cholinergic - release ACh
ACh activated nicotinic ACh receptors on postsynaptic cell
What is the sympathetic pathway?
Short cholinergic from thoracic and lumbar spinal cord - long adrenergic postganglionic
Target tissue express alpha and beta adrenergic receptors
What is the exception to the sympathetic pathway?
Adrenal medulla - chromaffin cells are similar to postganglionic neurones but release adrenaline - target is a and b adrenergic receptors
What is the parasympathetic pathway?
Long cholinergic neurons from brainstem and sacral spinal cord
Short cholinergic postganglionic neurones
Target tissues express muscarinic ACh receptors
What is the vagus nerve?
Cranial nerve 10
Carries 80% of parasympathetic outflow
Also carries visceral afferents
What mediates autonomic reflexes?
The spinal cord - also receives sensory afferent and brainstem input
Brainstem nuclei - mediate autonomic reflexes
Forebrain - cortical control could cause autonomic output e.g. anxiety
Visceral afferents - sensory from organs takes priority over cortical e.g. needing the toilet badly
What does the hypothalamus do?
Feeding
Thermoregulation
Circadian rhythms
Water balance
Sex drive
Reproduction
What are the principle transmitters in the ANS and where do they act?
Acetylcholine and NA
They act on nAChRs, mAChRs, alpha and beta adrenoceptors
How are cAMP and protein kinase A levels changed?
Gas - stimulates
1) stims adenylyl cyclase
2) This increases cAMP
3) This increases PKA
Gai - inhibits
1) inhibits adenylyl cyclase
2) lower cAMP
3) lower PKA
What is Gaq?
Part of g protein
It increases phospholipase C - increases IP3 + DAG - this increases calcium levels
What are the different g proteins?
Gs, Gi, Gq
They are g proteins
Gs - alpha - activated adenylyl cyclase
Gi - alpha - inhibits adenylyl cyclase
- betadelta - activates k+
Gq - activates PLC - increase calcium
What are cholinergic receptors?
- Nicotinic - agonists = nicotine, antagonist = curare
- Muscarinic - agonists = muscarine, antagonist = atropine
Both have ACh as agonist
What are the mAChR subtypes?
M1, M3, M5
- These have Gq -> increased PLC - Increased calcium
M2, M4
- These have Gi - inhibits adenylyl cyclase
Where are the different mAChRs found?
M1 = autonomic ganglia, glands, cerebral cortex - allows for gastric secretion and CNS excitation
M2 = atria, CNS - cardiac and neural inhibition
M3 = exocrine glands, smooth muscle, blood vessels - gastric and salivary secretion, GI SM contraction, vasodilation, eye accomodation
M4 = CNS - enhanced locomotion
M5 = substantia nigra, salivary glands - not known
How does our heart rate decrease?
Parasympathetic stimulation activated M2 receptors in atria - betadelta subunit will open k+ channels - moves out - more negative
- decreases HR
- slow AV conduction
- decrease atria force
What do M1 and M3 do?
Gq coupled -
contract smooth muscle (bronchoconstriction, GI motility, bladder voiding)
Stimulate secretion from glands (mucus, lacrimal glands, salivary, sweat)
What effect would muscarine have?
low BP, high saliva, high tear flow, high sweat, nausea
overdose: death from cardiac and resp failure
What effect would atropine have?
Inhibit secretion of saliva, tears, sweat ect.
Relax smooth muscle
Dilate pupils
Increase heart rate
What’s the name for drugs that indirectly enhance cholinergic transmission?
Cholinomimetic
Inhibit acetylcholinesterase
Anticholinesterase drugs:
1) long acting (irreversible)
2) nerve gas (organophosphates, pesticide)
What are noradrenaline and adrenaline receptors?
On tissues responding to postganglionic sympathetic neurons
Beta - All Gas - all increase cAMP
What adrenaline receptor effects the heart?
NA (sympathetic neurones), A (chromaffin cells) bind to B1 receptors on ventricles and nodes
1) binds
2) stims adenylyl cyclase - more cAMP and PKA
3) This phophorylates calcium channels
4) calcium enter - contraction
What causes SM relaxation in bronchioles?
B2 activation - Gas activation - stims adenylyl cyclase - more cAMP, more PKA - phosphorylates SM
What are clinical uses of adrenoceptor agonists?
Adrenaline - cardiac arrest & anaphylaxis
B2 selective - bronchodilator (salbutamol)
What are clinical uses of adrenoreceptor antagonists?
Can treat hypertension, heart failure, anxiety
But can cause bronchocontriction and cardiac depression
What germ layers do epithelia develop from?
Endoderm (GI lining)
Mesoderm (CV lining)
Ectoderm (Epidermis)
- in every organ
What are the functions of epithelia?
- protection - skin
- absorption - SI
- barrier - BBB
- diffusion - lung
- secretion - gland
What are the common properties of epithelia?
- can import or expel substances
- have tight junctions
- have apical (faces external environment) and basolateral domains with differing membrane properties (polarised)
Are epithelia cellular?
Entirely!
- avascular (no blood vessels)
- lack extracellular fibres
- little extracellular space
Are epithelia polar?
Yes!
There are differences between the apical and basal membranes (both specialised in different ways)
What is the basement membrane?
Separates cells from underlying connective tissue (collagen IV).
ECM proteins secreted by epithelial cells: collagens, laminins, proteoglycans
Structural support - basal lamina, reticular lamina (anchors BM to connective tissue below)
What are tight junctions?
Impede paracellular (between cells) movement
Protein strands (claudins) determine tightness - 24 claudin genes
Have high barrier function e.g. renal thick ascending limb
Are leaky e.g. proximal tubule
Variation in the permeability
What are adhering junctions?
Form belt around cell - under tight junctions - linked actin and cadherins
Disruption can cause spread of cancer (metastasis)
What regulates epithelia?
- underlying mesenchymal cells form epithelium as cadherins change expression
- this is epithelial-mesenchymal transition (EMT)
- used for embryonic development and cancer metastasis
What are gap junctions?
Lateral communication between cells - allows small molecule diffusion between cytoplasms - cells electrically coupled
What are the junctional complexes of epithelia?
- Tight junctions
- Adhering junctions
- Gap junctions
- Desmosomes
What are desmosomes?
Strong adhesion - has extracellular domains (cadherin).
Anchor proteins (plaques) link cadherin domains to intermediate filaments
There are some myosin filament interactions - contract
What links epithelia to basement membrane?
Actin-linked cell matrix junction
Hemidesmosome
How are epithelial cells replaced?
From stem cells - tissue homeostasis
Intestines - 5 days
Lungs - 6 months
What are the four types of epithelia?
Simple - single layer
Stratified - many layers (skin)
Pseudostratified - upper resp
Transitional - urothelium
What are the simple epithelia?
Simple squamous - thin, allow rapid passage
Simple cuboidal - secretion/absorption of molecules by active transport - some have cilium
What is simple columnar and pseudostratified?
Simple columnar: may have cilia/microvilli, majority of GI tract, in fallopian tubes, in some respiratory
Pseudostratified: single layer but looks like more, can be ciliated - these have goblet cells
What are the stratified epithelia?
Stratified squamous: most common stratified, in areas of abrasion
Stratified cuboidal: less common, glands
What epithelia can change shape?
Stratified columnar: rare - in pharynx, anus, male urethra, embryo
Transitional: round cells when relaxed
What secretes mucus, sebum and protein?
Mucus: mucus glands
Protein: serous glands e.g. salivary
Sebum: sebaceous glands e.g. oils on face
What are skeletal muscles responsible for?
- voluntary movement of bones
- control of inspiration by diaphragm
- skeletal-muscle-pump - returns venous blood
What is the skeletal muscle structure?
Striated
Myofilaments - myofibril - muscle fibre - fascicle
T tubules and sarcoplasmic reticulum form triad
H and I change shape
A doesn’t
What causes skeletal muscle contraction?
ACh at neuromuscular junction - action potential in membrane of muscle
Wave of depolarisation through t-tubule to interior of cell - runs near 2 areas of SR - triad
Reaches sarcoplasmic reticulum
Increase of intracellular calcium
What are the steps in cross-bridge formation and sarcomere contraction?
1) ATP binds to myosin head - dissociation of actin-myosin complex
2) ATP is hydrolysed - returns to resting state
3) crossbridge forms - myosin head binds to actin
4) Pi released
5) change in myosin - power stroke - filaments slide
6) ADP released
5 times a second
How many myosin heads in a thick filament?
~ 300 heads
each head cycles 5x a second
What are the 3 types of muscle fibers?
Type 1 (slow oxidative) - non fatigue, red, low glycogen, high mitochondria e.g. soleus
Type IIa (fast oxidative) - non fatigue, red, some glycogen, higher mitochondria e.g. gastrocnemius
Type IIb (fast glycolytic) - fatigable, white, high glycogen, anaerobic, few mitochondria e.g. biceps
What are slow and fast fibres?
Slow - half the diameter and take longer to contract
Fast - take 10 msec or less
What is muscle twitch?
Involuntary contraction - in three phases: latent - contraction - relaxation
What is isometric and isotonic contraction?
Isometric - muscle at fixed length - tension generated e.g. plank
Isotonic - muscle stimulation causes a change in length e.g. bicep curl
What is botulinum toxin?
Linked to food poisoning - muscle weakness, paralysis - endoproteinase which cleaves exocytosis of ACh
can be used for cross-eyedness (strabismum), uncontrolled eye movements (blepharospasm), and botox
ADD TOXINS FOR ALL CHANNELS
What is the integumentary system?
- skin
- largest organ - 12-15% of body weight
- layers by 4 months in utero, 3rd trimester skin hardens (pigment absorbs light, blood and fat scatters light)
What are the layers of the skin?
Epidermis (epithelia)
Dermis
Hypodermis (adipose tissue)
What is the dermis?
2mm in soles/ 0.2 mm in eyelid
Fibroblasts produce ECM proteins: collagen, laminin/fibronectin
2 zones:
- papillary - thin loose connective tissue, motibility of leukocytes, mast cells and macrophages
- reticular - thick dense irregular - adipocyte clusters
Has all accessory organs: hair, nail, sweat glands
Rich layer of blood, nerve endings and lymphatic vessels
What is the dermal-epidermal boundary?
Wavy boundary - dermal papillae (raised areas e.g. fingerprint), epidermal ridges
The papillae facilitate nerve fibres reaching close to the surface
What is the epithelia in the epidermis of the skin?
keratinised stratified squamous epithelium
What are the layers of the epidermis?
Stratum corneum
lucidum - stress protect
granulosum
spinosum
basale
Thin doesn’t have lucidum - thick does
No blood vessels
Self-regeneration
What is the stratum basale?
Has keratinocytes - in touch with basement membrane (stem cells)
Melanocytes give skin colour
Merkel/tactile cells connected to sensory nerves
What are melanocytes?
Release melanin - UV absorb, antioxidant
pheomelanin - red/yellow
eumelanin - brown/black
Pigment of skin = melanin + carotine (in fat + corneum) + blood
Form melanosomes which are phagocytosed by keratinocytes
What is the stratum spinosum?
Several keratinocyte layers - usually thickest (unless thick skin - corneum)
Produce keratin filaments - keratinocytes are linked by desmosomes so water retention
Dendritic cells present
What is the stratum granulosum?
3-5 layers of flat keratinocytes
Have dark staining granules
Cells undergo apoptosis
Produce glycolipid-filled vesicles which produce barrier between stratum spinosum
What is the stratum corneum?
Most superficial
15-30 layers of flattened corneocytes (dead keratinocytes)
- stratum disjunctum: have corneodesmosomes which regulate desquamation
- stratum compactum
have a cornified envelope full of keratins - enclosed within proteins and surrounded by lipid envelope
What are nails?
Derivative of stratum corneum
Packed with keratin
New cells added in nail matrix
Iron deficiency = fat/concave
Hypoxemia = clubbed
What is hair?
Filament of keratinised cells from follicle.
Hair bulb - in dermal papilla - hair matrix above
Lanugo (soft hair) - vellus - terminal
medulla - loose cells
cortex - keratinised cuboidal cells
cuticle - surface scaly cells
What are the 5 skin glands?
Eccrine/merocrine sweat glands - watery perspiration, controlled by SNS, temp regulation
Apocrine sweat glands - cells pinch off and released into scent follicles - respond to stress and sex - armpits and gentials
Holocrine sebaceous glands - cell disintegrates - oily skin and hair
Ceruminous glands - e.g. earwax
Mammary glands
How is skin a barrier?
Physical - keratin scaffold
Biochemical - mild acidic, sebaceous glands (FAs inhibit bacteria, C6H)
Immunological - dermal and epidermal langerhans cells
What are epidermal langerhans cells?
Immunological barrier - process antigens
How does vitamin D synthesis work?
Fat soluble - increases intestine absorption of Calcium
Previtamin D3 in the keratinocytes is photolysed by UV acts via a nuclear receptor prohormone - first step
Photochemical reaction
How does skin help with thermoregulation?
Anterior hypothalamus senses body temp
Receptors
Insulation
Sweating
Vasodilation/constriction
There are arteriovenous anastomoses - have sympathetic innervation - low temp - increase innervation ect.
What is cardiac muscle?
Striated - branched with intercalated disks
There are electrical coupling between myocytes by gap junctions
What is smooth muscle?
Involved in mechanical control of organ systems
Non-striated - multiple actin fibres join at dense bodies
Can be multiunit or unitary
How is calcium increased in skeletal muscles?
Depolarisation activates L-type calcium channels in T-tubule membrane - influx of calcium
There’s a mechanical tethering between the L-type channels in t-tubules and Ca channels (Ryanodine receptors) in sarcoplasmic reticulum - they open
Does cardiac muscle have t-tubules?
Yes! but only one branch of t-tubule is near SR (no triad)- dyad at the Z line
No mechanical interaction between t-tubule receptors and ryanodine receptors
The calcium instead triggers the receptors on the SR
Calcium induced calcium release
How is calcium removed from muscle cells?
1) across the membrane by plasma membrane calcium ATPase (PMCA) or Na/Ca exchanger
2) back into SR via calcium ATPase
How do we increase calcium in smooth muscle?
No t-tubules, no triads or dyad - instead have shallow invaginations - caveolae
Have two parts of SR - peripheral (next to caveolae) and central
L-type ca channels still activate from action potential
Activation of ryanodine receptors - calcium induced calcium
Activation of Gq-coupled - IP3 production - IP3 receptors in SR (calcium channels)
What role does calcium have in cross-bridge formation?
Calcium binds to TnC - causes TnT to pull tropomysosin and TnI out of the way
Myosin can now bind
When calcium dissociates - everything goes back to normal
How does smooth muscle contract?
No troponin!!
There’s calponin and caldesmon instead.
Calmodulin is stimulated by calcium
Myosin light chain is phosphorylated by myosin light chain kinase
- allows formation of crossbridge
To stop - de-phosphorylate with MLCP
What is a motor unit?
Motor neuron and muscle fibres
What is the function of the circulatory system?
Primary - distribute gases
Secondary:
- fast chemical signalling
- dissipation of heat
- mediated inflammatory and host defences
What are the two types of circulation?
Left - systemic
- Parallel pathway from left to right
- Usually through single capillary bed - two in kidney ect.
Right - pulmonary
- single pathway from right to left
What does branching do for blood vessels?
Radius decreases with branching
Combined cross-sectional area in daughter cells>parent cells
CSA increase highest in capillaries
What are the layers in a blood vessel?
Endothelial cells -> elastic fibres -> collagen fibres -> smooth muscle cells
Adventitia (outside) -> Media -> intima
What are the elastic arteries?
Large arteries - high compliance and can cope with high pressures
What are muscular arteries?
Medium sized - there are smooth muscle cells arranged circumferentially - can vasoconstrict and dilate
What are arterioles?
Connect to capillaries - have precapillary sphincters which monitor blood flow
also have terminal regions - metarterioles
smooth muscle regulated flow - regulated microcirculation
What are venules?
Are porous - exchange nutrients and waste - excellent reservoirs - have thin smooth muscle
What are capillaries?
Only endothelial and basement membrane - exchange gases, water, nutrients and waste
Three groups:
- fenestrated
- continuous
- sinusoidal (discontinuous)
What is starling’s forces?
Fluid transfer in capillaries
Jv = Kf [(Pc-Pi) - (Pi c - Pi i)
+ = filtration, - = absorption
Jv = fluid movement
Kf = hydraulic conductance
Pc/i = Capillary/intestinal hydrostatic
Pi = oncotic
Pc declines down the capillary
What is the lymphatic system?
Drains excess interstitial fluid
Maintains blood volume
Transports dietary lipids
Immunology
How are valves attached to the heart?
AV (mitral + tricuspid) connected by chordae tendinae and papillary muscles
What is in the heart wall?
Epicardium, myocardium (have cells connected by intercalated disks) and endocardium - all electrically active
- have conducting (spread AP) and contractile (contract due to AP) cells
What is the myocardial cell structure?
Has gap junctions - allows current to flow
Desmosomes anchor fibres together
Undergoes excitation-contraction coupling
What is the cardiac cycle?
Depolarisation starts at SAN - spreads to AVN by gap junctions or conducting pathways.
There’s an AV ring - prevents spread to ventricle then carried to ventricle muscle
What is the cardiac cycle sequence?
1) Atrial systole - atrial depolarisation (contracts) - v fill
2) Isovolumetric ventricular contraction (mitral & tricuspid close)
3) Rapid ventricular ejection - semi lunar valves open
4) Reduced ventricular ejection - ventricle repolarisation
5) Isovolumetric ventricular relaxation - SLV close
6) Ventricular filling
LOOK AT GRAPH
What ions are involved in the cardiac cycle?
Na+ = depolarise
Ca+ = contracts myocytes
K+ = repolarises
Pacemaker current
What is an ECG?
Electrodes detect currents from different angles of the heart
What’s on an electrocardiograph?
P wave = atria depolarisation
QRS = ventricular depolarisation
T wave = ventricular repolarisation
What is the BP like in arteries?
Arteries - high pressure, have low compliance, volume = stressed volume
What is the blood pressure in arterioles?
Has tonically active smooth muscle
Have highest resistance to blood which is effected by:
- sympathetic nerves (increases resistance) - alpha receptors = contract skin ect., beta = relax skeletal muscle and heart arterioles - need a balance
- catecholamines e.g. adrenaline
- vasoactive substances e.g. NO
What is the blood pressure in capillaries?
Low pressure - controlled by diameter of arterioles
What is the blood pressure in venules/veins?
Low pressure
Has less elastic than arteries
Has largest percentage of blood in CV - unstressed volume
Large capacitance
Has symp nerve fibres in smooth muscle + alpha adrenergic receptors - reduced capacitance - decreased unstressed volume
What is the velocity of blood in vessels?
V = Q/A
Q - flow (mL/s)
A - cross sectional area (cm)
Small vessels have higher velocity
What is the blood flow equation?
Q (mL/s) = pressure difference (mmHg)/resistance
What is resistance to blood flow?
R = 8nl/pi x r^4
n = viscocity
l = length of blood vessel
Directly proportional to length and viscosity
Inversely proportional to fourth power of radius
Series resistance = within an organ: artery-arteriole-capillary ect. Arterioles have largest decrease
Parallel resistance - branches - no loss of pressure
What pressures are in systemic circulation?
Arterial (Pa) - oscillations reflect diastolic and systolic pressure
Venous (Pv) - by veins and venules (less than 10mmHg)
Pulmonary circulation has lower pressure
Greatest pressure drop in arterioles
What is pulse pressure and mean arterial pressure?
PP = systolic - diastolic pressure
MAP = diastolic + 1/3 pp
How do we regulate BP?
Baroreceptors - in carotid and aortic sinuses
Solitary sinus receives signal and directs SNS and PNS changes via medullar CV centres
PNS –> vagus nerve –> SAN
SNS –> SAN –> arteriole vasoconstrict –> vein vasoconstrict –> cardiac muscle contracts more
There’s also chemoreceptors - increase BP if low O2 (low pH)
What is a long term control of BP?
RAAS: low perfusion in kidney - renin released - converts angiotensinogen to angiotensin I to II.
Angiotensin II increases aldosterone - increases Na and releases ADH - more water - also vasoconstricts arterioles
What does chronic hypertension do?
Desensitise baroreceptors - reduces stretch sensitivity - reduced sympathetic inhibition - hypertention not corrected
people here don’t usually experience a dip in BP at night - higher risk of heart attack ect.
Can be treated by lifestyle changes, ACE inhibitors, Ca channel blockers, diuretics, beta blockers
What is in blood?
Cellular components in plasma
- erythrocytes
- leukocytes
- platelets
What is in plasma?
Albumin
Fibrinogen - precursor of fibrin
Immunoglobulins
Proteins in coagulation cascade
What are erythrocytes?
Most abundant
non-nucleated biconcave disks
3 main functions: co2/o2 carriage, buffering
What are the white blood cells?
Granulocytes:
neutrophils (phagocyte)
eosinophils (combat viruses and parasites)
basophils (release histamines ect.)
Non-granular:
lymphocytes (mature into B and T)
monocytes (macrophages and dendritic)
What are platelets?
Bud off megakaryocytes in bone marrow - thrombopoesis in response to thrombopoetin and IL-3
1) Platelets bind to TPO
2) megakaryocytes not generated
3) If no platelets bind to TPO (as little platelets) - TPO stimulates megakaryocytes and platelets
150000 - 450000 in blood
What is haemostasis?
Prevention of a haemorrhage
1) vasoconstriction (serotonin, thrombin ect.)
2) Increased tissue pressure
3) platelet plug (primary haemostasis)
4) clot formation (secondary haemostasis)
What is the structure of a platelet?
No nucleus - have mitochondria, lysosomes, peroxisomes, alpha granules (VWF, fibrinogen, clotting factor, platelet derived growth factor), dense factors (ATP, Ca)
Have lots of receptors
Tubulin helps maintain shape
Cytoskeleton has actin and myosin
What are the three parts of a platelet plug formation?
1) platelet adhesion
2) platelet activation
3) platelet aggregation
What is platelet adhesion?
Exposed endothelium exposes collagen - VWF binds to collagen and platelet receptors
Endothelial cells also release VWF
Binding cause IC cascade - activate
What is platelet activation?
Cascade causes:
- secretion/exocytosis of dense and alpha granules (VWF and ADP - both activate it further)
PDGF - wound healing
Thromboxane - vasoconstrict and inflammation
Cytoskeleton changes
Expression of fibrinogen receptors
What is platelet aggregation?
Fibrinogen binds to platelet receptors - forms bridges between platelets - this plugs the break in endothelium
Eventually actin and myosin contract - stronger plug
What is a blood clot?
More permanent fibrin mesh
Mass of erythrocytes, leukocytes, serum and the mesh already there
Thrombus = intravascular clot
What is the intrinsic and extrinsic pathways in clotting?
Intrinsic (slow) - factors in blood contact with negatively charged membrane of platelet - causes cascade of protease reactions - ends in factor Xa
Extrinsic - endothelium injury causes tissue factor (receptor) to become activated when in contact with factor VII - results in factor Xa
xa from both enter common pathway - generates thrombin - produces fibrin
What prevents haemostasis?
Normal endothelial cells - through paracrine and anticoagulant factors
Paracrine factors - e.g. prostacyclin promotes vasodilation - inhibits platelet steps
Many anticoagulant factors - some stop thrombin
Promotion of pro-thrombotic state via vascular damage and hypoxia
Turbulent flow causes endothelial injury - caused by stenosis, large radius and high velocity
What are virchow triad’s risk factors?
Thrombosis:
Abnormal blood flow
Endothelial injury
Hypercoagulability
How much Na+ and water is excreted through our urine?
water - 1.5L per day in urine (1.1 by respiration, stools and sweat)
Na+ - 140 mmoles per day in urine (10mmoles in stool and sweat)
What is the anatomy of the kidney?
from T12 to L3 - around 10cm long and 5.5cm wide
Capsule
Cortex
Medullary ray
Pelvis
Ureter
What are the two types of the nephron?
Superficial nephron (85%) in the cortex
Juxtamedullary nephron - 15%
What are some congenital abnormalities in the kidney?
Ectopic kidney
Horseshoe kidney - fused
Renal agenesis - lack/failure to develop
What is renal failure?
Fall in GFR (usually 125ml/minute) - increase in serum urea and creatinine
Can be:
- acute (reversible)
- chronic (irreversible)
What are the differences between acute and chronic renal failure?
Chronic has longer history
Haemoglobin level lower in chronic
Renal size lower in chronic
Chronic has peripheral neuropathy
What is renal failure progression?
Thickening glomerular membrane –> damaged glomeuli –> scarring –> reduced renal size
What is uraemia?
Describes the symptoms of renal failure
- hypertension
- nausea
- anaemia
- bone diseases
- neuropathy
ect.
What happens at each stage of renal failure?
As the stages progress - GFR decreases
Uraemic syndrome becomes more severe
Serum biochemistry gets severe
Begins with anaemia and bone disease – dialysis
What causes renal failure?
30% - glomerulonephritus
25% - diabetes
10% - hypertension
What does the lymphatic system do?
Drain excess interstitial fluid and return to blood via subclavian vein to maintain blood volume
What features of a cardiac cell enable the heart to beat?
Gap junctions
Intercalated disks
Sarcolemma T tubules
Desmosomes
What is the first step in producing urine?
Glomerulus (200 micrometers) - ultrafiltration - 180 litres daily
GFR = 125 ml/min
Filtration - allows H2O and other molecules
Ultrafiltrate - protein free plasma
What is the second step of producing urine?
Filtrate modification
There is reabsorption in PCT and secretion from the blood in the tubules
What are the types of tubular transport?
Transcellular reabsorption
Transcellular secretion
Paracellular secretion and reabsorption
How are genes related to nephron transport?
Produce transport proteins
What happens at the proximal tubule?
Bulk reabsorption (70%)
- 70% water and sodium
- 100% glucose and amino acids
90% bicarb
Sodium pumped out basally by Na/K pump - Na and glucose/phosphate(NaPiIIa)/aa then cotransport into the cell apically - water then diffuses paracellularly
What is the NaPiIIa knockout mouse?
- caused less Pi reabsorption
- more lost in urine
- issues in renal mineralisation
- more stones
- increased calcification
What is NHE3 in proximal tubule?
Bicarb reabsorption - NHE3 removes H+ (which reacts with bicarb apically - makes h2O and CO2 which can move in an dissociates back to bicarb and H+) and allows Na to move in - Na then leaves and takes bicarb into blood
Knockout mice:
- lower pH as bicarb falls
- inhibits H+ secretion, Na/HCO3- transport
What is secreted by PCT?
Foreign compounds e.g. penicillin
Removal of plasma proteins bound substances
What happens in the loop of henle?
Concentration of urine
Reabsorption of Na, Cl and water
Reabsorption of Ca and Mg
Site of action of loop diuretics
What are the limbs in the loop of henle?
Thin descending - H2O moves out
Thick/thin ascending - Na/Cl moves out
Which channels move Sodium and Chlorine out of the thick ascending limb of the LOH?
NKCC2 moves sodium, 2 chlorine and a potassium into the cell
Sodium potassium pump - pumps sodium out
CLCK - move Cl out basolaterally
ROMK - move k+ out apically
Calcium and magnesium move paracellularly
What is bartter’s syndrome?
Recessive - 1 in 1 million
Causes mutations in NKCC2, CLCK and ROMK - loop of henle - Cl accumulates, type 1 = NKCC2 mutations
Causes hypotension
Salt wasting
Hypokalaemia
Alkalosis
Hypercalciuria - high calcium in urine
Polyuria
What are loop diuretics?
Furosemide
Bumetanide
Effects NKCC2
- treats high blood pressure
- has bartter’s like symptoms
What is the early DT?
Early distal tubule
- reabsorption of Na and Cl
- reabsorption of Mg
- sensitive to thiazide diuretics
What channels are involved in the early distal tubule?
NCC - cotransports Na/Cl into cell
Na/K pump - pumps sodium out basolaterally
CLCK - pumps calcium out basolaterally
Mg and Ca enter through channels
Thiazide stops NCC - treats high BP - has Gitelman’s symptoms
What is Gitelman’s syndrome?
Recessive - 1 in 40,000 - 1 in 1000 in Asian populations, 1% of Caucasian are carriers
Affects NCC in distal tubule
- salt wasting
- hypotension
- hypokalaemia
- metabolic alkalosis
- hypocalciuria - low calcium in urine
How can we see the impact of mutations on Na+ transport?
Xenopus oocyte expression studies
- inject RNA
- protein made
- evaluate if the channel is made
What does it mean if you carry a mutation for ROMK, NCC or NKCC2?
Protection from hypertension
What are some NMJ inhibitors?
- K+ - dendrotoxin
- ACh release - botulinum toxin, tetanus toxin
- Ca2+ - w-conotoxin
- Neuronal Na+ - tetrodotoxin, saxitoxin
- Acetylcholinesterase - physostigmine, DFP
- Muscle Na+ - tetrodotoxin, saxitoxin
- AChR channel - a-bungarotoxin, d-tubocurarine
What do the late distal T, collecting T and the cortical collecting duct do?
Concentration of urine
Reabsorb Na and H2O
Secrete K and H
What cells are in the late DT and cortical collecting duct?
Principal: reabsorb Na and H2O
secrete K and H+
Intercalated:
- alpha - H+ secretion, bicarb reabsorption
- beta - H+ and Cl- reabsorption, bicarb secretion
What channels does the principal cells have?
ENAC - allows Na to enter cell apically
ROMK - allows K+ to leave apically
Aquaporin 2 - allows water in apically
Sodium/potassium channel - allows sodium to leave basolaterally
Kir2.3 - allows K+ to leave basolaterally
Aquaporin3/4 - allow water to leave basolaterally
What does amiloride do?
Stops ENaC in a principal cell - no Na+ can be reabsorbed
Used for Liddle’s syndrome - reduces blood pressure
What is liddle’s syndrome?
Autosomal dominant - ENaC isn’t removed - more Na
Na+ retention - fluid retention
Hypertension
Hypokalaemia
Metabolic alkalosis
Low renin and aldosterone
What is ENaC like in Liddle’s syndrome?
COOH tail in beta or gamma subunit is mutated
Proline is deleted - there is a reduced removal of ENaC
Therefore more ENaC - more Na leaves - more water reabsorbed - causes hypertension (MAP = CO x HR)
Also means more K+ secretion - hypokalaemia
What channels are in alpha intercalated cells in late DT and CCD?
Proton pump apically - pumps H+ out
AE1 exchanges a bicarb out basally, brings in Cl-
Cl- exits basally
What channels are in beta intercalated cells in late DT and CCD?
AE1 - bicarb out apically, Cl- into cell
Proton pump - pumps H+ out basally
Cl- leaves basally
What is the medullary collecting duct?
Low Na+ permeability
High urea and H2O permeability in presence of ADH
What happens when someone has acute renal failure?
Fall in GFR
Impaired fluid and electrolyte homeostasis
Accumulation of nitrogenous waste
Needs dialysis
What are the symptoms of acute renal failure?
Hypervolaemia
Hyperkalaemia
Acidosis
High urea and creatinine
What is the fall in GFR called?
Oliguria - due to hypotension - pre-renal cause
Treated by IV saline, add HCO3-
Where does most Na reabsorption happen?
PCT - 70%
Loop - 20%
DT and CD - 9% - by aldosterone
Where does most H2O reabsorption happen?
PT - 70%
Loop - 5%
DT and CD - 24% - by ADH
Where does most K+ get reabsorbed?
PT - 80%
Loop - 20%
DT and CD - only in aldosterone
How is the SA node innervated?
By vagus nerve (parasymp) - depresses heart rate - this is called negative chronotropic action and is mediated by M2 acetylcholine receptors
Symp - catecholamines increase HR by activating B1 adrenoreceptors - increases cAMP - PKA activation - activates L-type Ca channels and Ca channels on ER
What did Otto Loewi see with the frog heart?
He collected the fluid bathing heart and applied it on a different heart - it slowed - this meant that it was a chemical, not electrical, released from vagus nerve
What is the Langendorff preparation?
1) Anesthetise the animal
2) Cut open chest and remove heart
3) Place heart in dish of warm Ringer’s solution - press on heart slightly to remove any blood
4) Tie aorta to cannula and perfuse with warmed, aerated Ringer’s solution - this perfuses the coronary arteries
5) Place in water jacket to keep heart warm
6) attach hook to apex of ventricles and connect to force transducer - allows us to convert physical movement to electrical signal
Where is ADH produced?
Supra-optic and paraventricular nuclei
What are the hypothalamic osmoreceptors?
Supra-optic and paraventricular nuclei detect a change of 3 mosmol/Kg of H2O (normal range is 280-300)
Causes release of ADH and thirst - at normal osmolality there is still ADH in the plasma
What affects the release of ADH?
Increase: water deficiency, stress, drugs (nicotine and ecstasy)
Decrease: excessive fluid, drugs (alcohol)
What does ADH do in principle cells?
ADH binds to a V2 receptor which causes insertion of AQP2 channels by activating PKA to stimulate vesicles
- dilutes plasma
- increases H2O reabsorption
- fall in body osmolality
- fast (~ 15 minutes)
What is diabetes insipidus?
Lots of dilute urine
- we can use a desmopressin nasal spray to stop ADH release
- we can defect the V2/AQP2 channels
What does aldosterone do?
Released from adrenal cortex - zona glomerulosa (mineralcorti)
Regulates (increases) Na, K and body fluid volume
Released in response to high K, low Na or low volume
Acts on late distal/cortical and medullary collecting duct
How does aldosterone act on principle cells?
1) binds to cytosolic mineralcorticoid receptor
2) transport to nucleus
3) increases expression of transport proteins
4) There will be Na reabsorption and K/H+ secretion
Can take a few hours
Na comes in via Na/H exchanger - goes to blood by Na/K pump - K leaves apically
What does aldosterone do to alpha intercalated cells?
1) binds to cytosolic mineralocorticoid receptor
2) transports to nucleus
3) increases transcription of protein transport channels
4) H+ is secreted
What is pseudohypoaldosteronism?
There is Na loss but high aldosterone - loss response
There are mutations in mineralocorticoid receptor mutations
What does renin-angiotensin regulate?
Body fluid volume, plasma Na and K+
What is RAAS?
Renin released from the juxtaglomerular apparatus
Renin causes angiotensinogen to be converted to angiotensin 1
ACE1 (from lungs) causes angiotensin I to convert to angiotensin II
What does angiotensin II do?
Causes zona glomerulosa to release aldosterone
Vasoconstricts arterioles - increase BP
ACE inhibitor - BP treatment
What are the two types of respiration?
Internal - within the cell
External - ventilation, gas exchange
What are the different parts of the respiratory system?
External convection
Pulmonary diffusion
Internal convection
Tissue diffusion
What are the branches of the lungs?
Trachea –> bronchi –> bronchioles (terminal and respiratory) –> alveoli (from terminal bronchiole)
Conducting zone - air travel
Respiratory zone - air diffusion
What is the conducting zone?
Nose, nasopharynx, oropharynx, pharynx, larynx, trachea, bronchial tree
- filters, warms and humidifies air
What is the structure of the bronchial wall?
Cartilage
Smooth muscle
Elastic tissue
Mucous glands
What is respiratory epithelium?
Ciliated epithelia
Goblet cells
Sensory nerve endings
What is the structure of bronchioles?
Lack of cartilage
Has respiratory epithelium
Has more smooth muscle than bronchi proportionally
What is the air blood barrier?
Created by flattened cytoplasm of type I pneumocyte and capillary wall
What is quiet inspiration?
Involves primary muscles: diaphragm and external intercostals
- follows Boyle’s law: pressure volume relationship
What is forced inspiration?
Uses primary muscles (diaphragm and external intercostals) and accessory (sternocleidomastoid, scalenes, back and neck) muscles
What is quiet expiration?
Passive - due to elastic recoil
What is forced expiration?
Uses accessory muscles, internal intercostals, abdominal muscles and neck and back muscles
What is the pleura?
Pleural cavity - prevents lungs from sticking to wall or collapsing - allows free expansion
Parietal is the outside
Visceral is the inside
What is pneumothorax?
Collapsed lung
What is compliance?
= distensibility
c = change in volume/change in pressure
low compliance = more work to inspire e.g. pulmonary fibrosis
high compliance = more work expiring (less elastic recoil) e.g. emphysema
What are the components of elastic recoil?
Anatomical - elastic nature and extracellular matrix
Surface tension = due to differences in forces, there’s a balance between pressure and surface tension
What is Laplace’s law?
Pressure = 2(tension)/radius
What is surfactant?
Produced by type II pneumocytes - prevents alveoli collapsing and reduces surface tension
What is dead space?
Anatomical - volume of conducting airways
Physiological - volume of lungs not participating in gas exchange - conducting zone + non-functional respiratory zone
What are some spirography values?
IRV - inspiratory reserve volume (maximum inspiration - tidal volume)
FRC - functional residual capacity
During exercise - changes
Can’t measure RV
What is Poiseuille’s law?
Impact of resistance to flow
R = (8/pi) x (viscocityXlength/radius ^4)
R = 1/r^4
What is the normal airway resistance?
1.5 cm H2O.s.litres
What factors affect airway resistance?
Anything affecting airway diameter
- increase mucus secretion
- oedema
- airway collapse
What controls bronchial smooth muscle?
Parasymp - ACh from vagus acts on MAChR - constricts
Symp - noradrenaline causes dilation
Adrenaline in blood - dilation
Histamine - constriction
How can we calculate residual volume?
Breathing with a balloon with helium - gets diluted (measure conc before and after)
Is airflow proportional to pressure gradient?
yes! directly
It is indirectly proportional to resistance
Where is most of the resistance in the airways?
Pharynx/larynx - 40%
Airways>diameter 2mm - 40%
Airways<diameter 2mm -20%
What is the composition of air at 760mmHg?
Dry (atmospheric) - mostly nitrogen (78%), then oxygen (21%)
Wet (trachea) - similar but has H2O
Henry’s law: [gas] = solubility coefficient x pp
What is Dalton’s law?
The total pressure of a mixture of gases is the sum of their individual partial pressures
How can we work out the conc of a gas dissolved in a solution?
Using Henry’s law:
[Gas]dis = s (solubility coefficient) x Partial pressure of gas
How is oxygen transported?
O2 is has a low solubility in saline - 0.003 ml/100ml blood
This is too little so haemoglobin is needed
What is haemoglobin’s structure?
Tetrameric - 2 alpha and 2 beta
Has a haem group and a globin chain
Can be tensed (low O2 affinity) or relaxed (high O2 affinity)
What is the structure of the haem unit?
Porphyrin ring with an iron atom
For O2 to bind, iron must be in state Fe2+
Methaemoglobin reductase converts Fe3+ to Fe2+
Haemoglobin can be relaxed or tensed
What is the oxygen-haemoglobin dissociation curve?
X axis = pp of O2
Y axis = haemoglobin saturation
Increases then plateaus
At high temp = carries less, low temp = carry more
At high pH = carries more, low pH = carries less - BOHR EFFECT
At high 2,3 diphosphoglycerate conc = carries less, at low conc = carries more
What causes a right shift in the oxygen-haemoglobin curve?
- increased temp
- increased CO2 production
- decreased pH
What is fetal haemoglobin?
Beta chains are replaced by y chains - left shift in curve - higher O2 affinity
How is CO2 transported in the blood?
CO2 + H2O <-> H2CO3 <-> HCO3- + H+
The blood can carry CO2 in many ways e.g. carbonic acid, bicarb, dissolved CO2 - grouped as total CO2
What is carbon transport?
CO2 is in plasma - can remain or enter RBC - 10% remains
Remain - can dissolve, bind to plasma protein, some form bicarb (slow with no carbonic anhydrase)
Entering the RBC - can cross by AQP1 or Rh protein or diffuse through bilayer
Some dissolves in RBC fluid, some bind to haemoglobin (Hb-NH-COO-) doesn’t bind to iron, rest is converted to bicarb by carbonic anhydrase - bicarb can leave by bicarb/Cl exchanger
When at lungs - this is reversed
Why do we have a GI system?
Breaks down food into nutrients so we can use them for energy and growth& repair
Eliminates waste and undigested food
Helps regulate blood sugar, immune system, promote good mental health
What is the GI tract?
A muscular tube - intestines are suspended in the cavity by mesenteries
Hollow organs are separated by sphincters
Accessory organs secrete into the lumen
Functions include: Motility propels food, digestion, absorption
What is the structure of the GI wall?
Mucosal layer: epithelia (villi), lamina propria (capillaries, enteric neurones, immune cells), thin muscularis mucosae
Submucosal layer: connective tissue, glands, larger blood vessels
Circular and longitudinal smooth muscle
Serosa (squamous epithelia)
What is the mouth?
For mastication
Has exocrine glands: lipase and amylase, saliva lubricates bolus, antimicrobial, buffers and dissolves food
Sensory information is relayed to brainstem
What is the oesophagus?
Has stratified squamous epithelia
Swallowing causes upper oesophageal sphincter to close - initiates peristaltic wave
Continued distention = second peristaltic wave
Vagovagal reflex controls lower oesophageal sphincter - PNS vagus does this
How is the GI tract regulated?
By three divisions of ANS:
- extrinsic = PS + S
- intrinsic = ENS (primary)
ENS has two main plexuses - ganglia in submucosal and myenteric plexuses, submucosal is between mucosa and circular muscle, myenteric is between circular and longitudinal
Lots of neurones - >100 million
How is the parasympathetic NS involved in the GI tract?
Ganglia in plexuses coordinate information to SM, endocrine and secretory cells
Postganglionic neurones are either cholinergic (ACh) or peptidergic (peptides e.g. substance P)
How is the sympathetic NS involved in the GI tract?
Postganglionic nerve fibres release noradrenaline - mixed efferent and afferent - relayed between GI tract and CNS
What are the three phases to motility in the stomach?
1) receptive relaxation in thin-walled orad (fundus and some body) stomach
2) 3 layers of caudad region (body and atrium) contract to mix food with gastric juices from mucosal glans (ANS control) - makes chyme - HCl, Pepsinogen –> pepsin, intrinsic factor, mucus
3) gastric emptying through pyloric sphincter into duodenum - fat and H+ slow this
What causes motility (GI)?
Subthreshold slow waves produce weak contraction (tonic)
Action potentials on top (phasic contractions)
Low pressure organs separated by sphincters (6 + sphincter of oddi)
Regulate antegrade (forward) and retrograde (backward) movement
What is the most contractile tissue?
Unitary smooth muscle - cells electrically coupled by gap junctions
What are the types of GI contractions?
Tonic - constant level of contraction
Phasic - periodic contraction then relaxation
Contraction is preceded by electrical activity - cells of cajal
What is the small intestine?
Digestion and absorption of nutrients - chyme is mixed with digestive enzymes and pancreatic secretions
There are many hydrolytic enzymes in brush border
Duodenum –> jejunum –> ileum
SA increases - plicae - villi - microvilli
What is the pancreas?
Secretes pancreatic juice (1L daily) into duodenum
- rich in bicarb (by centroacinar and ductal cells) to neutralise H+
- enzymes secreted by acinar cells
PNS secretes, SNS inhibits
In cephalic phase - gastic and intestinal
What are the GI accessory organs?
Pancreas, liver and gallbladder
What does the liver and gall bladder do?
Hepatocytes secrete bile - gall bladder stores and ejects - CCK is released from SI when chyme enters which relaxes sphincter of oddi
What is in bile?
Water
Amphipathic bile salts (aids fat digestion)
Bilirubin
Cholesterol
Phospholipid
Electrolytes - Na, K, HCO
- 95% bile salts recirculate to liver by enterohepatic circulation
What are the contractions in the SI?
Peristaltic contractions propel chyme
Segmentation contractions split and expose chyme to secretions - enterochromaffin cells release serotonin - peristaltic reflex
Material not absorbed passes through ileocaecal sphincter into caecum of LI
What regulates the GI system?
GI peptides:
- hormones e.g. GIP
- paracrines e.g. somatostatin
- neurocrines - from neurone after action potential
What are the functions of the large intestine?
1) absorbs water and electrolytes (aldosterone increases Na absorption)
2) makes and absorbs vitamins K + B
3) forms and propels faeces
What is the LI structure?
Surface columnar epithelium - interspersed with crypts
Has taenia coli - 3 longitudinal muscles and haustra
Caecum and proximal colon mix contents
What are the two types of lung disease?
Obstructive - reduced flow through airways
Restrictive - reduced lung expansion
Both reduce ventilation
What is the flow-volume relationship?
Highest flow at low volume then gradual decreases
Negative flow = flow out
What is obstructive lung disease?
Narrowing airways
Could be due to:
- excess secretions
- bronchoconstriction (asthma)
- inflammation
Increased resistance
FEV1<80% FVC
FVC is usually normal - FEV1 affected
There is a sharp fall in flow-volume - graph isn’t a straight line (normal) - looks like a banana
What are some obstructive diseases?
Chronic bronchitis - persistant cough and mucus
Asthma - inflammatory
COPD
Emphysema - loss of elastin
What is asthma?
Hyper-active airways
Trigger could be:
- atopic (extrinsic) = allergies
- non-atopic (intrinsic) = cold air, stress, exercise, drugs, irritants, resp infections
Causes bronchoconstriction
Short acting treatment = salbutamol (B2 adrenoreceptor agonist)
Long acting treatment = inhaled glucocorticoid steroids or long acting B2 agonists
What is restrictive lung disease?
Reduced chest expansion - chest wall abnormalities, muscle contraction deficiencies
Loss of compliance - ageing, increased collagen, environment
Vital capacity is reduced - FEV1 is the same
Flow-volume graph tends to be normal
What is asbestosis?
Slow build up of fibrous tissue leading to loss of compliance
What are the two medullary centres?
Dorsal respiratory group - controls inspiration by sending signals to inspiratory muscles - spontaneously active
Ventral respiratory group - controls inspiration and expiration - inactive during quiet respiration - helps when forceful
What two centres are in the pons?
Pneumotaxic centre - increases breathing rate by shortening inspiration - inhibitory effect on inspiratory centre
Apneustic centre - increases depth and reduces breathing rate by prolonging inspiration - stims inspiratory centre
Can stretch receptors feedback for breathing?
Yes!
Hering-Breuer reflex - stretch receptors in lungs send signals to medulla and limit inspiration and prevent over-inflation
Phrenic nerve –> diaphragm –> lung stretch receptor –> vagus nerve –> inspiratory centre inhibited
Can chemoreceptors feedback for breathing?
Yes!
Central: monitor CSF CO2 and pH - if rise in CO2 - increase ventilation
Peripheral: in carotid body and aortic arch - respond to increased CO2, decreased pH, decreased O2 - increases ventilation
What is the pre-botzinger complex?
Provides breathing rhythm - pattern generator
What is the secretion in the Gi tract?
Controlled by hormonal, paracrine and neurocrine control.
> 9L of fluid daily - most absorbed in SI - rest lost in LI or in faeces
Salt and water balance regulates ECF volume and BP
What is the secretion in the stomach?
Distal: gastrin, somatostatin, pepsinogens
Proximal: HCl, pepsinogens, intrinsic factor, mucins, bicarb
What is the stomach’s main three functions?
Secretion
Motor
Humoral (gastrin, somatostatin)
What are the stomach’s secretory cells?
Mucosal layer
Secrete >2L daily
Body: oxyntic glands
- epithelial cells (bicarb)
- mucous neck cells (mucus)
- Parietal cells (HCl, intrinsic factor)
- enterochromaffin-like cells (histamine)
Antrum: pyloric glands (same as pyloric but no parietal cells)
- G cells (gastrin hormone)
- Chief cells (pepsinogen)
- enterochromaffin cells (serotonin, VIP, substance P)
- D cells (Somatostatin)
What do the stomach’s secretions do?
Protective:
- Bicarb - neutralises acid and combines with mucus to form a protective barrier
- Mucus - protects epithelia
Hydrolytic:
- HCl - activated pepsinogen and denatures proteins
- Pepsinogen - precursor of pepsin - digests protein
Endocrine:
- Gastrin - increases HCl secretion and pepsinnogen release-
Intrinsic factor - B12 absorption
Histamine - increases parietal cell HCl secretion
Serotonin/VIP - motility and secretion, VIP decreases HCl
Substance P - SM contract
Somatostatin - inhibit gastrin release
What is the parietal cell structure?
While resting: cytoplasmic pool of tubulovesicular membrane - contains acid secreting H,K-ATPase
Stimulated: induces cytoskeletal changes - tubulovesicular and canalicular membranes fuse - increases SA by 50/100x, microvilli are present, insertion of H,K-ATPase pump, K+ + Cl- channels
How is gastric acid secreted by parietal cells?
H2CO3 in the cell - H+ is secreted apically through H+/K+ ATPase
Cl- follows out
HCO3- absorbed into blood via Cl–bicarb exchanger
There are Na/K+ exchangers basally
Theres K+ channels allowing K+ to exit the cell apically
What regulated HCl secretion?
Stimulation: ACh (Vagus), histamine (ECL) and gastrin (G cells)
Inhibition: low pH, somatostatin, prostaglandins
What is fluid and electrolyte absorption like along the intestine?
SI and LI have crypts of leiberkuhn - secrete fluid and electrolytes
Si absorb fluid and Na/K/Cl/bicarb by villi, Li by surface epithelia
Crypt epithelial cells - secrete fluid + electrolytes - protective
LI - has a net absorption of water/ Na/ Cl, secretes bicarb and K
SI - have plicae (folds of kerckring), villi and microvilli - increase SA by 600x
Duodenum and jejunum is the primary site for Na/Cl/K/bicarb absorption
How does secretion in the intestine happen?
In epithelial cell of crypts of leiberkuhn
Na/K/Cl cotransporter brings ions into the cell from the blood
Cl diffuses into the lumen through Cl channels - open when cAMP increases due to GPCR - open by ACh/VIP ect.
Na follows paracellularly (passive)
Water follows
How does absorption happen in the jejunum?
All Na absorption - Na/K ATPase
Low intracellular Na (by sodium potassium exchanger) drives entry via Na channels/ Na-H exchangers/ Na-glucose/aa cotransport - secondary active transport
The Na/H exchangers are stimulated by bicarb
Net absorption of NaHCO3
How does absorption happen in the ileum?
Same as jejunum but also involves Cl
Has a bicarb/Cl exchanger which brings Cl into the cell
There is a Cl transporter - Cl absorbed
Net NaCl into cell
What happens in pancreatic secretion?
Acinar cells secrete CCK
Bicarb secreted into pancreatic juice by Cl/bicarb exchanger
H is transported into blood by NaH exchanger
Net secretion of bicarb and H absorption
Ductal cells - recs for CCK, ACh and secretin to upregulate production
What is absorption in the large intestine?
Aldosterone causes Na to enter colon cell apically
Na leaves into blood by Na/K ATPase
This brings in potassium - leaves apically
What products do the jejunum and ileum absorb?
Carbohydrases: alpha/beta amylase, maltase, sucrase, trehelase, lactase —- into villus blood
Protease: pepsin, trypsin, chymotrypsin, elastase, carboxypeptidases —- into villus blood
Lipases and bile salts —- into lacteals in villus
How does the SI absorb carbohydrates?
Epithelial cells
SGLT1 - brings Na and Glucose/galactose in
GLUT5 - brings fructose in
GLUT2 - takes all sugars to blood
Na/K pump basally
How does the SI absorb protein?
Na brings in amino acids
H brings in di/tripeptides - peptidases break them down in the cell
A channel takes AAs into blood
Theres a NA/H exchanger apically
Na/K pump basally
How are lipids absorbed?
Pancreatic lipase and other lipids hydrolyse by bile salts in duodenum and jejunum
Products: cholestrol, lysophospholipids, monoglycerides, micelles (have amphipathic bile salts)
In mucous gel layer epithelia - FAs become protonated and cross the enterocyte by diffusion, carrier mediated transport, incorporated into membrane
Products are resterfied in SER - packaged into chylomicrons - absorbed into lacteals
What are the islets of langerhan?
In kidneys
Beta cells (65%) - insulin, pro insulin, C peptide, amylin
Alpha cells (20%) - glucagon
Delta cells (10%) - somatostatin
There are also:
F cells - pancreatic polypeptide
e cells - ghrelin protein
enterochrommafin cells - not in islets
Richly perfused with blood
What is the communication to the islets?
Small arteries enter islet - distribute by fenestrated capillaries
Vascular arrangement
How do the islets cells communicate to eachother?
Gap junctions between beta and alpha cells
Delta cells send dendrite-like processes to beta cells
What are the islets innervated by?
Adrenergic, cholinergic and peptidergic neurones
How is insulin secretion regulated?
High blood glucose stimulates
Symp stimulation: Beta-adrenergic increases secretion, alpha decreases
Parasymp stimulation: vagus ACh increases release
GIP (SI K cells), Amylin (beta cells) and somatostatin
Drugs e.g. sulphonylureas act on KATP increasing insulin secretion
How is insulin secreted?
GLUT2 lets glucose in - makes ATP from glycolysis
ATP closes k+ channels - depolarisation
Ca channels open causing exocytosis
CCK acetylcholine - Gq coupled
Somatostatin decreases, Glucagon and beta adrenergic agonists increases
How does insulin act to a receptor?
Heterotetramer - alpha/beta subunits + IC tyrosine kinase
Receptor activation activates or inhibits - PKC, phosphatases, phospholipases, G proteins
Causes cell growth, division, gene expression
High insulin levels –> receptor downregulation
What is insulin’s action?
Binds to receptor –> signal transduction cascade –> causes exocytosis of a vesicle with GLUT4 —> allows glucose to enter
Target all cells - especially muscle and liver to make glycogen - increases fat cell glucose intake when glycogen levels replenish
How is the liver acted on by insulin?
Promotes glycogenesis
Inhibits glycogenolysis
Inhibits gluconeogenesis
How does insulin effect muscle?
1) Promotes glucose uptake (GLUT4)
2) Promotes glycogen synthesis
3) Promotes glycolysis and carbohydrate oxidation
4) Promotes proteinsynthesis and inhibits protein breakdown
How does insulin effect adipocytes?
Increases GLUT4 expression, converts glucose to FAs (stores as triglycerides), increases lipoprotein lipase - makes triglycerides from FAs, inhibits oxidation of fat
Overall decreases levels of FAs and keto acids
How does insulin cause satiety?
Promotes K+ uptake through Na/K ATPase
This effects hypothalamic satiety centre
What is type I diabetes?
This is where there is islet destruction - autoimmune
There is hyperglycaemia and increased blood fatty acids and keto acids
Hyperkalaemia
Hypotension
Polyuria
Symptoms: hunger, increased thirst, weight loss, fatigue, fruity breath, blurred vision
Treatment: insulin replacement therapy
What is type II diabetes?
Insulin resistance
Symptoms: increased thirst, hunger, urination, weight loss, headaches, tired, blurred vision
Treatments: sulphonyurea drugs e.g. tolbutamide (stimulate insulin secretion), biguanide drugs e.g. metformin (upregulate receptors on targets), weight control
What are the functions of the female reproductive system?
- Produces haploid gametes
- Facilitate fertilisation with spermatozoan
- Site for implantation of the embryo
- Provide physical and nutritional needs to nurture baby (mammary glands)
What are the ovaries?
Female gonads - mature ova
Medulla - blood vessels and lymph
Cortex - outer epithelia layer containing oocytes (in a follicle - folliculogenesis)
Follicular cells secrete steroid hormones:
- granulosa - 17b oestrogen
- theca - progesterone
Primary follicle - graafian follicle - corpus luteum
What are the fallopian tubes?
Transport egg to uterus - 10cm
Has Isthmus -> ampulla -> infundibulum with fimbriae.
Smooth muscle (circular & longitudinal) in walls - peristalsis
Has highly folded mucosa - ciliated and secretory cells
What are the walls of the uterus?
Perimetrium (outer)
Myometrium
Endometrium
What is the endometrium?
Uterus inner layer
Simple columnar with leukocytes and macrophages
Lamina propria - lots of connective tissue
Compound tubular glands
Has spiral arteries
What is the cervix?
Connects uterus to vagina
Has external and internal os
Cervical glands secrete mucus - prevents microbes
What is the vagina?
Birth canal 8-10cm
Thin wall of:
- adventitia
- muscularis
- mucosa
Has stratified squamous epithelium (with glycogen) which ferments to lactic acid to prevent bacteria
Also has dendritic cells
What are the two female cycles?
Ovarian (follicular and luteal) and endometrial (menstrual) (menses, proliferative and secretory)
What drives the endometrial cycle?
The hypothalamic-pituitary-gonadal axis - hypothalamic neurones release gonadotropin-releasing hormones (GnRH)
This travels to the anterior pituitary by the hypophyseal portal system
GPCRs on pituitary (gonadotrophs) release gonadotropins:
- FSH
- LH
What do LH and FSH do?
Stim ovarian follicular cells to secrete steroid hormones: progesterone (theca cells) and 17b-oestrodoil (granulosa - these also release inhibin (decreases FSH) and activin (increases FSH))
This produces mature gametes
LH - triggers ovulation
FSH - grows and matures follicles
What regulates the ovarian cycle?
HPGA is controlled by +ve and -ve feedback
Follicular phase: 17b-oestrodiol - -ve feedback
Luteal phase: progesterone - -ve feedback
Ovulation (midcycle): follicular cell proliferation, oestrodoil rapidly decreases - +ve feedback - more FSH/LH - triggers ovulation of oocyte
What happens at phases of ovarian cycle?
Follicular - FSH/LH - increases follicles so there is a surge of oestrogen as they are making more (proliferative phase)
The oestrogen reaches a point where it causes positive feedback - LH and FSH - ovulation happens
Luteal - corpus luteum secretes progesterone - this stimulates endometrial glands - they will secrete (secretory phase)
At day 22 - corpus luteum will degenerate - endometrium is lost - as oestrogen and progesterone is falling
What causes changes in endometrium?
17B-oestrodiol and progesterone cause the changes
What happens to the mucus levels in the follicular and secretory phases?
Follicular: mucus copious, watery and elastic, forms channels to propel sperm
Secretory: mucus is thick
What is the proliferative phase?
In endometrial cycle
17B-oestrodiol increases loads
Causes growth of:
- endometrum
- glands
- stroma
- spiral arteries elongate
What is the secretory phase?
After ovulation - dominated by progesterone
Proliferation slows - thickness decreases
Glands have glycogen and mucus
Spiral arteries elongate and coil
Ends in menses
What are some hormonal contraceptives
- oestrogen and progesterone - decreases LH/FSH so no ovulation or folliculogenesis
- progesterone only
- monophasic (fixed dose)
- multiphasic (varying dose)
How is Progestin a contraceptive?
Only progesterone
Thick cervical mucus - no sperm penetration
Less uterus and fallopian tube motility
Less endometrial glycogen
How does the morning after pill work?
High oestrogen and progesterone dose
- interferes with implantation
- inhibit ovulation
- thickens mucus so sperm can’t reach
How do contraceptives work?
Some feedback on hypothalamus - less GnRH - low FSH and LH - no ovulation or folliculogenesis
What is fertilisation?
Gametes are transported to the ampulla of the oviduct
The oocyte is surrounded by granulosa cells
Sperm(150-600 million): capacitation, SM contraction and cervical mucus helps the sperm
The sperm penetrates via an acrosomal reaction
This activates the oocyte - increases calcium - causes 2nd meiotic division and prevents another sperm in (polyploidy)
The haploid pronuclei fuse = diploid zygote
Happens early in fallopian tube
What happens after fertilisation?
Move along oviduct for three days - nourished by oviduct secretions - isthmus contractions slow it down to allow endometrium to prepare
Will divide until 8 - then becomes morula then blastocyst - then implanted (6 days)
What is the blastocyst?
Before implantation - fluid filled cavity.
Lined by trophoectoderm layer - this makes the yolk sac, fetal placenta and amnion
What is implantation?
At 6-10 days after ovulation
Blastocyst promotes stromal cells from endometrium to transform into decidual cells (predecidualisation)
Endometrial reception to blastocyst - low oestrodiol:progesterone (secretory phase)
There is several parts of the invasion
What are the trophoblastic cells?
In blastocyst:
- inner cytotrophoblast: single mitotic layer which differentiates into syncytiotrophoblast
- outer syncytiotrophoblast: produces hormones e.g. HCG
How does the blastocyst invade the endometrium?
1) Hatching: zona pellucida (outer layer) degenerates due to lytic factors - releasing inner cells
2) Apposition: the trophoblastic and endometrial epithelium meet
3) Adhesion: intracellular and extracellular integrins bind to receptors on the deciduous endometrium
4) Invasion: syncytiotrophoblast cells penetrates endometrium
What is the outer layer of the blastocyst called?
Zona pellucida
How does the placenta develop?
Allows materials to pass from maternal system to foetus
Have 120 spiral arteries from the mother - empty into intervillous places - washes over foetal projections and decreases the force from the mothers blood
Syncytiotrophoblast lacunae - merge and fill with maternal blood
Syncytiotrophoblast and cytotrophoblast form villi and microvilli
How is foetal and maternal blood separated in the placenta?
- foetal capillary epithelium
- mesenchyme
- cytotrophoblasts
- syncytiotrophoblasts
What is transported between maternal and foetal blood?
From maternal:
- glucose (fac diff)
- amino acids (2nd active transport)
- vitamins (active transport)
- antibodies/hormones (endocytosis)
From foetal:
- waste urea and creatinine
What are the hormonal changes in trimester 1?
Trophoblast: HCG (rescues the corpus luteum) - up to week 9
Corpus luteum: progesterone and oestrogen to support endometrium
What happens in trimester 2/3?
Placenta: steroid hormones.
This includes human placental lactogens (hCS) which:
- coordinate fuel economy
- develop mammary glands
Progesterone from cholesterol
Oestrogen from foetal-placental
What is stage 0 of parturition?
Stage 0 (quiescence): before birth, uterus is relaxed and insensitive to uterotonic hormones, progesterone suppresses myometrial contractions, braxton-hicks
What is stage 1 of parturition?
Stage 1 (activation): cortisol increases by H-P-adrenal axis - this increases oestrogen - contracts and stimulates prostaglandin release (promotes formation of gap junctions and softens and thins cervix)
Contraction- associated proteins are expressed e.g. uterotonic recs of oxytocin
Enzymes to hydrolyse collagen are expressed
What is stage 2 of parturition?
Stimulation of birth:
PG increase: myometrial contraction, cervical dilation
Increased myometrial connectivity and responsiveness
positive feedback loops: ferguson reflex and uterine contraction increasing PG + oxytocin
Labour: dilation –> expulsion –> placental
What is parturition stage 3?
Recovery from birth
Haemostasis - vasoconstriction of spiral arteries
Decrease in oestrogen - myometrium will regress
The endometrial lining will reestablish after 3-5 months
What is lactation?
From secretory unit of breast = alveoli (contractile cells and adipose tissue)
During pregnancy: oest and prog stim breast growth, oest will stimulate anterior pituitary to release prolactin but prog and oest prevent it acting on breast
Postpartum: oest increases cell proliferation, prolactin initiates milk, oxytocin increases contraction and release of milk, prolactin and cortisol maintain milk
What does prolactin do?
For milk production
Inhibiting dopamine releases prolactin from anterior pituitary
Oxytocin is released from posterior pituitary
Downregulates GnRH to inhibit ovarian cycle
What is the spirometer graph?
Look on the lab on lt
Where do we place the lead II ecg electrodes?
+ve - left ankle
-ve - right wrist
earth - left wrist
If the electrical vector moves towards +ve vector - positive defection
What are the AV valves?
Mitral - left
Tricuspid - right
