Physiology + Pharmacology Flashcards
What do all cells require to correctly function?
Constant Internal Conditions, must be in a fluid environment.
Broadly, how is a constant internal environment achieved and maintained?
Homeostasis
What strucutre is responsible for preventing unwanted particles entering body tissues at exchange surfaces?
Tight junctions
What difference in osmolarity between the cell and its environment is needed to prevent lysis?
They must have a near equal osmolarity.
What 3 fluid environment make up the internal environment of the body?
Blood plasma, Interstitial Fluid, and Intracellular fluid
What is perfusion?
The passage of through the circulatory system or lymphatic system to an organ or tissue.
What vital parameters are controlled across the entire body?
Arterial blood pressure + blood volume
What vital parameters are controlled across the internal environment:
Plasma levels of O2, nutrients and electrolytes.
Core temperature.
What vital parameters are controlled across the cellular level?
ATP and Ion levels
What are the 4 components of the response mechanism to disruptions to a steady state?
Receptors -> control centre - > output -> effector
Where are the control centres located controlling homeostasis?
The hypothalamus + brainstem
What is meant by the term redundancy?
Multiple mechanisms used to reduce the chance of failure.
What do negative feedback loops do?
When a physiological adjustment occurs they work in the opposite direction, returning parameters to their original level.
What do positive feedback loops do?
When a physiological adjustment occurs they work in the same direction, to further move a parameter from its original level/value.
What is pharmacology?
The study of mechanisms by which drugs affect the function of living systems.
What are the fundamental principles of pharmacology?
Drug action must be explicable in terms of chemical interactions
Drug molecules must be bound to particular constituents of cells to produce an effect.
Drug molecules exert chemical influence on one or more constituents of cells in order to produce a pharmacological response.
Main difference between the neural and hormonal system in homeostatic mechanisms?
Neural is faster + hormonal is slower
What medium is used to transport hormones across large distances?
The blood
Where are hormone receptors within a cell?
The cell surface, in its cytosol or in its nucleus.
Peptide hormone synthesis:
From amino acids
Amino acid derived hormone synthesis:
Derived from tyrosine -> synthesis req. specific enzymes
Steroid hormone synthesis:
Metabolites of cholesterol + req. specific enzymes.
Secretion of Peptide hormones:
Secretory granules undergo exocytosis
Secretion of Amino acid derived hormones:
Vesicles via exocytosis (except thyroid hormone)
Secretion of Steroid hormones:
Lipid soluble and can diffuse out.
Location of receptors for Peptide hormones:
Cell membrane surface
Location of receptors for Amino acid derived hormones:
Cell membrane surface
Location of receptors for Steroid hormones:
Intracellular receptors in cytosol or nucleus.
what are the main 7 endocrine glands?
Pituitary (ant and pos)
Thyroid
Parathyroids
Adrenal (cortex and medulla)
Ovaries
Testes
Endocrine Pancreas
Endocrine tissues other than the 7 main glands:
Hypothalamus
Kidney
GI tract
Heart
Liver
Adipose tissue
What are the two “blurred line” categories of hormones?
Paracrine factors + neurpeptides
Neruopeptides:
Molecules that operate as both hormones and neurotransmitters
Thyroid gland: Hormones
Tyrosine - T3 and T4:
Pro-hormones produced by follicular cells and stored extracellularly as prohormone in colloid
What is colloid?
Extracellular purple fluid.
What chemical is used by the thyroid to initiate Tyrosine uptake into the blood.
Iodine is used to uptake tyrosine from the colloid into the follicular cells and then into the capillaries via faciliated diffusion.
What processes is tyrosine a key hormone for?
Development, Growth, and metabolism.
What does the parathyroid gland secrete?
Parathyroid hormone (PTH)
What does PTH target?
Bone tissues, GI system and the kidneys
What is the role of PTH in the body?
To regulate the plasma levels of Ca2+ and phosphate
Adrenal cortex secretions:
Steroid hormones, Glucocorticoids, and mineralocorticoids.
Example of a Mineralocorticoid:
Aldosterone
Example of a Glucocorticoid:
Cortisol
Adrenal Medulla secretions:
Adrenaline and Noradrenaline
What group are adrenaline and noradrenaline a part of?
Catecholamines
What cells release adrenaline in the adrenal medulla?
Chromaffin cells
What cells secrete testosterone within the testes?
Leydig cells
What is the function of testosterone:
Stimulates proteins synthesis and leads to development and growth
What hormone is secreted by the testes?
Testosterone.
What is secreted by the endocrine pancreas?
Insulin and glucagon.
What cells in the endocrine pancreas secrete insulin?
Ꞵ cells
What cells in the endocrine pancreas secrete glucagon?
α Cells
What is the Adenohypophysis?
The anterior lobe of the pituitary gland (develops from an upward projection of the pharynx)
What is the Neurohypophysis?
The posterior lobe of pituitary (develops from a downward projection of the brain)
What is the portal system?
The movement of blood from one tissue to another without returning to the heart.
What is the hypophyseal system?
A system of blood vessels in microcirculation at the base of the brain, connecting the hypothalamus with the ANS posterior.
What are tropic hormones?
Hormones which effect the release/expression of other hormones often by stimulating glands. e.g TSH (thyroid stimulating hormone)
What are the 3 ways hormone secretion is regulated?
neural mechanisms, Tropic hormone action, and positive/negative feedback loops.
Who was responsible for the foundations behind the concept of receptors?
Langley
What chemical from what plant was used in Langley’s experiments?
Pilocarpine from jaborandi trees.
What effect on frogs and dogs does pilocarpine have?
Slower heart rate + increased saliva production.
What are the two antagonistic hormones langley used?
Pilocarpine + Atropine
When comparing affinity what is meant by relative mass?
Concentration
What is affinity?
The tendency of a chemical/molecule to bind to a receptor
What are receptors?
they are macromolecular proteins that serve as recognition sites. Or they can be any cell protein that binds to a molecule/drug with an effect on some intracellular activity.
What information is taken from receptors to design drug?
The structure of receptors.
What information is taken from receptors to design drug?
The structure of receptors.
What information is taken from receptors to design drug?
The structure of receptors.
What is the general pathway of chemical communication and cell signalling:
Extracellular signal molecules bind to specific receptors -> intracellular signals -> alters cell behaviour
How many cells can most extracellular signal molecules act on?
More than one, allowing for coordinated responses.
What is meant by the amplification of cell signalling?
The initial signal protein may cause a secondary cascade e.g a cAMP pathway.
What are the 4 types f intercellular communication?
contact-dependent, paracrine, synaptic, and endocrine
Paracrine Signalling: Summary
Paracrine signals are released by cells in the extracellular fluid and act locally
Contact-Dependent Signalling: Summary
A cell-surface-bound signal molecule binds to a receptor protein on an adjacent cell
Synaptic Signalling: Summary
Neuronal signals are transmitted electrically along a nerve cell axon, when it reaches the nerve terminal it causes the release of neurotransmitters onto adjacent cells across synapses.
Endocrine Signalling: Summary
Hormones produced by enodcrine glands are secreted into the bloodstream and are distributed widely across the body.
What are the two main functions of contact-dependent signalling?
Development and Immune responses (T-cells)
What is an example of the therapeutic manipulation of contact-dependent signalling?
CAR T immunotherapy: Uses contact-dependent signalling to kill cancer cells -> use CAR (engineered receptors designed to recognise cancer cells) -> inserted into genome of patient T-cells
What is meant by autocrine signalling?
A type of paracrine signalling where the mediators released are received by the cell which released them.
What are the 3 main functions of paracrine signalling?
Inflammation, cell proliferation and wound healing.
How are the chemical messengers stored in paracrine signalling?
Stored in vesicles or are synthesised on demand.
What is an example of the pharmacological manipulation of paracrine signalling?
Counter allergy medications bind to histamine receptors and block histamine action -> preventing swelling and itch. Some drugs regulate the intracellular signalling induced by chemical messengers.
What effect does Nitric Oxide have on smooth muscle cells?
NO causes smooth muscle to relax and causes vasodilation.
How does Viagra work?
Viagra inhibits the enzyme responsible for the breakdown of cGMP, prolonging the action of NO.
Where do drugs acting on neurotransmission act?
Either the pre or post synaptic neurone. At pre -> influences neurotransmitter synthesis, storage, or release. At post -> influences neurotrans. receptors
What is an example of the pharmacological manipulation of endocrine signalling?
Treatments for type 1 and type 2 diabetes.
Type 1: Drugs mimic insulin
Type 2: Drugs increase signalling through insulin receptor
Anaphylaxis: Adrenaline auto-injectors
What are bioassays used for?
To measure the pharmacological activity of new or chemically undefined substances, To investigate endogenous mediators, and to measure drug toxicity and unwanted effects.
What is defined as a mediator?
A chemical, peptide, or protein that conveys information from one cell to another.
When are mediators released?
In response to a stimulus of some kind, a mediator is released and produces a particular biological response.
What are the criteria req. for a substance to be a mediator?
-Must be released from cells in sufficient amounts to produce a biological action on target cells within an appropriate time frame.
-Application of an authentic sample of the mediator reproduces its biological effect.
- Interference with the synthesis, release, or action ablates or modulates the original biological repsonse.
What is ablation?
The removal or destruction from an object by vaporisation, chipping, erosive processes or by other means.
What are the two ways in which chemical mediators are synthesised?
Synthesis of smaller molecular mediators is regulated by by specific enzymes. Synthesis of peptides is regulated by transcription.
What in the cell determines which mediators are produced?
The genes and enzymes active in the cell.
How many types of mediator can a single cell produce?
A single cell can produce multiple types of mediator.
How many types of mediator can a single vesicle store?
More than one type of mediator
What is constitutive secretion?
Secretion of vesicles occurs continuously with small amounts stored in a cell. (e.g the release of plasma proteins and clotting factors by liver cells)
What is meant by regulated secretion?
Occurs in response to increaseed intracellular Ca2+ or other intracellular signals -> significant amount of stored secretory vesicles released.
What are the two main groupd of chemical mediators?
Mediators that are pre-formed and mediators that ar eproduced on demand.
What is different about the way the two main groups of mediators are released by cells?
Pre-formed mediators are stored in vesicles and are released by exocytosis, whereas mediators produced on demand are released by diffusion or constitutive secretion.
Difference in speed of the two main mediator groups?
Pre-formed mediators work more rapidly, whereas on demand mediators take longer to act.
Examples of on demand mediators:
NO, and prostaglandins
Examples of pre-formed mediators:
Noradrenaline and peptide mediators.
What is the type of secretion by which pre-formed mediators are released by?
Regulated secretion
What is the name of the hypothesis which predicted the existence of vesicles?
The quantal hypothesis.
What piece of apparatus was used to identify vesicles?
Transmission Electron microscope
What is the name of the sensor protein which allows for vesicles to detect calcium in regulated secretion?
Synaptotagmin.
How does synaptotagmin aid regulated exocytosis?
Allows for the vesicles to bind to membrane proteins in the presence of Ca2+ -> allows for
membrane fusion
Why is termination of neurotransmitter action necessary?
To ensure neurotransmission accurately represents the action potential frequency.
What are the two mechanisms by which neurotransmitter action is terminated?
Enzyme action (breakdown of neurotransmitters at synapses)
Uptake of neurotransmitters into pre-synaptic neurone or supporting cells. (Transport proteins in the plasma membrane and vesicular transporters)
What would therapeutic drugs interfering with neurotransmission be used for?
Alleviation of symptoms of neurological conditions
Examples of drugs that interfere with neurotrasmission:
Prozac(Fluoxetine) -> targets transporters -> prevents the reuptake of neurotransmitters
What is the benefit of synthesising drugs with greater specificity to a receptor?
Fewer side effects as the drug binds to less receptors unintentionally.
What are the 4 classes of proteins commonly targeted by drugs?
Enzymes, Transporters, Ion Channels, Receptors
Example of drugs that target ion channels in neurotransmission:
Lignocaine and Gabapentin
What are ion channels?
Transmembrane proteins that allow for non-lipophilic molecules/ions to cross the membrane
What does Lignocaine bind to when regulating neurotransmission?
Lignocaine blocks Na+ channels, inhibiting the formation of action potentials.
Example of illegal drug that targets receptors involved in cell communication:
Morphine (opium)
What are the uses of using drugs that target receptors in cell communication:
Regulate cellular processes, enable the communication between cells, and allows for the coordination of tissue/organ/bodily responses.
How many families of receptors exist within the mammalian genome?
25
What is the definition of receptors in pharmacology?
Proteins that serve as recognition sites and allow the binding of chemical mediators.
What are the 3 functions of Receptors?
regulation of cellular processes, chemical recognition and binding, and intracellular signal generation.
What are the 4 main classes/ super families of receptor?
Ligand-gated ion channels, G protein-coupled receptors, kinase-linked receptors, and Nuclear receptors.
What are the shared characteristics of receptors on the cell surface membrane?
-Transmembrane segments of 20-25 hydrophobic amino acids
-Extracellular ligand binding domain
What are the characteristics/features of nuclear receptors?
-Regulate gene transcription
-DNA-linked
-Ligand bound can cross the plasma membrane (lipophilic)
Example of a nuclear receptor:
Oestrogen Receptors
What is a ligand?
Any molecule that binds to the receptor
What is an agonist?
Drug or chemical mediators that bind to a receptor to produce a response.
What is an antagonist?
Drugs that prevent or inhibit the response of an agonist, they bind to the receptor however don’t elicit a response.
-Majority of clinically useful drugs
Examples of Agonists:
Pilocarpine, nicotine, acetylcholine, and morphine
Examples of Antagonists:
Atropine and curare
Example of malfunction of ligand-gated receptors causing disease:
myasthenia gravis -> 1/2000 -> Muscle weakness in neuromuscular junction -> treated with anti-cholinesterase (prevent breakdown of ACh) and immunosuppresants
What factors effect how long a chemical signal lasts?
How long the agonist is present, how long the downstream effects remain active, the mechanisms involving the termination of the signalling.
What is the order of the 4 receptor classes in order of speed (fastest to slowest)
ligand-gated ion channels (ms) -> G-protein-coupled receptors (s) -> Kinase-linked receptors (h) ~ nuclear receptors (h)
Why do kinase-linked receptors and nuclear receptors have similar transduction speeds?
Both of their pathways involve gene transcription and gene synthesis before cellular effects are experienced.
Summarise what a ligand-gated ion channel does to induce a change in a cell:
It changes the permeability of a cell to a specific ion (hyperpolarisation or depolarisation)
Summarise what a G protein-couple receptor does to induce a change in a cell:
G protein activated upon mediator binding to receptor -> either binds to ion channels or effector which synthesises second messengers -> induce effects.
Summarise what a Kinase-linked receptor does to induce a change in a cell:
upon binding -> phosphorylates a secondary messenger -> leads to gene transcription -> protein synthesis -> cell effected
What is the alternative name for ligand-gated ion channels?
Ionotropic receptors
Structure of Ligand-gated ion channels:
3-5 subunits (proteins)
Each subunit has 2-4 transmembrane domains
Complex of subunits arranged to form an aqueous pore
What is meant by a desensitised state?
Where an agonist is bound to a receptor however has no effect.
What are two key examples of ligand-gated ion channels?
nAChR - Nicotinic Acetylcholine Receptor (At NMJ, Autonomic Ganglion Neuron, and Brain Neurons) and Glutamate receptor
What are the Agonist and Antagonist that work at nAChR?
Agonist: ACh, Nicotine
Antagonist: tubocurarine
What differs between sub-types of receptors within a family?
Their subunit compositions and pharmacology
What does the nomenclature of receptor describe?
The receptors subunit composition.
What type of diseases can be caused by the malfunction of ligand-gates receptors?
Autoimmune diseases e.g (myasthenia gravis)
Which two types of receptors are most often used by chemical mediators/neurotransmitters?
Ligand gated ion channels and G protein-coupled receptors.
How many proteins make up a G protein coupled receptor?
A single protein.
How many transmembrane domains does a G protein coupled receptor have?
7 transmembrane domains (7TM)
How many genes code for GPCRs?
800+
What is an “orphan” GPCR?
A GPCR with an unknown ligand to bind to.
What occurs in a GPCR following the binding of an agonist?
signal transduction occurs via the activation of heterotrimeric G proteins.
How can GPCRs link?
Different GPCRs can target the same heterotrimeric G protein, allowing for the interaction between some GPCR pathways.
In depth signal transduction of Heterotrimeric G proteins:
Upon ligand binding to the receptor, receptor-G protein undergoes conformational change promoting the exchange of GDP for GTP -> G protein dissociates from receptor + ligand disociates -> alpha-GTP and Beta Gamma subunits dissociate -> Both subunits interact with enzymes, before reassembly of the trimer and association with the receptor.
What are the types of effectors:
Ion channels and enzymes
What are 2nd messengers?
Small diffusible molecules that spread a signal.
What are Ga(s) and Ga(i)
Ga(s) is a stimulatory G protein complex and Ga(i) is an inhibitory G protein complex. Both acct on Adenylyl cyclase.
What does Adenylyl cyclase catalyse?
The conversion of ATP to cAMP.
What cAMP regulate?
The activity of other proteins involved in the signal transuction (including PKA)
What effect does cAMP have on PKA activity?
cAMP increases PKA activity.
What is PKA?
Protein kinase A -> enzyme involved in signal transduction
Does cAMP have different effects in different cells?
Yes, cAMP has a variety of effects specific to tissues.
How does PKA regulate “downstream” effectors?
Phosphorylates proteins to activate proteins. e.g Ion channels, receptors, metabolic enzymes, signalling proteins, or transcription factors.
What does phospholipase C do?
Breaks down the bonds between lipids, producing DAG (Diacyl glycerol) and IP3. DAG activated PK C and IP£ activated ligand binding channels on the ER -> allowing for Ca2+ to leave into the cytosol.
What protein complex activates Phospholipase C?
Ga(i)
What two pathways are used for smooth muscle contraction:
GPCRs coupled with Gq proteins + PLC signalling (Phospholipase C)
What is the advantage of cross-talk between receptors?
Allows for multiple stimuli to be responsible for specific changes to cell behaviour, allowing for control/more deliberate responses to changes to the external/internal environment.
What are the major components of the Nervous System?
The afferent Somatic Nervous system and Visceral nerves.
The CNS
The Efferent Somatic Nervous System (V)
and the Autonomic nervous system (IV)
The effectors (Skeletal muscle + smooth muscle, cardiac muscle, glands)
What are visceral nerves?
Sensory nerves within organs that detect internal changes
What are the two major efferent pathways of the ANS:
Sympathetic and Parasympathetic:
What is the generalised term for the sympathetic ANS pathway?
Fight or Flight
What is the generalised term for the parasympathetic ANS pathway?
Rest and digest
When is the sympathetic pathway activated?
Exercise, Excitement, emergency, embarrassment
When is the parasympathetic pathway activated?
Digestion, defecation and diuresis
How is the sympathetic pathway activated?
Co-ordinated, whole body response or discrete and organ specific.
How is the parasympathetic pathway activated?
Function in a discrete organ specific manner.
Effect of sympathetic stimulation on: Eyes
Pupil dilation -> increase visual field and observation abilities
Effect of sympathetic stimulation on: Heart
heart rate increases + contractility-> effects atria and ventricle -> increases supply of oxygenated blood to organs
Effect of sympathetic stimulation on: Blood vessels
Blood vessels at surface constrict -> more blood is directed to heart and muscles -> less digestion -> more blood at liver for glycolysis
Effect of sympathetic stimulation on: Lungs
bronchodilation -> increases airflow and maintains gaseous concentration gradient to maximise gaseous exchange.
Effect of sympathetic stimulation on: Liver
Glycolysis + gluconeogenesis -> increase blood sugar levels to provide glucose to muscles for respiration
What is contractility?
The force of heart contraction.
Effect of parasympathetic stimulation on: Eyes
Pupils constrict
Effect of parasympathetic stimulation on: heart
Heart rate decreases -> only effects atria
Effect of parasympathetic stimulation on: Gastrointestinal tract
Increase secretion
Effect of parasympathetic stimulation on: Bladder
contraction -> forces diuresis
Effect of parasympathetic stimulation on: reproductive organs
maintains erection
One word to describe the relationship between the sympathetic and parasympathetic division:
Synergistically
What is the benefit of the sympathetic and parasympathetic divisions antagonistic interactions:
Allows for rapid precise control of tissue function
What structures are solely innervated by the sympathetic division?
Sweat glands, Hair follicles, blood vessel smooth muscle, the adrenal medulla.
What is the general organisation of the ANS?
The CNS with preganglionic neurons -> linked to postganglionic neuron in the peripheral ganglion -> linked to target cell.
What are two essential components of the ANS within the CNS?
The spinal cord and Brainstem nuclei.
Role of the spinal cord in the ANS:
Mediates autonomic reflexes, Receives sensory afferent and brainstem input.
Role of the Brainstem nuclei in the ANS:
Mediate autonomic reflexes.
What does the hypothalamus control?
Hunger, thermoregulation, Circadian rhythms, water balance, sex drive, reproduction
Other than the hypothalamus what else regulates ANS output?
Forebrain + Visceral Afferent neurons
What is the role of the Forebrain in the ANS?
Minimal conscious conrtical control. e.g Anxiety can lead to GI disturbance + fear initiates fight or flight.
What is the role of Visceral Afferents in the ANS?
Sensory input from visceral afferent neurons takes priority over cortical functions -> e.g bladder distension will cause diuresis.
What is the importance of the vagus nerve in the ANS?
The Vagus nerve carries 80% of total parasympathetic outflow. It also contains many of the visceral afferents and therefore is responsible for much of the ANS stimulation
What is the primary neurotransmitter of preganglionic neurones?
ACh
What does ACh activate on a post synaptic cell?
nicotinic ACh receptors (ligand channels) -> allowing the entry of Na+ and K+ leading to excitation
Organisation of the sympathetic pathway:
Short cholinergic preganglionic neurons from thoracic and lumbar spinal cord -> long, adrenergic postganglionic neurons -> tissue expresses alpha and beta adrenergic receptors.
Meaning of Adrenergic:
Releases adrenaline (epinephrine), noradrenaline
Where are cervical neurons located?
The neck
Where are thoracic neurons located?
near the thorax
Where are lumbar neurons located?
The lower back
Where are sacral neurons located?
near the tail bone
What neuronal pathway is an exception in the sympathetic division?
The innervation of the adrenal medulla. Adrenaline is used and acts as hormone -> transported in the blood.
Organisation of the parasympathetic division:
long, cholinergic preganglionic neurons from the brainstem and sacral spinal cord -> short, cholinergic postganglionic neurons -> target tissues express ACh receptors
What does cholinergic mean?
Involves Acetylcholine e.g secretes ACh
What are the two prinicipal transmitters in the Auntonomic Nervous System?
Acetylcholine and Noradrenaline
Cholinergic receptors:
Either nicotinic or muscarinic:
(Muscarinic -> 5 subtypes)
Found on postsynaptic neurons in parasympathetic ganglion neurons and sweat glands.
Antagonists for Nicotinic Cholinergic Receptors:
Curare
Antagonists for Muscarinic Cholinergic Receptors:
Atropine
What are the effects of M1, M3, and M5 mAChR action?
Gq, ↑PLC, ↑IP3, ↑ intracellular Ca2+
What is IP3?
A chemical messenger produced by the hydrolysis of PIP2 -> works with DAG to transduce a biological signal.
What are the effects of M2 and M4 mAChR action?
Gi ↓Adenylyl cyclase ↓ cAMP
How many subtypes of mAChR (muscarinic acetylcholine receptors) are there?
5: M1, M2, M3, M4, M5
Main location of mAChR M1 receptors:
Autonomic ganglia, Glands, Cerebral Cortex
Main location of mAChR M2 receptors:
Atria (heart) + CNS (widely distributed in nodal tissues)
Main location of mAChR M3 receptors:
Exocrine Glands, Smooth muscle (eye, airways, bladder), Blood vessels (endothelium)
Main location of mAChR M4 receptors:
CNS
Main location of mAChR M5 receptors:
CNS, salivary glands, iris /ciliary muscle
Functional response of mAChR M1 receptors:
Gastric secretion + CNS excitation
Functional response of mAChR M2 receptors:
Cardiac + neuronal Inhibition: activate GIRK K+ channels and inhibit L-type Ca2+ channels
Functional response of mAChR M3 receptors:
Gastric + salivary secretion
Vasodilation
Ocular Accommodaiton
Functional response of mAChR M4 receptors:
Enhanced locomotion
Functional response of mAChR M5 receptors:
Not known
What are GIRK Potassium Channels?
G protein-activated inward rectifying K+ channels -> inhibit/work against the generation of an action potential
What type of receptor of M1 and M3 mAChRs?
Gq coupled receptors
What are the dangers of muscarine?
In high dosages can cause nausea -> lower blood pressure -> increases secretions of tears, saliva and sweat -> abdominal pain -> and Death from cardiac + respiratory failure.
Why is the clinical use of mAChr limited?
Most mAChR agonists aren’t selective and will cause many unintentional side effects.
What are the two mAChR agonists used clinically?
Cevimeline and Pilocarpine
Cevimeline treatment:
-M3 selective
-Improves salivary and lacrimal secretions in Sjogren’s syndrome (Dry mouth and eyes)
Pilocarpine treatment:
Non-selective mAChR agonist
-Applied as eyedrops to treat glaucoma
What is Glaucoma?
Glaucoma describes a group of eye conditions affecting vision which can cause blindness.
What causes Glaucoma?
Drainage tubes (trabecular meshwork) within the eye become slightly blocked, preventing eye fluid from draining and increasing intraocular pressure -> leading to optic nerve damage
Muscarinic Antagonists:
Atropine Example
Atropine:
-non-selective mAChR antagonist
-Can be used to reverse poisoning by antichoninesterases
-Reverse action of mAChR agonists
Muscarinic Antagonists:
treatments
Pirenzipine (M1 selective) - treats peptic ulcers
Darifenacin (M3 selective) - treats overactive bladder
What is the term used to describe drugs acting indirectly to enhance cholinergic transmission?
Cholinomimetic
Anticholinesterase drugs:
Physostigmine used topically to treat glaucoma
Other clinical uses: Reverse action of neuromuscular blocking drugs after an operation
- Treatment of myasthenia gravis,
Alzheimer’s Disease
What are the different types of adrenoreceptors?
Alpha 1, Alpha 1, Beta 1, Beta 2
What cells release adrenaline?
Chromaffin cells
What cells release noradrenaline?
sympathetic neurons
Clinical uses of adrenoceptor agonists:
Adrenaline (non selective): Cardiac arrest + Anaphylaxis
B2 Selective Respiratory System: Bronchodilator + Nasal Decongestant
What ion channel mediates the heart rate and contractility of the heart?
Ca2+ channels
Effect of Amphetamines at the synapse:
Amphetamines are structurally related to noradrenaline -> act indirectly by increasing release of endogenous noradrenaline.
Repeated use leads to tolerance -> leads to depletion of neurotransmitter.
Exocytosis is not involved in release process of NA.
Clinical use of Adrenoceptor Antagonists:
Prazosin (a1 selective) - Hypertension
Carvedilol (a & b) - heart failure
Propranolol (b1 and b2) - Anxiety
Unwanted effects from the clinical use of Adrenoceptor Antagonists:
Fatigue
Bradycardia
Cold extremities
Cardia Depression
Bronchoconstriction
What are the 4 types of epithelial tissue?
Simple, Stratified, Pseudo-stratified, Transitional
What is the main role of epithelial tissue?
To form a boundary between a controlled internal environment and uncontrolled external environment
What are germ layers?
The primary cell layers formed in the earliest stages of embryonic development.
What are the 3 germ layers?
The Endoderm, Mesoderm, and Ectoderm
What are the 4 functions of epithelia within the body?
Diffusion, Secretion, Absorption and Filtration
Simple Squamous Eplithlia:
-Thin single cell layer -> facilitate rapid passage of molecules
-Found at the alveoli and serosa (peritoneal membrane on the outside of the intestine)
Simple Cuboidal Epithelia:
-Secretion/absorption of materials via active transport
-Nuclei near the apical surface of the cells
-E.g kidney tubules and gland ducts
Pseudostratified columnar epithelia:
-Single cell layer (muti-layered appearance)
-Nuclei at different levels
-All touch the basement membrane
-often interspersed with goblet cells
Stratified Squamous epithelia:
-Most common type of stratified epithelium in body
-Apical cells appear squamous, basal cells cuboidal
-Found in area of high abrasion ( Skin upper layers and oesophagous)
Stratified Cuboidal Epithelia:
Less common stratified tissue found in glands
Stratified Columnar epithelia:
Rare - found in conjunctiva, pharynx, anus, male urethra, and embryo
-Allow the tissue to stretch and contract.
Transitional Epithelia:
-Can become relaxed and distended.
-Cells round when relaxed and flatten upon distension.
-Facilitates shape change in distension without damage to epithelial lining.
What are the two types of secretion from glands:
Ducts(Exocrine) + Ductless(Endocrine)
What are the two types of substances from glands:
Mucous (mucous gland) + Protein (serous gland)
What is meant by epithelial cells having polarity?
They have an apical external side and a basal side.
What are the reticular lamina?
Reticular fibres anchoring the basal lamina to underlying connective tissue (collage/elastin)
What are the components of the basal lamina?
Lamina lucida and lamina densa
What are the components of the basement membrane?
Basal lamina and the Reticular Lamina
What is a vital component of all epithelial separative from underlying connective tissue?
The basement membrane
What structure is responsible for the lateral communication of epithelial cells?
Gap junctions
Are desmosomes in all epithelial cells?
no
What are the two cell-cell anchoring junctions?
Adherens Junctions and Desmosomes
Adherens Junction:
Connects actin filament bundle in one cell with that in the next (adj.) cell.
Desmosome:
Connects intermediate filaments in one cell to those in the next cell.
Function of gap junctions between epithelial cells:
A channel-forming junction that allows the passage of small water-soluble molecules from cell to cell.
Function of tigtht junctions between epithelial cells:
Seals the gap between epithelial cells.
What are the two cell-matrix anchoring junctions?
Actin-linked cell-matrix junctions and Hemidesmosomes
Actin-linked cell-matrix junctions:
Anchors actin filaments in cell to the extracellular matrix
Hemidesmosomes:
Anchors the epithelial cell’s intermediate filaments to the extracellular matrix.
What 3 structures are part of the junctional complex between epithelial cells?
Tight junctions, Adherens junctions, and desmosomes
What causes the great rate of cell death amongst epithelial tissues?
The cells are exposed to the hostile external environment.
What causes an increased cancer risk factor for epithelial tissue?
Due to the hostile environment more mitosis takes place as to replace damaged cells. Increasing the rate of mitosis increases the risk of harmful mutation.
Epithelial-Mesenchymal Interactions:
The expression of cadherins (adhesion molecules) induces mesenchymal cells to form epithelium
Mesenchymal cells:
Cell from fibroblasts that form barrier surfaces
What is the role of skin in the nervous system and Homeostasis?
A sensory role -> containing a variety of receptors responding to pressure, vibration, pain, and temperature
What is the integumentary system?
Skin and its accessory organs (hair, nails, cutaneous glands)
What are the 3 layers of the skin, from outermost to innermost:
Epidermis, Dermis, and Hypodermis
The Dermis:
Connective tissue beneath epidermis.
Thicker than epidermis.
Mainly collagen with elastic and reticular fibres.
Rich layer of blood and lymphatic vessels.
Has two main zones/layers.
What are the two main layers of the dermis?
The papillary layer and the reticular layer.
Dermis: The papillary layer
Thin region of loose connective tissue allowing mobility of leukocytes, mast and macrophage cells.
Dermis: Reticular layer
Thick layer of dense irregular connective tissue, less cells, adipocyte clusters.
What cells produce the proteins laminin and fibronectin for the extra cellular matrix in the dermis?
The fibroblast cells
What structures in the dermis are important for the thermoregulation of the skin?
The arteriovenous anastomoses.
The Dermal-epidermal boundary:
“wavy” boundary of finger-like projections increasing connection. The Dermal papillae are raise areas and the epidermal ridges are lower areas. The dermal papillae facilitate nerve fibres reaching close to the surface in highly sensitive areas.
What are the main cells within the epidermis?
Keratinocytes, dead keratinocytes, Dendritic cells, Tactile cells, Melanocytes, langerhan cells, merkel cells, stem cells
What are the two types of skin?
Thick skin - found on palms + feet -> no hair - 5 layers.
Thin skin - rest of body - 4 layers
What are the 4 layers of a keratinised stratified squamous epithelium epidermis?
The stratum corneum, stratum granulosm, stratum spinosm, and the stratum basale
Stratum Basale:
- Keratinocytes most prevalent, mitotically active on BM
-Melanocytes give skin colour
-Tactile/Merkel cells -> sense of touch
-Dermal pipilla interdigitate with the epiderma rete ridges at tissue junctions.
What are the two pigments controlled by melanocytes:
Pheomelanin - red soluble pigment
Eumelanin - brown insoluble pigment
Melanocytes:
Release melanin - UV absorbent, antioxidant and radical scavenging - prevent the skin from UV damage.
Stratum Spinosm:
Several layers of keratinocytes, usually the thickest layer, innermost cells are mitotic and mitosis ceases as cells move upwards. Tight junctions ensure water retention.
Stratum Lucidum:
Thin translucent zone, 2-3 layers, made from tightly packed dead keratinocytes -> indistinct cell boundaries -> cytoplasm granules of eleidin
Only present in “thick skin”
Stratum Granulosum:
3-5 layers of flat keratinocytes, post-mitotic, bound by tight junctions. Cells undergo apoptosis. Contains dark-staining keratohyalin granules.
What converts keratohyalin granules bound to the cytoskeleton into keratin in the Stratum Granulosum?
Tranglutaminase enzymes
What forms the waterproof barrier between the Stratum spinosum and the Stratum Granulosum?
Cells coated with Glycolipid-filled vesicles produced by the Stratum Granulosum
Stratum Corneum:
15-30 layers, resistant to abrasion, penetration, and water loss.
Upper part mostly dead keratinocytes.
Comprised of two layers, the Stratum compactum and the stratum disjunctum.
Outermost layer of the epidermis
What is the main therapeutic use of nails?
They can be used to indicated the presence of health defects.
Term for region with hair.
Non-glaborous
Term for region without hair:
Glaborous
What are the 3 stages of hair growth:
Lanugo - fine, unpigmented hair on foetus
Vellus - fine hair on skin surface
Terminal - longer coarser hair -> post puberty
What are the 5 types of glands within the skin?
Merocrine (Sweat)
Apocrine (scent)
Sebaceous (Sebum)
Ceruminous (Ear wax)
Mammary Gland (breast milk)
What are the 3 barrier functions of the skin?
Physical barrier, biochemical barrier, immunological barrier
Skin: Physical Barrier
Cross-linked keratin layer upon a scaffold of keratinocytes -> protects from physical injury (except burns, cuts and vectors)
Skin: biochemical Barrier
Slight acidity (pH 4-6)
Bacteriocidal agents: saturated and unsaturated fatty acids inhibit growth, lysozymes cleave cross linkages in bac. cell walls.
Skin: Immunological barrier
Commensal organisms (e.g bacteria) -> discourage growth of harmful pathogens.
Why are burns very harmful to the skin?
Burns damage proteins in the skin and decrease the water content of the body.
Langerhans Cells:
Immunological barrier - can self renew. Take up and process antigens. - Present antigens at lymph nodes and to lymphocytes.
Where are thermoreceptors in the skin?
The epidermis
Where are central body hot/cold receptors?
The preoptic anterior hypothalamus
How does the flow of blood in the skin aid thermoregulation?
There is a counter current heat exchange between venous and arterial blood in the extremities (skin).
What are arteriovenous anastomoses?
direct connection between the small veins and small arteries.
What is skeletal muscle responsible for in the body?
Voluntary movement, control of inspiration by diaphragm contraction, skeletal-muscle pump (helps return venous blood)
What is the name of a single contractile unit of striated muscle ?
A sarcomere
What is the light central region of a sarcomere?
The H band
What are the two inner horizontal lines in a sarcomere?
Myosin
What is the I-band?
The light region surrounding the vertical Z-lines.
What initiates contraction of skeletal muscle?
Release of ACh at neuromuscular junction initiates a wave of depolarisation across the sarcolemma through the T-tubule network.
What is the immediate effect of the depolarisation of the sarcolemma?
An increase in intracellular [Ca2+]
What is the sarcolemma?
Collection of myofibrils contained within a plasma membrane with T-tubule invaginations.
Properties of Slow oxidative muscle fibre:
Fatigue resistant, red, oxidative metabolism, low glycogen content, aerobic ATP synth, high mitochondria, soleus muscles.
What are the 3 classes of muscle fibres?
Slow Oxidative, Fast Oxidative, and Fast Glyolytic.
Properties of Fast glycolytic muscle fibres:
Fatigable, white, glycolytic metabolism, high glycogen, anaerobic ATP synth, fewer mitochondria, biceps brachii muscles
Comparison of the diameters of muscle fibres:
Slow fibres are half the diameter of fast fibres and take longer to contract after nerve stimulation.
How long does it take fast fibres to contract?
10msec or less
Inhibitors of K+ channel in pre-synaptic neurone:
Dendrotoxin
Inhibitors of ACh release in pre-synaptic neurone:
Tetanus toxin, Botulinum toxin
Botulinum Toxin:
-Linked to food poisoning
-Inhibits release of ACh
-Can lead to muscle weakness -> paralysis -> death
-1st symptoms > dry mouth, double vision, 2nd symptoms > gastrointestinal (vomiting), 3rd symptoms > paralysis of limbs and respiratory system.
Clinical use of botulinum toxin:
-Treatment of strabismus (cross eyedness)
-Blepharospasm (uncontrolled eyelid movements)
-Cosmetics (Botox)
Aerobic exercise:
-Sustained low level exercise
-stimulates slow fibres
-Converts Fast glycolytic fibres into fast oxidative fibres
-Increases fatigue resistance
Anaerobic Exercise:
-Typically brief + intense
-Stimulation of fast fibres
-No change to number of muscle fibres
-Enlarges myofibril size by increasing myofilaments numbers
- increases diameter of muscle fibre.
What is PCr in energy release?
Phosphocreatine
Purpose of phosphocreatine in energy release?
The reduction of ADP into ATP by creatine kinase
Anaerobic energy release:
Anaerobic metabolism via glycolysos -> substrates enter glycolysis by glycogenolysis and gluconeogenesis. Glucose uptake from blood by GLUT4. Pyruvate undergoes reduction steps (produces lactic acid NAD+)
What causes muscle fatigue?
The build up of lactic acid leading to the cell pH lowering.
Cardiac Muscle Structure:
Cardio myocytes - striated, shorter and branched. -> join together at intercalated disks. -> electrical coupling between adj. myocytes at intercal. disks by gap junctions. Desmosomes provide structural connection.
Where is the action potential of cardiac muscle initiated?
Pacemaker cells in the sino-atrial node.
Role of smooth muscle:
control of organ systems (e.g digestive system) + also blood vessel and airway diameter
Two classes of smooth muscle:
Multiunit + unitary
Smooth muscle properties:
Non-striated -> join at “dense bodies” -> thick filaments intersperse around thin filaments
-Large variations in action potential depending on muscle type.
What do smooth muscle cells do to transport a signal if they can’t generate an action potential?
They respond to graded changes in membrane potential.
Where is Ca2+ stored within a sarcolemma?
T-tubule
How is Ca2+ released from the T-tubule in the sarcolemma into the myofibrils?
The depolarisation of the T tubule leads to the opening of the L-type Ca2+ channels -> These channels tether to ryanodine receptors in the SR membrane -> Ca2+ moves into the cytoplasm.
Mechanisms for increasing intracellular calcium in Cardiac Muscle:
Ca2+ induced Ca2+ release -> influx of calcium stimulates ryanodine receptors to release Ca2+ from stores.
How is muscle contraction terminated?
The removal of Ca2+ ions from the cytoplasm across the cell membrane using Plasma membrane calcium ATPase or back into the SR via sarco/endoplasmic reticulum Ca2+ ATPase.
What is used to help accumulate Ca2+within stores in the sarcolemmas?
Ca2+ binding proteins.
Mechanisms for increasing intracellular calcium in Smooth Muscle:
Smooth muscle lacks T-tubules -> have shallow invaginations (caveolae) -> Change in action potential activates L-type Ca2+ channels -> leads to CICR via activations ryanodine receptors in the SR membrane.
What is CICR?
Ca2+ indued Ca2+ release
Mechanism of Contraction in Smooth Muscle:
No troponin in smooth muscle -. uses calponin and caldesmon -> inhibit interaction between actin and myosin. -> stimulation of calmodulin by Ca2+.
Downstream effects of smooth muscle contraction’s mechanism:
Activations of myosin light chain kinase phosphorylates MLC -> removes inhibitory effects of calponin and caldesmon facilitating crossbridge formation and contraction.
To stop contraction MLC needs to be de-phosphorylated using myosin light chain (MLCP)
What is the evolutionary consequence of the development of circulatory systems?
An increase in the size and complexity of organisms
Functions of the circulatory system: Primary
Primary function - distribution of gases/molecules (for nutrition, growth, and repair)
Functions of the circulatory system: Secondary
Secondary Functions -
Fast chemical signalling, dissipation of heat, mediates inflammatory and host defence responses to invading microbes.
Structure of the left circuit of the circulatory system :
Systemic circulation:
-parallel pathways from left to right.
-Usually flows through a single capillary bed
-Two capillary beds are in series
-Capillary beds can also run in parallel (e.g in intestines)
Structure of the right circuit of the circulatory system:
Pulmonary circulation:
-Single pathway from right to left side of the heart.
Which type of blood vessel has the highest number in the circulatory system?
Capillaries
Which type of blood vessel has the highest aggregate cross sectional area in the circulatory system?
Capillaries
Which type of blood vessel has the smallest cross sectional area number in the circulatory system?
Capillaries
Which type of blood vessel has the highest mean velocity in the circulatory system?
Aorta - 21 cm/s
Which type of blood vessel has the smallest mean velocity in the circulatory system?
Capillaries
What are the 4 building blocks in vascular walls?
Endothelial cells, elastic fibres, collagen fibres, smooth-muscle cells
What are the 3 layers of Blood vessel walls:
Intima - (Tunica interna)
Media - (Tunica Media)
Adventitia (Tunica Externa)
Function of the elastic fibres in the large arteries:
-High Compliance: Walls stretch easily without tearing under pressure changes
-Enables Vessels to cope with peak ejection pressures
-Recoil of elastin fibres forces blood to move even when ventricles relaxed.
Muscular arteries:
- Smooth muscle cells are arranged circumeferentially.
-Capable of greater vasoconstriction/dilation to adjust blood flow rate.
-Vascular tone - partial contraction maintains vessel pressure and flow.
From largest to smallest what are different types of artery:
Elastic arteries, muscular arteries, arterioles.
Arterioles:
-Smooth muscle enables blood flow regulation to capillary networks regulated microcirculation.
-Precapillary sphincters monitor blood flow to capillary
-Highest resistance to blood flow
What are the terminal regions of the arterioles called?
Metarterioles
Large veins:
-Valves contain backflow
-Defective, leaky valves allow backflow and can lead to varicose.
-More elastic than arteries
-Large capacitance
- Adrenergic receptors innervate smooth muscle and reduce capacitance. -> decrease “unstressed” volume and increases “stressed” volume
Capillary Exchange:
Capillary:
-Exchange site for gases, water, nutrients, waste products
-Additional Functions: Glomerular filtrate, skin temp regulation, Hormone delivery, Platelet delivery.
Starling’s forces equation:
Fluid movement = Hydraulic conductance [(Capillary hydro pressure - Interstitial hydro pressure) - (Capillary oncotic pressure - interstitial oncotic pressure)]
What is oncotic pressure caused by?
The colloid osmotic pressure caused by serum proteins (e.g albumin)
The lymphatic system control of blood volume:
-Drains excess interstitial fluid
-Maintains circulating volume of blood
-Lymph returned to cardiovascular system via subclavian veins
The 3 roles of the lymphatic system:
-Transport of dietary lipids
-Immunology
-Maintenance of blood volume
Purpose of valves within the heart:
Prevent the backflow of blood during the cardiac cycle
Atrioventricular valves:
(Mitral and tricuspid) - connected to the cardiac wall via chordae tendinae and papillary muscles
Semilunar valves:
(aortic and pulmonary) - small fibrous nodules which come together.
What are the 3 layers in heart wall?
Epicardium, myocardium, and endocardium
What are conducting cardiac cells?
Cells which rapidly spread ation potentials across the heart (E.g SAN, atrial internodal tracts, AVN, Bundle of His, and Purkinje fibers)
What are contractile cardiac cells?
Respond to action potentials by coordinating contraction -> generates a force and pressure to move the blood.
What are the 4 currents responsible for the action potential control of cardio myocytes?
Na+ currents, Ca+ currents, K+ current, and the pacemaker current
Na+ current:
Rapid depolarising phase -> action potential in atrial and ventricular muscle + purkinje fibres.
Ca+ current:
-Rapid depolarising phase SAN, AVN + triggers contraction all cardiomyocytes.
K+ current:
Repolarising phase for all cardiomyocytes.
Pacemaker current:
Pacemaker activity -> stimulates SAN, AVN and Purkinje bundle cells.
What is the depolarisation sequence of the cardiac cycle/
Cells of the SAN depolarise -> this increases/decreases the heartrate. -> travels to the AVN -> the action potential is carried to the ventricular muscle network via the His-Purkinje fibre system.
What are the 7 stages of the cardiac cycle?
Atrial Systole -> Isovolumetric ventricular contraction -> Rapid ventricular ejection -> Reduced ventricular ejection -> isovolumetric ventricular relaxation -> rapid ventricular filling -> reduced ventricular filling.
Atrial systole:
Atrial depolarisation -> contraction of atria (increase atria pressure) -> ventricles fill with blood.
isovolumetric ventricular contraction:
Purkinje fibre activation -> ventricles contract -> increases pressure. -. AV valves close.
Rapid Ventricular ejection:
Ventricular pressure rises and exceeds aortic pressure -> SLV open and blood rapidly ejected -> ventricular volume decreases.
Atrial filling begins -> increases pressure slowly.
Reduced ventricular ejection:
Ventricle repolarisation -> decrease pressure(stops contraction).
Blood still ejected.
Isovolumetric ventricular relaxation:
Begins after ventricles have fully repolarised -> ventricles relaxed (decreases pressure). All valves closed.
Rapid ventricular filling:
When atrial pressure is greater ventricular pressure, blood flows through AV valves into ventricles -> increasing volume at low pressure.
Reduced Ventricular filling:
Longest phase of cardiac cycle -> induces last portion of ventricular filling.
How does an electrocardiogram function;
Electrodes on the body’s surface detect the sum EC currents (formed by the movement of ions during depolarisation-repolarisation)
What is the P wave on an electrocardiogram?
The wave representing the depolarisation of the atria on the far left.
What is the PR interval on an electrocardiogram?
The length of AV node conduction (time between atrial depolarisation and ventricle depolarisation)
What is the QRS complex on an electrocardiogram?
The depolarisation of the ventricles (tallest peak surrounded by two troughs)
What is the T wave on an electrocardiogram?
The repolarisation of the ventricles
What controls the resistance to blood flow in the arterioles?
Somatic nervous system (adrenergic receptors -> contraction), circulating hormones, vasoactive substances.
Examples of vasoactive metabolites:
Angiotensin, Bradykinin, Histamine, Nitric Oxide, Vasoactive Intestinal peptide
Velocity of blood flow equation:
Velocity = Flow/Cross sectional area
Why is flow a constant when calculating the velocity of blood flow?
The blood is within a closed system
Flow equation:
Flow = Pressure difference/ resistance.
What is blood flow determined by?
Pressure difference between the inlet and outlet of a vessel.
Resistance of vessel to blood flow.
What is Total Peripheral Resistance?
The resistance of the entire systemic vasculature.
How can the resistance in a single organ be calculated?
Use the Q = Delta(P)/R, substitute Q with renal flow
What is Poiseuille’s law: equation
Resistance = 8ղl/πr^4
ղ = blood viscosity
l = length of blood vessel
What is Poiseuille’s law:
The factors that determine resistance to flow are: Blood vessel diameter, length, series/parallel arrangement, Viscosity.
What is the haematocrit?
The proportion of red blood cells within the blood.
How do calculate series resistance? (within an organ)
Total resistance = the sum of individual resistances -> pressure decreases through each sequential component
How do you calculate series resistance? (within an organ)
Total resistance = the sum of individual resistances -> pressure decreases through each sequential component
How do you calculate parallel resistance? (within an organ)
Less resistance than individual resistances -> leads to no loss of pressure.
Why does blood pressure decrease when it flows through areas of increased resistance?
Energy is lost overcoming frictional resistance -> decreasing pressure.
What is the pulse pressure equation?
Pulse pressure = systolic - diastolic pressure
What is the mean arterial pressure equation?
Mean Arterial Pressure = diastolic pressure + 1/3 pulse pressure.
What type of receptors respond to changes in blood pressure?
Baroreceptors in the carotid and aortic sinuses
What regions of the brain coordinate/regulate blood pressure:
Brainstem cardiovascular centres within reticular formations of the medulla and lower pons.
Effects of Angiotensin II:
Stimulates aldosterone synthesis in the Adrenal cortex.
-Increases Na+ reabsorption
-Stimulates Na+ - H+ exchange within the kidney
-Hypothalamus -> increase thirst and ADH secretion -> +ve water reabsorption
-Vasoconstriction of the arterioles
What is the name of the long acting system in control of arterial pressure.
Renin - angiotensin - aldosterone system
(RAAS)
Hypertension treatments:
Angiotensin-converting enzyme (ACE) inhibitors, Renin Inhibitors, and Angiotensin II receptor blockers (ARBs) -> Prevent increase in pressure in response to decrease towards healthy range.
What diseases/conditions does hypertension increase the risk of?
Heart disease, heart attacks, strokes, heart failure, aortic aneurysms, peripheral arterial diseases, kidney disease, vascular dementia
What are the two type of respiration (not aerobic and anaerobic)
Internal respiration and External Respiration
External Respiration:
Ventilation, exchange and transport of gases around the body.
What are the two zones within the lungs?
The conducting zone and the respiratory zone.
What is the conducting zone of the lungs?
The zone providing pathways for the air to travel through
What is the respiratory zone of the lungs?
The zone providing sites for gaseous exchange
What components of the lungs are contained within the conducting zone?
Trachea, Bronchi, Bronchioles
What components of the lungs are contained within the conducting zone?
Respiratory bronchioles, alveolar ducts + alveolar sacs
How does the conducting zone prepare air for gaseous exchange?
The air is filtered, warmed, and humidified.
What non-lung components are part of the conducting zone?
Nose, nasopharynx, oropharynx (mouth), pharynx, and the larynx
Structure of the Bronchial wall:
-Reinforced cartilage rings -> keep bronchi open
-Smooth muscle -> controls diameter of airways
-Mucous glands -> trap particles + foreign bodies
-Elastic tissue -> Maintain pressure
-Epithelial Layer -> removes particles from lungs
Role of the respiratory epithelium:
Ciliated epithelia waft particles trapped in mucous secreted by goblet cells out of the lungs.
Sensory nerve endings sense for noxious chemicals and stimulate coughing.
Structure of bronchioles:
Lack cartilage support, lined with respiratory epithelium, proportionately more smooth muscle.
Alveoli structure:
Large SA
Fed from terminal bronchiole
Thin walled
Close proximity to capillaries.
Coated with surfactant.
The Air Blood Barrier:
“sandwich” created by flattened cytoplasms of type 1 pneumocytes and the capillary wall. -. gaseous exchange occurs primarily across the type 1 pneumcytes.
O2 must travel across 5 bio membranes to enter RBC’s (erythrocytes)
The two processes of ventilation:
Inspiration and expiration.
What are the primary muscles of inspiration?
Diaphragm and external intercostal muscles.
What is the name of thw law air movement abides by?
Boyle’s law
Quiet expiration:
Passive process using elastic recoil -> there are no primary muscles of expiration.
Which muscles are engaged during forced expiration:
Accessory muscles, internal intercostal muscles, abdominal muscles, neck and back muscles
What is the Pleura?
The double-membrane surrounding the lungs. Stops the lungs and the chest from sticking togethers, allowing for the free expansion and collapse of the lungs.
What is the pericardium?
The double membranous sac surrounding the heart -> provided lubrication and aids distension
What are the 3 components of the Pleura?
The (outer)parietal pleura. (inner)visceral pleura, and the (inter)pleural cavity.
What is an important feature of the pleural cavity in the pleura?
It has a sub-atmospheric temperature allowing for the lungs to expand during inspiration.
What kind of injury can cause the lungs to collapse?
Piercing of the pleural membranes allows air into the IPS, increasing it’s pressure making it no longer sub-atmospheric. This causes the lungs to collapse as they are not able to expand during inspiration.
What is compliance?
A measure of elasticity of the lungs
What is the compliance equation:
Compliance = Change in volume / change in pressure
What is the effect of a high lung compliance?
Expiring is more diificult
What is the effect of a low lung compliance?
More work is required to inspire
What is Laplace’s equation?
Prssure = (2 x surface tension) / radius
What cells synthesiss surfactant?
Type II pneumocytes
Functions of surfactant:
-Prevents alveolar collapse.
-Regulates alveolar size
-Increase compliance
-prevents oedema
Anatomical Dead Space:
Volume of conduction airways (150ml)
Physiological dead space:
Volume of lungs not participating in gas exchange:
-Conducting zone and non-functional areas
What is oedema?
Increased fluid retention in the lung tissue will cause swelling and narrowing of the airways, increasing resistance
What are the factors that impact airway resistance?
Diameter, Mucus secretion, Oedema, Airway collapse
Dalton’s law:
The total pressure of a mixture of gases is the sum of their individual partial pressures.
What is the composition of air’s total partial pressure?
760mmHg
What is Henry’s Law?
The conc. of disosciated gas = solubility coef x partial pressure of the gas
Which enzyme aids the binding of oxygen to the iron ion within haemoglobin?
Methaemoglobin reductase by converting Fe3+ into Fe2+
What are the two states of haemoglobin?
Tense: Low O2 affinity
Relaxed: High O2 affinity
Effect of increased temp on haemoglobin O2 affinity:
Decreases affinity
Effect of increased pH on haemoglobin O2 affinity:
Decreases affinity
What are the two categories lung diease?
Obstructive and restrictive:
Brief description of obstructive lung disease:
Reduce flow thrpugh airways -> decreasing the pressure within the lungs
Brief description of restrictive lung disease:
Reduce the lung expansion -> caused by the inability to expand chest
Bronchoconstriction:
Smooth muscle constricts, reudcing the diameter of the lumen
What can lead to the narrowing of airways in obstructive lung disease?
Excess secretions, Bronchoconstriction, inflammation
Effect of an obstructive lung disease on a spirometer:
Increases the time taken for expiration
Flow-volume line for an obstructive lung disease:
Initial/peak flow can be similar to normal however there is a sharp fall in flow, causing a concave shape to the curve.
Examples of obstructive diseases:
Asthma, Emphysema, Chronic obstructive pulmonary disease COPD, Chronic Bronchitis
What is Emphysema?
The loss of elastin -> destruction of structural tissue of the lungs, causing collapse of airways
What is Emphysema?
The loss of elastin -> destruction of structural tissue of the lungs, causing collapse of airways
Asthma:
Hyper-active airways -> triggered by either atopic of non-atopic factors. Inflammatory cells in airways release mediators causing uneccesary bronchoconstriction.
What is an atopic trigger?
An extrinsic trigger e.g allergies
What is an a non-atopic trigger?
An intrinsic trigger e.g respiratory infection, cold air, stress, exercise, and inhaled irritants
What causes restrictive lung disease?
-Reduced chest expansion (Chest wall abnormalities, muscle contraction deficiencies)
-Loss of compliance (Normal aging, increased collage, environmental factors)
Two types of asthma treatment:
Short-acting Beta 2 - adrenoreceptor agonists (inhaler) -> dilates airways
Longer acting: Steroids, glucocorticoids -> reduce inflammatory responses.
Restrictive lung disease spirometry:
Decrease vital capacity + no change in flow rate
Restrictive lung disease flow-volume loop:
Maintains shape of normal curve, however volume reduced on x axis
What is asbestosis?
Slow build-up of fibrous tissue leading to the loss of compliance
Describe breathing as a mechanism:
An involuntary mechanism that can be consciously overridden (e.g hyperventilation and holding breath)
What part of the medulla controls quiet inspiration?
DRG (Dorsal respiratory group)
What part of the medulla controls forced inspiration and expiration?
The VRG (Ventral Respiratory Group)
What part of the medulla is responsible for the tidal pattern of breathing?
The Pre-botzinger complex
Pons Medulla: Centres
Pneumotaxic centre: increases the breathing rate by shortening inspirations
Apneustic centre: increases the depth and reduces the rate by prolonging inspirations
What bis the Hering-Breuer reflex?
Stretch receptors in the lung send signals back to the medulla to limit inspiration and prevent the over-inflation of the lungs. (inhibits inspiratory centre)
Central chemoreceptors:
Monitor the conditions in the cerebral-spinal fluid -> sensing CO2 and pH. -> a rise in CO2 and decrease in pH will lead to an increased ventilation rate.
Peripheral Chemoreceptors:
Within the carotid body and aortic arch -> respond to increase in CO2, decrease in pH and O2 -> stimulation leads to an increase in ventilation.
What are the 3 germ layers from which epithelial tissue derive from?
The Endoderm, Mesoderm, and Ectoderm
Which types of hormone target intracellular receptors?
All steroid hormones and some peptide-derived hormones
Plasma:
Watery solution of electrolytes, plasma proteins, carbohydrate, and lipids.
What are the principal proteins within blood plasma?
Albumin, Fibrinogen, Globulins, other coagulation factors
Erythrocyte cytoskeleton:
Erythrocyte shape is maintained by a cytoskeleton anchored to the plasma membrane by glycophorin and Band 3 Cl- HCO3 exchanger complex.
What do platelets bud off of in the bone marrow?
Megakaryocytes
What is platelet production dependent on?
TPO and IL-3 levels in the blood.
Platelets:
Nucleus free. Have mitochondria, lysosomes, peroxisomes, a granules, and dense-core granules. Have a coat of platelet receptors and an internal skeleton of a circumferential band of tubulin microtubules.
What is turbulent flow?
The parabolic profile of velocity is blunted, leading to a lower max velocity.
When does turbulent flow occur?
In large radii, high velocity or local stenosis (increasing velocity)
What is a thrombus?
Intravascular blood clot which forms in pathological situations within the blood.
How is blood fluidity maintained?
Endothelial cells use paracrine and anticoagulant factors
Clotting intrinsic pathway:
Surface contact activation on membrane of activated platelets.
Clotting extrinsic pathway:
Membrane bound tissue factor activation -> activated when blood contacts material from damaged cell membranes.
Platelet adhesion:
Platelets adheres to Von Willebrand factor which binds to subendothelial collagen.
Platelet aggregation:
Conformational change in receptor caused by activation -> allows binding to fibrinogen -> molecular bridges form between platelets.
Intracellular cation concentrations:
K+ 148mM
Na+ 10mM
Intracellular anion concentrations:
Cl- 4mM
Protein 55mM
Extracellular cation concentrations:
K+ 5mM
Na+ 140mM
Extracellular anion concentrations:
Cl- 103mM
Protein 15mM
What are the outputs of H2O and Na+ from the human body?
(predominantly) Urine, respiration, stool, sweat
Possible birth defects (congenital abnormalities) of the kindeys?
Renal agenesis -> death
Ectopic kidney -> Damage and renal stones.
Horse shoe kidney -> Kidneys fused -> renal stones
Where is most of the nephron located?
Cortex (excluding loop of henle and collecting duct)
Renal failure:
A fall in the glomerular filtration rate -> leads to increase in serum urea and creatine in the blood. Acute is reversible, chronic is irreversible.
Peripheral neuropathy:
Peripheral nerve damage leading to problems with sensation and movement
Renal failure progression: Damage to kidney:
Uraemia:
-Thickening of glomerular membranes.
-Damage to glomeruli
-Progressive scarring glomeruli
-Reduction renal size
Renal failure progression: Symptoms
-Failure to excrete salt and water -> hypertension, hyperkalaemia, mild acidosis.
-Poor urea/creatine excretion -> anorexia, nausea, vomiting
-Leak of protein in urine -> neuopathy, pericaditis
-Failure production erythroprotein -> anaemia
-Failure to excrete phosphate -> lowers Ca2+ -> bone disease
Causes of renal failure:
Hypertension, glomerulonephritis, diabetes mellitus, polycystic kidney disease + others
Glomerular filtration rate value:
125ml/min
What is in ultrafiltrate?
Protein-free plasma (1% albumin)
What are the 3 modes of tubular transport?
transcellular reabsorption (lumen to capillary), transcellular secretion (reverse), paracellular secretion and reabsorption (through gaps between epithelial cells)
What are the 3 modes of tubular transport?
transcellular reabsorption (lumen to capillary), transcellular secretion (reverse), paracellular secretion and reabsorption (through gaps between epithelial cells)
What are the systems by which secretion by the proximal tubule takes place?
Organic cations and organic anions
What is the transport maximum? (kidneys)
The reabsorption of substances using maximum number of membrane at their maximum rate.
Renal Epithelial Cell in the Proximal tubule:
Na+, K+ ATPase – primary active transport protein – Keeps intracellular Na+ low.
Basolateral K+ channel and Na+, K+ ATPase help to lower the membrane potential. This provides an electrochemical gradient to drive coupled Na+ entry into the cell.
Na+ coupled transport proteins transport PO4-, glucose, and amino acids into the cell. Transport proteins in the basolateral membrane the translocate these into the interstitial fluid and the capillaries.
Process of transcellular reabsorption -> drives the reabsorption of water -> iso-osmotic reabsorption.
SGL T1 and T2 both ion channels.
What is NaPiII?
A coupled transport protein that translocates Na+ and PO4 2- from the tubular fluid into the cell.
Reabsorption of Bicarbonate by renal epithelial cells:
NHE3- uses Na+ conc and potential gradient -> drives H+ ion out of the cell into
H+ binds to the Bicarbonate to form carbonic acid.
Carbonic anhydrase is an external enzyme located on the proximal face of the epithelial cell .
System works to maintain the pH of the body fluid.
Overall reabsorption of Na+ and bicarbonate -> this movement drives the osmosis of water from the apical face to the basolateral face.
Permeability of the descending limb of the loop of henle:
water permeable but not permeable to Na+ and Cl-
Permeability of the ascending limb of the loop of henle:
- both thick and thin have low permeability to water but high permeability to Na+ and Cl-
Thin – small diameter
Thick – large diameter
Thick ascending limb renal epithelial cell: Key transport proteins
Apical:
NKCC2, ROMK, CLCK,
Basolateral:
Barttin, Na+ K+ ATPase, K+ transport protein
Role of Barttin in TAL:
Intracts with CLCK ion channels to control its activity. Both must be operational for the facilitated diffsuion of Cl- into the interstitial fluid to occur.
Thick ascending limb renal epithelial cell: NKCC2
-cotransport protein that uses the electro gradient -requires the binding of all 4 ions for conformational change to occur to translocate the ions into the intracellular fluid.
-Binds to Na+, 2Cl-, K+
Thick ascending limb renal epithelial cell: purpose
-Net reabsorption of chloride and Na+, whereas the K+ is recycled into tubule.
-Establishes salt gradient
Bartter’s Syndrome: Disease type and symptoms
Recessive genetic disease -> leads to salt wasting and polyuria, hypotension, hypokalaemia, metabolic alkalosis, hypercalciuria, renal stones
Bartter’s Syndrome: Intracellular impact
Can lead to function altering mutations in NKCC2, ROMK, and CLCK -> proteins lose their function
What is fractional excretion and why is it an important measurement?
Fractional excretion = amount in urine/ amount filtered
-Used to assess impact of mutations and impact on nephron function
Why is a mutation in ROMK detrimental to nephron function?
the K+ levels in the tubule fluid will drop to low and this will reduce the reabsorption of Cl- into the body.
What drugs can be used to treat high blood pressure? (Ascending limb)
Furosemide and Bumetanide -> cause Bartter’s syndrome like side effects.
They block NKCC2 -> increase polyuria and salt wasting to decrease body fluid volume and blood volume
Function of the early distal tubule:
Reabsorption Na+ & Cl-
Reabsorption Mg2+
Sensitive to thiazide diuretics
Early distal tubule cell:
-NCC - Na+ Cl- cotransporter
-Mg2+ channel -> reabsorbed by unknown pathway
-K+ channels
-CLCK, Barttin
- Reabsorption of Na+ Cl- sets up driving force for reabsorption of water.
Gitelman’s syndrome: Disease type and symptoms
Recessive genetic disease.
~Same symptoms as Bartter’s however instead has Hypocalciuria
Gitelman’s syndrome: Effect on cell
Effects EDT (early distal tubule) cell -> NCC loses function -> salt wasting in tubule fluid -> water enters tubule -> water loss
High blood pressure treatment: (EDT)
Chlorothiazide -> inhibits NCC -> Gitelman’s like side effects
What genetic property can protect from hypertension?
Carrying one mutation for the loss of function of ROMK, NCC, or NKCC2
What are the 2 cell types in the Late distal tubule and the collecting duct:
Principal Cells, and intercalated Cells.
What is the function of principal cells (Kidney):
Na+ and H2O reabsorption.
K+ and H+ secretion.
What is the function of intercalated cells (Kidney):
alpha IC and Beta IC
H+ secretion and reabsorption
HCO3- reabsorption and secretion
What are the transport proteins in a principal cell?
Apical:
ENaC, ROMK, Aquaporin 2
Basolateral:
Na+ K+ ATPase, Kir2.3, AQ3, AQ4
Function of Kir 2.3 K+ channel in principal cells?
decreases the cell potential to provide a motive force to drive the transport of Na+ into the cell.
What is the function of aquaporins in principal cells?
They’re water channels which uses osmotic driving force to move H2O from the DT or CD to the blood.
What is the role of ENaC in principal cells?
To pump Na+ from the tubule fluid into the cell and tissue fluid, to provide a motive force for the transport of water.
What are the diseases which can effect the Principal cell (kidneys)?
Diabetes Insipidus -> AQP2
Liddle’s syndrome -> ENaC
Pseudohypoaldosteronism
What treatment for high blood pressure effects principal cells?
Amiloride -> targets ENaC -> less Na+ reabsorbed -> less motive force for water reabsorption -> small interstitial fluid vol. -> decreased blood pressure.
Alpha Intercalated Cell:
H+ secretion by ATPase channel/carrier.
HCO3- reabsorbed by Cl- antiport (AE1), Cl- channel recycles Cl- into tissue fluid.
beta Intercalated Cell:
H+ & Cl- reabsorption
HCO3- secretion by AE1
Medullary collecting duct:
Low Na+ permeability, High H2O and Urea permeability (In presence of vasopressin)
What hormones control the reabsorption at the collecting duct?
Aldosterone (Na+ and K+) and Vasopressin (water)
Treatment for acute renal failure:
Dialysis
Symptoms of acute renal failure:
Hypervolaemia- increased interstitial fluid volume
Hyperkalaemia- lack of K+ secretion -> cardiac excitability
Acidosis - depression CNS
High urea/creatinine -> impaired mental function, nausea, vomiting
What receptors does vasopressin bind to on principal cells?
V2 receptors -> activates cascade -> activates protein kinases -> phosphorylation and fusing of AQP2 containing vesicles to the apical membrane.
Aldosterone:
Mineralocorticoid, regulates plasma Na+, K+ and body fluid volume. Released in response to increase in K+, decrease in Na+, or decrease in ECF volume
Renin-angiotensin:
Regulates body fluid volume, plasma Na+. and K+ conc.
Renin converts ang into Ang I. Ang I is converted in active Ang II by ACE (commonly in lungs).
Where is renin releasewd from?
The juxtaglomerular apparatus (JGA), more specifically the macula densa (circular cell structure on next to the afferent and efferent arteriole)
What are the impacts of active angiotensin II?
Causes the zona glomerulosa to release aldosterone -> arterioles constrict (increases blood pressure)
net effect = increase plasma [Na+] + ECFV + blood pressure + ACE inhibitors.
Mouth secretions:
alpha amylase, lingual lipase, kallikrein, mucous
Oesophagus secretions:
Mucus, HCO3- (bicarbonate)
Stomach Secretions:
HCl. Pepsinogen, intrinsic factor, mucus
Small intestine secretions:
Mucus, HCO3-, pancreatic juice + bile
Large Intestine Secretions:
Mucus
approximately how much fluid is secreted in the GI tract?
8.5L
Role of Bicarbonate in the GI tract:
To protect surfaces from acidic conditions
What is a mechanical feature of the oesophagus that prevents food from leaving through the oesophagus?
Rings of muscle prevent the retrograde movement of food.
What’s the difference between oxyntic glands and pyloric glands in the stomach?
Pyloric glands don’t contain parietal cells and are located at the stomach antrum.
Oxyntic glands:
Contains multiple cells:
Epithelial Cells -> secrete HCO3-
Mucus neck cells - Mucus
Parietal Cells - secretes HCL + intrinsic factor
Chief cells - secrete pepsinogen
Pyloric glands:
G cells - secrete gastrin
D cells - somatostatin
Gastric acid secretion: Parietal cells
-Increase blood pH (alkaline tide) as HCO3- is removed from the blood coupled with Cl- entering the cell.
-Bicarbonate and H+ derived from Carbonic acid from CO2 and H2O catalysed by carbonic anhydrase.
-HCl secreted by Cl- following H+ ions into the lumen.
-K+ H+ ATPase transporter
How is HCL secretion regulated?
Stimulated by: Histamine, ACh (vagus nerve), gastrin
Inhibited by:
low pH, somatostatin, prostaglandins
What medication decrease/inhibit the upregulation of H+ secretion into the stomach:
Atropine -> ACh
Cimetidine -> Histamine
Omeprazole -> all (H+ K+ ATPase)
What distinguishes the small intestine from the large one?
SI absorbs hydrolysed food after digestion via luminal and brush border enzymes
What cell secrete fluid and electrolytes to protect the intestines from bacteria/toxins?
Crypt epithelial cells
What is diarrhoea caused by?
The over-secretion of fluid to flush out toxins and pathogens.
The primary function of the intestines:
Absorb fluid, electrolytes, via villus cells/surface epithelia.
Secretion in the intestines:
Hormones/ Neurotransmitters bind to the G coupled protein receptor -> activates Adenyl Cyclase -> allows second messenger to upregulate the secretion of Cl- ions.
Over stimulation of Adenyl Cyclase leads to increased loss of fluid and Cl-.
Cellular transport in the jejunum (intestines):
Draw in sodium along with sugar and amino acid (cotransport) -> utilise the electrochemical gradient -> into the cell.
Carbonic acid dissociates -> H+ ions pushed into lumen in exchange for Na+
Sugar and amino acids diffuse from the cell into the blood.
Sugar and amino acids require cotransport to be drawn in due to high intracellular concentration.
Cellular transport (absorption) in the ileum (intestines):
Similar to jejunem:
Addition of apical Bicarb/Cl- exchanger and Cl- channel on basolateral face.
Pancreatic Secretion:
Takes place in ductal cells: bicarbonate is secreted by a Cl- HCO3- exchanger.
Basolateral layer has Na+ K+ ATPase and a H+ Na+ exchanger.
Absorption in the colon (large intestine)
Epithelial cell.
Apical face:
Aldosterone controlled Na+ channel into cell and K + channel into lumen.
Basolateral face:
Na+ K+ ATPase and a K+ channel into the blood.
Lipid hydrolysis in the intestines:
Pancreatic lipase, colipase, milk lipase and other esterases, aided by bile salts complete lipid hydrolysis in the duodenum and jejunum.
products form micelles and are absorbed across the luminal surface. These are then modified in the golgi and secreted into the lacteal.
absorption of carbohydrates (intestines):
Glucose and Galactose are reabsorbed through the coupled absorption of Na+. Fructose moves down it’s conc. and-so doesn’t have to be co-transported.
Absorption of proteins (intestines):
Most dipeptides and tripeptides are broken down by peptidase and then co-transported into the blood by Na+.
Function of the female reproductive system:
-produce haploid gametes
-Facilitate fertilisation
-Site for the implantation of the embryo
-Provide physical and nutritional needs to nurture neonate (new born infant)
Ovaries:
-Female Gonads
-Development and maturation of ova
-oocytes enclosed within follicle
-Follicular cells secrete steroid hormones
Ovary cortex:
Outer zone with germinal epithelial layer containing oocytes
Ovary inner medulla:
Blood vessels and lymph
Fallopian Tubes:
transport egg from ovary to uterus (10cm)
Infundibulum with fimbriae (finger like protrusions that catch oocyte)
-Isthmus and Ampulla
-Highly folded mucosa - ciliated and secretory cells.
Cervix:
interior os and exterior os at its margins.
Connects to the cervical canal
Cervical glands secrete mucus to prevent entry of microbes.
whata re the two femal cycles:
Ovarian and endometrial (menstrual)
What part of the brain drives the endometrial cycle:
the hypothalamic-pituitary-gonadal axis
Endometrial cycle: how is it controlled:
HPG axis -> releases gonadotropin-releasing hormone (GnRH) -> attaches to G-protein coupled receptor in anterior pituitary -> exocytosis of gonadotropins FSH and LH
What do FSH and LH stimulate the ovary to secrete?
The Theca: progesterone
Granulosa: 17 beta-oestradiol, inhibin, activin -> produce mature gametes.
function of 17 beta-oestradiol and progesterone:
Develop ovum, maintain corpus luteum, maintain pregnancy.
How is the ovarian cycle regulated?
the Hypothalamic-pituitary axis is controlled by negative and positive feedback mechanisms at different stages.
What are the 3 stages of the ovarian cycle?
Follicular phase, midcycle, luteal phase.
Hormonal “morning after” pill:
Inhibits ovulation and interferes with implantation -> preventing pregnancy post-coitus.
