Human Physiology

Yr 1

Total body water

60%

42L, 71mL/100g

Less in fat

Decreases with age

Liposome

If you put phospholipids into an aqueous solution, they would form a structure with the smallest surface area

Chemical disequilibrium and composition of body fluids

Extracellular: high Na+, high Cl-, low K+, low proteins (low in blood plasma, very low in interstitial fluid)

Intracellular: low Na+, low Cl-, high K+, high proteins (because of enzymes)

Different composition due to cell membrane’s permeability to molecules

Cell membrane permeability

• Highly permeable to water

• Larger size = lower permeability

• Lipid soluble = increased permeability

• Charge = cannot pass (most important factor)

Diffusion

Collisions cause random movement [high] to [low] down [gradient]

<3nm H2O soluble molecule can cross membrane this way

Can take place in open system or across partition that separates two systems

Filtration

High pressure through pores (holes in membrane)

E.g. kidney - phosphate ions pass through pores to be excreted in urine, proteins too big

Osmosis

Movement of ions across a membrane in response to a solute [gradient] (low to high solute gradient)

Cell = sealed environment

Osmotic pressure, P

Pressure which would prevent H2O moving. All compartments normally at osmotic equilibrium

Facilitated diffusion

[High] to [low]

down [gradient]

no energy needed

Carrier and channel proteins

Active transport

[Low] to [high]

Against [gradient]

ATP → ADP

ATPase releases energy

Endocytosis

Into cells

Proteins and very large molecules

Two types: pinocytosis and phagocytosis

Pinocytosis

Invaginated membrane pinches off pockets, e.g. fat uptake

Phagocytosis

Arms of cytoplasm encapsulate, e.g. immune response

Exocytosis

Out of cells

E.g. hormones and neurotransmitters

Two types of excitable cells

Muscle - smooth, skeletal and cardiac - contract

Nerve - neurones - conduct - send constant electrical signal over long distance

Neurones

Secretory - release chemicals called neurotransmitters at synapses

Cell body communicates with nerve terminals by electrical signals

Excitable cells - transmit electrochemical signals along their membranes by moving charged ions across the cell membrane = action potentials

Transmembrane resting potential

Electrical gradient between extracellular and intracellular fluid; inside cell slightly negative

Electrical gradient = membrane potential, or Vm = voltage difference across cell membrane

A form of stored or ‘potential’ energy which can be used to open voltage-gated membrane channels and send electrical signals

-70mV inside cell

What creates transmembrane resting potential?

Diffusion of K+ (leak channels) out of cell

• Channel always open

• K+ crosses membrane down [gradient]

Sodium pump/Na+K+ATPase (active transport)

• Moves 3Na+ out of cell and only 2K+ in

• Keeps intracellular concentration of K+ high and Na+ low

• Electrogenic pump - net loss of one positive charge from cytoplasm - helps maintain electrochemical gradient

Negative proteins inside cell

Voltage gated Na+ and K+ channels

Are normally closed in membrane at rest but are important in action potential generation

Opened by voltage change (depolarisation)

K+ channel slower to open and close

Both take time to reset

Membrane distribution for each ion is a balance

[gradient] and electrical gradient

E.g. Cl- leave down electrical gradient but enter down [gradient] - little transfer at rest

Na+ wants to enter down both gradients

Local, non-propagated response to transmembrane ion distribution changes

E.g. synaptic/graded or generator potential

Usually at dendrites and soma (EPSP, IPSP)

Loses strength through cytoplasm

Propagated disturbance of transmembrane ions

Action potential

At axon

All-or-none response - if sufficient stimulus get constant amplitude response

Does not diminish in strength as travels through neurone

Action potentials

Transient reversal in potential

All or nothing response - if sufficient response get constant amplitude response

Larger stimulus → increased frequency of action potentials

Absolute refractory period = cell cannot fire = no more AP - ensures one way travel of AP

Relative refractory period = only larger-than-normal stimulus can initiate new AP

Local anaesthetics block Na+ channels to stop action potentials

Action potential movement

Starts at axon hillock

Travels in one direction down axon

Orthodromic conduction

To nerve endings = synapse

Only pass message in one direction

Each section of the axon experiences a different phase of the action potential

Myelinated axon

Postsynaptic potentials

Local graded change in transmembrane potential

Not propagated and quickly decay in intensity and distance

No refractory period

Therefore can summate

Change postsynaptic cell’s excitability making it more or less likely to fire an action potential

Excitatory Postsynaptic Potential (EPSP)

ACh neurotransmitter

At NMJ 2 ACh bind and (nicotinic acetylcholine) receptor changes shape

Opens Na+ channel - depolarisation

Small, graded, local, short-lasting depolarisation of postsynaptic membrane

If threshold for action potential is reached, muscle contracts/AP generated in postsynaptic neurone

More likely to fire AP

Inhibitory postsynaptic membrane (IPSP)

GABA - inhibitory neurotransmitter

Chloride enters

Cell made more negative

Inside local hyperpolarisation

Transmembrane potential further from threshold

Less likely to fire AP

Convergence

Summation of IPSP and EPSP

Excitatory synapse mainly on dendrites

Inhibitory synapses tend to be on cell body

Synapses closest to axon hillock have greatest effect on action potential and firing

Spatial summation and temporal summation

Spatial summation

2 EPSPs on adjacent membrane add together

Temporal summation

2 EPSPs close in time can add, IPSP and EPSP can cancel out

Modulation of synaptic activity at the axon terminal

Amino acid neurotransmitters

Glycine

GABA

Classical neurotransmitters

Noradrenaline

Acetylcholine

Peptide neurotransmitters

TRH

Substance P

Other neurotransmitters (not peptides, amino acids, or classical)

ATP

Nitric oxide

Autonomic nervous system

‘Visceral nervous system’ - control over internal organs

Subconscious control - heart rate, pupil diameter, blood vessel contractility, hormonal secretions, gastrointestinal motility

Homeostasis

Afferent

Goes to CNS

Efferent

Goes away from CNS

Organisation of autonomic nervous system

Axons have:

• A two-neurone chain

  • Preganglionic (first) neurone extends to ganglion

  • Postganglionic (second) neurone extends from ganglion to effector organ

• Ganglia = cell bodies of many peripheral autonomic neurones occurs in clusters and form swellings on nerve trunks

Motor (efferent) pathways of ANS

Axons that form synapses with ganglion cells = preganglionic autonomic fibres

Axons innervating effector cells = postganglionic autonomic fibres

Postganglionic neurone has many varicosities from which a neurotransmitter is released

Neurotransmitters of the autonomic nervous system:

• Preganglionic nerves

• Postganglionic nerves

• Pre and postganglionic nerves

• Acetylcholine - cholinergic transmission

• ACh and Noradrenaline (noradrenergic transmission)

• Non adrenergic non cholinergic neurotransmission (NANC) and co-transmitters (neuromodulators)

Sympathetic vs parasympathetic

Function separately

Have opposing effects in some states (e.g. heart rate, GI tract) but not others (e.g. salivary gland secretion, blood vessels)

Sympathetic activity increases in stress (aroused state, fight or flight, pupils dilated, hair erected, increased blood sugar, increased heart rate, increased blood flow through muscle, blood diverted from GI tract)

Parasympathetic activity predominates during satiation and repose - rest and digest

Both systems exert continuous physiological control under normal conditions, at neither extremes - cooperate

Influences by sensory information via control centres in the brain

Parasympathetic nervous system pre and postganglionic fibres

Preganglionic axons emerge from cranial and sacral regions of CNS

Preganglionic axons form synapses in ganglia near to/adjacent to/within effector tissues

Sacral nerves - form pelvic plexuses containing scattered ganglia and some ganglia within tissues - pelvic and abdominal viscera (bladder, rectum, genitalia etc.)

Parasympathetic preganglionic fibres are long, postganglionic fibres are short

Sympathetic nervous system pre and postganglionic fibres

Preganglionic sympathetic axons entering chains terminal in:

• Paravertebral sympathetic chains

  • Both pre and post ganglionic axons may run for some distance up or down the sympathetic chain before forming synapse/emerging

• Prevertebral ganglia/plexuses

  • In the abdominal cavity: 3 main - coeliac ganglion, superior mesenteric ganglion, hypogastric (or inferior mesenteric) ganglion

• Adrenal medulla

  • Some preganglionic fibres emerging from 10th and 11th thoracic segments run in greater splanchnic nerve and terminate on chromaffin cells in the medullae of adrenal glands. Chromaffin cells analogous to sympathetic ganglia cells

In general, sympathetic preganglionic fibres are short, postganglionic fibres long

Different ways in which preganglionic sympathetic fibres may synapse with postganglionic fibres

Parasympathetic nervous system

AKA craniosacral division

Keeps body energy use low

Predominates in individuals in relaxed states

Blood pressure, heart rate, respiratory rates low

GI activity high

Rest and digest

Inhibitory effect on many tissues and organs

Cranial outflow of parasympathetic nervous system

Oculomotor (III) - smooth muscles of eyes

Facial (VII) - facial glands (lacrimal, salivary)

Glossopharyngeal (IX) - salivary glands

Vagus (X) - postganglionic fibres usually in target organ: heart, lungs, bronchi, stomach, oesophagus, liver, small intestine, pancreas, kidneys, proximal part of large intestine

Sacral outflow of parasympathetic nervous system

Nerves from pelvic plexuses containing scattered ganglia. Some ganglia are within tissue

Nerve innervate distal part of large intestine, bladder, ureters, reproductive organs

Parasympathetic neuroeffector pathway

Neurotransmitter synthesis, action and degradation at cholinergic synapses (parasympathetic)

ACh acts postjunctionally on nicotinic receptors at ganglionic synapses

ACh acts postjunctionally on muscarinic receptors at effector cell, e.g. heart and smooth muscle

ACh receptors

1. Nicotinic - at ganglia (and brain, neuromuscular junction). Ionotropic

2. Muscarinic - at autonomic target tissues (and brain). Metabotropic (M1-M3)

M1

Neuronal/gut (gastric acid secretion increased)

M2

Cardiac/presynaptic (heart rate/force decreased)

M3

Glandular (secretion increased), smooth muscle (contraction)

Parasympathetic drugs

Parasympathomimetic - cholinomimetic agonists (pilocarpine, muscarine, nicotine) - increased PNS

Parasympatholytic - muscarinic antagonists (atropine) - decreased PNS

Cholinesterase inhibitors (ACHEI) - increased PNS

Ganglionic blocking drugs - nicotinic antagonist - blocks both sympathetic and parasympathetic ganglia - decreased PNS and SNS

Parasympathetic control of heart

Postganglionic nerves release ACh which acts at M2 muscarinic receptors to decrease heart function

Sinoatrial node (pacemaker) - decreases heart rate (bradycardia)

Atrial muscle - decreases contractility (force and duration of contraction)

Atrioventricular node (conducts electrical impulses) - decreases rate of conduction

(Cardiac arrest - atropine (muscarinic antagonist) used for resuscitation)

Parasympathetic control of pupil diameter

Circular muscle/constrictor pupillae = smooth muscle arranged concentrically

Parasympathetic nerve activation → ACh → M3 muscarinic receptors → circular muscle contraction → pupil constriction/miosis

Inhibition of contraction → muscarinic antagonist (e.g. atropine) → blocks circular muscle contraction → passive dilation → myrdriasis

Parasympathetic control of focussing

Ciliary muscle relaxed

• Suspensory ligaments taut

• Lens flattened

• Focus for distant vision

Ciliary muscle contracts and moves in due to ACh action at M3 receptors

• Suspensory ligaments relax

• Lens gets fatter

• Focus for near vision/accommodation

Cycloplegia - paralysis of ciliary muscle → loss of accommodation

Mydriatic drugs (parasympathetic)

Muscarinic antagonist - passive dilation/mydriasis (loss of drive to constrictor pupillae) and cycloplegia (loss of accommodation to ciliary muscles)

Antiglaucoma and miotic drugs (parasympathetic)

Muscarinic agonist - pressure in eye builds up due to production of fluid (aqueous humour) and lack of drainage through canal of Schlemm. Dilated pupil - iris occludes canal. Muscarinic agonist constricts pupil/miosis → moves away from canal of Schlemm to increase outflow and decrease intraocular pressure

Anticholinesterases - enhancement of parasympathetic stimulation: miosis and accommodation (due to contraction of ciliary muscle)

Parasympathetic cotransmission

ACh and VIP (vasoactive intestinal polypeptide)

Low frequency stimulation - ACh released

High frequency stimulation - ACh and VIP released

Other cotransmitters: ATP and NO

Most sympathetic neuroeffector pathways

ACh and NA

Other sympathetic neuroeffector pathways

Autonomic neuroeffector junction

Controls autoinhibition (fine tuning amount of NA released)

Adrenoceptors

Metabotropic

On smooth muscle, endocrine and exocrine glands, cardiac muscle

Alpha 1 and 2 and beta 1, 2 and 3 are all postjunctional

Alpha 2 is the only prejunctional

Agonists: noradrenaline, adrenaline, isoprenaline

Agonist potencies for alpha adrenoceptors: NA > A > ISO

Agonist potencies for beta adrenoceptors: ISO > A > NA

Alpha 1 agonist - decongestant, glaucoma, mydriasis

Alpha 1 antagonist - antihyperintensive

Beta 1 agonist - enhance cardiac muscle contraction

Beta 2 agonist - bronchodilator (Salbutamol)

Beta antagonists - beta blockers - cardiac arrhythmias, angina, essential hypertension, cardioprotection after myocardial infarction

Diverse drug action at adrenergic varicosity (sympathetic nervous system)

Postjunctional actions

• alpha or beta receptor agonist - increase SNS

• alpha or beta receptor antagonist - decrease SNS

Prejunctional actions

• alpha 2 receptor agonist - decrease SNS

• alpha 2 receptor antagonist - increase SNS

• NA uptake inhibitor - increase SNS

• MAO inhibitor - increase SNS

• Stimulate release - increase SNS

• Impair/cause depletion release - decrease SNS

• Impair synthesis - decrease SNS

• False neurotransmitter - decrease SNS

Sympathetic control of pupil diameter

Radial muscle/dilator pupillae = smooth muscle arranged radially

Sympathetic nerve action → NA → alpha adrenoceptors on radial muscle → radial muscle contraction → pupil dilation/mydriasis

Mydriatic drugs (sympathetic)

Eye inspection and surgery

Sympathomimetic

Mydriasis due to contraction of dilator pupillae

Antiglaucoma drugs (sympathetic)

Sympathomimetic

Glaucoma - pressure in eye due to build up of aqueous humour and lack of drainage through canal of Schlemm

Vasoconstriction caused by sympathomimetic impairs secretion of aqueous humour from ciliary body and facilitates reabsorption from canal of Schlemm thus easing pressure

Sympathetic cotransmission

NA + NPY (neuropeptide Y) + ATP

Act together to cause vasoconstriction

NA works on alpha 1 receptors, ATP works on P2 receptors

Peripheral nervous system

Relay sensory information from periphery and internal environment into CNS via afferent pathways

Relay motor output from CNS to skeletal and smooth muscles via efferent pathways

Part of somatic nervous system

Voluntary responses

Information processed by somatic senses

Touch, temperature, pain, proprioception (awareness of body’s location and movements)

Information processed by special senses

Smell (olfaction), taste, hearing, balance, vision

Information processed by visceral senses

Blood pressure, distension of GI tract, internal body temperature, blood glucose control, internal pH

Common sensory pathway

Sensory receptors

Somatic sensory receptors = modified or free nerve endings of sensory neurones

Special sense receptors = receptor cells that synapse with sensory neurone

Located throughout body

Activated by specific stimuli

Somatic nervous system pathway

Mechanoreceptors

Location: mostly skin (also visceral organs)

Stimuli = physical distortion (touch)

Subtypes:

• Meissner’s corpuscles - glabrous, low threshold touch

• Merkel’s disk - glabrous, low threshold static touch

• Ruffini’s corpuscles - glabrous and hairy, high threshold stretch

• Pacinian corpuscles - largest, deepest vibration

• Free nerve endings: glabrous and hairy, very high touch threshold

Mechanoreceptor adaptation

Meissner’s and Pacinian corpuscles - action potential firing at the onset and offset of the stimulus only - rapidly adapting

Merkel’s disks and Ruffini’s endings - action potential firing throughout the presence of the stimulus = slowly adapting

Thermoreceptors

Location: mostly skin

Stimuli: temperature

Free nerve ending ion channels: TRPV1 - hot, TRPM8 - cold

Nociceptors

Location: mostly skin

Stimuli: stimuli that have the potential to cause tissue damage

Free nerve endings:

• Mechanical nociceptors

• Thermal nociceptors

• Chemical nociceptors

Proprioceptors

Location: muscles, tendons, ligaments, joints

Stimuli: muscle tension

Subtypes:

• Muscle spindles (aka stretch receptors) - muscle length (stretch)

• Golgi tendon organ - muscle tension (force of contraction)

• In joints - angle, direction and velocity of movement in a joint

Sensory transduction

Converting stimulus energy into electrical signals

Activation of receptor causes the movement of ions = change in membrane potential

Receptor = receptor potential

Sensory neurone = action potential

Receptive fields

Area in which the specific stimulus will activate the sensory receptor

High density of smaller fields = higher spatial resolution of the stimulus

Fingers and lips = highly discriminative

Back, leg and arm = less discriminative

Primary afferent neurones

Axons of neurones bringing in information from the somatic sensory receptors to the spinal cord

Primary afferent neurones have their cell body in the dorsal root ganglia and their axons project into the dorsal horn of the spinal cord through the dorsal roots

I, II, III - myelinated

IV - unmyelinated

Ascending tracts

Dorsal column-medial lemniscal pathway - touch and proprioception (from large dorsal root axons, up dorsal column through nuclei, through thalamus, to primary somatosensory cortex)

Spinothalamic pathway - temperature and pain (from small dorsal root axons, through medulla, through thalamus, to primary somatosensory cortex)

Somatosensory cortex

Lower parts of body get higher parts of cortex

Different parts of body get bigger parts of cortex depending on sensory innervation - hands and lips get bigger parts than back, for example

Taste

Tastants interact with particular taste receptor cell

Interaction leads to release of serotonin - able to bind to primary gustatory neurones

Binding of a neurotransmitter leads to action potentials which travel along axons

These axons of primary gustatory neurones make up 3 different types of cranial nerves - facial, glassopharyngeal and spinal nerves

Information transmitted along axons of these nerves straight to brainstem

No information going to spinal cord with special senses

Cranial nerves extend from brain and brainstem

Information is synapsed with second order neurone, which transmits info up to thalamus, key sensory relay centre, where it synapses with the third neurone that terminates win gustatory cortex in brain that allows us to interpret and process info about taste

Receptor cells all respond to slightly different tastes - how we’re able to differentiate

Hearing

Ability to detect auditory information in the form of sound waves

Enter inner ear via ear canal

Detected by particular sensory receptor cell - hair cells

Hair cells express cilia on top

Sound waves cause cilia to bend

This causes opening of ion channels

This causes a change in membrane potential leading to release of glutamate

Glutamate combines to primary auditory neurones, triggering action potential

Axons of primary auditory neurones make up 8th cranial nerve, the cochlear nerve

Info transmitted via brain stem to thalamus, to auditory cortex found in temporal lobes

Vision

Receiving visual info in the form of photons of light

Info transmitted through pupil of eye and hits retina in back

Hits particular sensory receptor cells in retina - photoreceptors - able to detect this particular light

Photoreceptors that express a specific protein are activated by specific wavelengths of light - causes change in membrane potential, getting a movement of ions

Allows change in neurotransmitter passed on to next cell

Photoreceptors not directly innervated by primary sensory neurones

Info passed on through more neurones before it reaches retinal ganglion cells

Axons of retinal ganglion cells make up second cranial nerve, optic nerve

Info passed along via optic nerve via optic tract, to thalamus then to third order neurone which terminates in visual cortex in occipital lobe

Olfaction

Odorants dissolve in olfactory epithelium that lines the naval cavity

Different odorants detected by receptors expressed on olfactory sensory neurones themselves

These are essentially free nerve endings - not receptor cells

Free nerve endings express particular receptors so that different odorants can be detected and causes a change in membrane potential

Axons of olfactory sensory neurones form part of first cranial nerve, the olfactory nerve, which forms part of olfactory bulb

Sensory info goes from nose via olfactory tract

Bypasses thalamus and is instead projected to piriform cortex or olfactory cortex for processing

Alpha motoneurones

Motor neurones of the spinal cord

Cell bodies in ventral horn

Axons project out to skeletal muscle

Synapse with muscle fibres - neuromuscular junction

Motor unit

Skeletal muscles made up of bundles of muscle fibres

Motor unit = single alpha-motoneurone and all the muscle fibres it innervates

Each alpha-motoneurone can synapse with multiple muscle fibres

Each muscle fibre receives input from a single alpha motoneurone - focal innervation

Safety feature - nerve terminals always release 8-10x more ACh than necessary so we always get muscle contraction with a single action potential

Neuromuscular junction

Tubocurarine

Nicotinic receptor antagonist

Blocks receptors, prevents ACh binding - numbs muscle

Smooth contraction

Each alpha-motoneurone innervates muscle fibres that are spread throughout the muscle

Alpha-motoneurones fire asynchronously

Contractile precision

Innervation ratio = number of muscle fibres innervated by each individual alpha-motoneurone

Innervation ratio inversely correlated with contractile precision

Fingers = very dextrous, 5-15 fibres per alpha-motoneurone

Abdominal muscles - course movements - 200-1500 fibres per motoneurone

Type I/slow twitch

slow, low force of contraction, high resistance to fatigue, energy source: oxidative, red colour, function: posture, examples: anti-gravity muscles, e.g. abdominal muscles