gross anatomy of cns cranial bones ascending (sensory ... · gross anatomy of cns cranial bones •...

PHRM 100 (2015) (Most of) APPP Miriam Ahmed

GROSS ANATOMY OF CNS Cranial Bones Brain Anatomy Cranial Meninges: 3 layers: dura mater, arachnoid mater & pia mater Cerebrospinal Fluid: contains nutrients and acts as a shock absorber • Formed by filtration of blood in

choroid plexuses in ventricles • Absorbed by arachnoid villi into

jugular vein Spinal Cord: cervical, thoracic, lumbar and cauda equine systems; conveys sensory info from periphery to brain & motor impulse from brain to periphery Spinal Cord: Grey Matter • Posterior (dorsal) horn: receives &

transmits sensory impulses from dorsal root to brain

• Anterior (ventral) horn: motor neurons send signals to skeletal muscle through ventral roots

• Lateral horn: contains preganglionic sympathetic motor neurons

Ascending (Sensory) Tracts: spinal cord white matter • Spinothalamic tract: ventral =

touch, pressure sensation; lateral = pain & temperature sensation

• Fasciculus gracilis & cuneatus = touch, proprioception, vibration, object quality

• Spinocerebellar tract = subconscious proprioception & motor control

Descending (Motor) Tracts: spinal cord white matter • Corticospinal: conscious

movement • Rubrospinal: tone & posture • Tectospinal: head movement in

response to stimuli • Vestibulospinal: regulate balance

(from medulla) Medulla Oblongata: • Ventral Medulla: pyramids contain

motor output (pyramidal decussation = tracts cross over)

• Dorsal Medulla: nucleus gracilis & cuneatus receive sensory inputs & relay to opposite side of cortex

• Reticular Formation: modulate consciousness & arousal

• Reflex Centers: cardiac center (heart beat & force of contraction); medullary rhythmicity area (breathing rate); vasomotor centre (diameter of blood vessels through ANS

PHRM 100 (2015) (Most of) APPP Miriam Ahmed

Pons: bridge between spinal cord & brain; contains cranial nuclei: pneumotaxic & apneustic areas (respiration) • Transverse fibers: connect

cerebellum to brain through cerebellar peduncles

• Longitudinal fibers: motor & sensory tracts

Midbrain (mesencephalon): • Tectum: superior colliculi

(integrates eye movement) & inferior colliculi (integrates head/ trunk movements to sound)

• Cerebral peduncles: major connection between upper and lower brain

• Nuclei: substantia nigra, red nucleus, oculomotor & trochlear nerves

Cerebellum: anterior & posterior lobes (subconscious movement of skeletal muscle) and flocculondar lobe (sense of equilibrium) • Motor coordination, posture and

balance • Double-crossed tracts (right

controls right) Thalamus: relays all sensory info from body to cortex except smell • Medial geniculate nucleus: hearing • Lateral geniculate nucleus: vision • Ventral posterior nuclei: sensations

and taste • Ventral lateral nuclei: voluntary

motor actions • Ventral anterior nuclei: voluntary

motor and arousal Hypothalamus: controls/integrates many body systems

Cerebrum: 2 cortical hemispheres linked by corpus callosum; 4 lobes (frontal, parietal, occipital & temporal) • Sensory areas • Motor areas • Association areas

PHRM 100 (2015) (Most of) APPP Miriam Ahmed

CELLULAR ANATOMY & ELECTRICAL ACTIVITY IN BRAIN Neurons: sensory afferent; motor efferent; association (inter)neurons • Soma: cell body • Dendrites: conduct impulses to cell • Axon: conducts impulses away

from cell o Axon hillock = initial segment o Axon collaterals = branches

• Axon terminals: contain synaptic vesicles

Neuroglia = glial cells • Schwann cells: myelinate (single)

PNS axon • Satellite glial cells: surround mono-

polar sensory neurons (similar to CNS astrocytes)

• Oligodendrocytes: myelinate (multiple) CNS axons

• Protoplasmic astrocytes: gray matter, regulate synaptic transmission

• Fibrous astrocytes; white matter, uptake excess ions/NTs release

Synapse: specialized intercellular jxn • Chemical synapse: release of

chemical mediator (one-way) • Electrical synapse: gap jxn allows

ions to pass (bi-directional) Pre-synaptic compartment: ending of axon; filled with vesicles containing neurotransmitters Post-synaptic compartment: has complimentary shape; contains receptors

NT gated ion channels: allows passage of ions in/out of cells • Excitatory: NMDA receptor

(glutamate) • Inhibitory: GABA channel G-protein coupled receptors: conformational change of receptor, activating G-protein triggering formation/degradation of 2nd msgers Resting Membrane Potential: concentration gradient unequal, creating electro-chemical potential Action Potential: 1. Stimulus brings potential to

threshold 2. Voltage-gated Na2+ channels open

= depolarization 3. Na2+ channels close 4. Delay before K+ channels open =

hyperpolarization Conduction velocity: speed at which AP propagates; related to diameter & myelination (via saltatory conduction) Excitatory postsynaptic potential: depolarization of postsynaptic cell (opens cation channels) Inhibitory postsynaptic potential: hyperpolarization of postsynaptic cell (opens Cl- channels)

PHRM 100 (2015) (Most of) APPP Miriam Ahmed

PERIPHERAL NERVOUS SYSTEM: Cranial Nerves: on, on, on they traveled and found Voldemort guarding very ancient horcruxes Functional Information: s = sensory; m = movement; b = both Some say marry money, but my brother says big brains matter more

I Olfactory II Optic III Oculomotor • Eye movement

• Pupillary constrictor • Ciliary muscles

IV Trochlear • Eyeball V Trigeminal • V1: ophthalmic

(sensory upper face) • V2: maxillary

(sensory maxillary face) • V3: mandibular

(sensory lower face; muscles of mastication)

VI Abducens • Pupils VII Facial • Muscles of facial

expression • Lacrimal/ salivary glands • Taste to anterior 2/3 of

tongue VIII Vestibulo-

cochlear • Hearing • Equilibrium

IX Glosso-pharyngeal

• Sensory to carotid body & sinus; taste to posterior 1/3 tongue; auditory tube

• Motor to stylopharyngeal muscle & posterior gland

X Vagus • Digestive & CV systems • Swallowing muscles • PNS to GIT, lungs, heart

XI Spinal accessory

• Muscles to mediate head turning

XII Hypoglossal • Tongue muscles

Dorsal Roots: convey sensory info to spinal cord; cell bodies in dorsal root ganglion Ventral Roots: convey motor output to muscles; cell bodies in ventral spinal cord

Spinal Nerve: dorsal + ventral roots combined; bifurcates into: • Dorsal rami: supplies back • Ventral rami: supplies front & limbs Dermatomes: • Arms: C5, C6, C7, C8 & T11 • Trunk: C4 & T2 • Thumb: C6 • Middle Finger: C7 • Little finger: C8 • Nipple: T4 • Umbilicus: T10

PHRM 100 (2015) (Most of) APPP Miriam Ahmed

AUTONOMIC NERVOUS SYSTEM

SNS PNS Cell of origin Thoracic &

upper lumber Brainstem & sacral spinal cord

# of nerves Many Few (vagus) Pre-ganglionic Short axon Long axon Ganglionic location

Near spinal cord

Near organ

Post-ganglionic

Long axon Short axon

Function Flight or fight Rest and digest

Heart: • SNS accelerates HR; increases

ventricular contraction force • PNS: slows heart rate Bronchioles: • SNS: dilates • PNS: constricts Eye (pupils): • SNS: dilates • PNS: constricts GIT: • SNS: relaxes muscle wall; contracts

sphincters • PNS: increases secretion; contracts

muscle wall; relaxes sphincters Urinary Bladder: • SNS: relaxes fundus; contracts

sphincter • PNS: constricts fundus; relaxes

sphincter

Glands: • SNS: secretes thick, mucous saliva;

sweat • PNS: secretes watery saliva Other: • SNS: contracts piloerectors, spleen

and blood vessels

Autonomic Ganglia: pre-synaptic SNS & PNS release acetylcholine (nicotinic receptors) Sympathetic postganglionic: noradrenaline (adrenergic): ACh (muscarinic); dopamine (D1) • α1: increase IP3 (release of Ca2+

from SR) and DAG (activates PKC) excitation

• α2: inhibits adenyl cyclase inhibition

• β: increase CAMP o β1: heart o β2: bronchial smooth muscle o β2: adipose tissue, bladder

Parasympathetic Postganglionic: acetylcholine (muscarinic) • M1: salivary gland, stomach • M2: heart • M3: bladder & airway smooth

muscle; eye Dopamine β hydroxylase deficiency: deficiency in enzyme which converts dopamine to norepinephrine • Progressive SNS denervation • Normal cholinergic innervation • Low HR (unopposed PNS); low BP

(orthostatic hypotension) Syncope: increase PNS tone & decrease SNS tone to SA node of heart • Decreases HR & increases

vasodilation • Decrease in systematic BP =

decrease in brain perfusion syncope

PHRM 100 (2015) (Most of) APPP Miriam Ahmed

MUSCULOSKELETAL SYSTEM Bone: hard bone made up of hydroxyapatites • Spongy bone: red marrow (blood

cells) • Compact bone: densely calcified • Medullary cavity: yellow marrow

(Ca2+, P, fat) • Endosteum: osteoblast layer in

medulla cavity • Periosteum: fibrous covering of

bone & inner osteoblast layer • Articular cartilage: hyaline cartilage

where joint forms • Concentric lamellae: rings of

calcified bone separated by lacunae (spaces)

• Canaliculi: canals that contain processes of osteocytes o Osteoblasts: form new

calcified bone o Osteocytes: mature bone cells o Osteoclasts: break down bone

(remove calcium) Joints: • Fibrous & cartilaginous • Synovial: joint cavity

o Articular capsule (outer) o Synovial membrane (inner);

secretes synovial fluid o Articular discs: between 2

bones Skeletal Muscle: myocyte/myofibril surrounded by sarcolemma • Fasciculi: bundles of muscle fibers;

separated by endomysium • Muscles wrapped in fascia (fibrous

connective tissue)

Myofibril: muscle fiber/cell • Sarcomere: group of myofilaments

(actin & myosin) that compose myofibril

• Sarcoplasmic reticulum: contains calcium stores

• Transverse tubules: extensions of SR that open to outside of fiber

Muscle contraction: 1. Depolarization opening of

nicotinic receptors (2 ACh bind to α subunit)

2. Release of Ca2+ from internal stores 3. Binding of calcium to myosin 4. Sliding of myosin along actin

shortening of sarcomere 5. Muscle contraction Muscle spindle afferent fibers: • Primary Aα fibers: changes in

muscle length & speed, muscle vibration, limb position & movements

• Secondary Aβ fibers: length change, position

Fusimotor innervation: • β-motor neurons; innervate intra &

extra-fusal fibers • γ-motor neurons: innerave

intrafusal muscles o Static: increase rate of Aα & Aβ

fibers in response to given muscle length

o Dynamic: increase rate of Aα in response to stretch (rate of change)

Golgi tendon organs: Aβ fibers at musculo-tendinous jxns (detect force)

PHRM 100 (2015) (Most of) APPP Miriam Ahmed

Cutaneous receptor mechanoreceptors: skin stretch receptor; slowly adapting; ruffini endings Joint mechanoreceptors: joint movement at limits of range of joint movement Monosynaptic reflex: monosynaptic connections from Aα to motor neurons Polysynaptic connections: Aα & Aβ

fibers via interneurons

PHRM 100 (2015) (Most of) APPP Miriam Ahmed

MOTOR PLANNING Basal Ganglia: comprised of 5 brain structures • Dorsal striatum: inhibitory GABA

neurons & cholinergic neurons caudate nucleus & putamen

• Globus pallidus: inhibitory GABA • Subthalamic nucleus • Substantia nigra: DA & GABA Basal ganglia in motor planning & execution: excitatory input from cortex & thalamus go to striatum & GP • Direct pathway: increase

movements • Indirect pathway; decrease

movements • Output goes back to thalamus,

where it is fed into prefrontal cortex and premotor cortex to modulate cortical activity

Cerebellum: vermis & 2 cerebellar hemispheres; connected to brain by 3 pairs of cerebellar peduncles • Vestibulocerebellum: maintains

equilibrium & modifies eye movements

• Spinocerebellum: compares motor input & coordinates ongoing movement

• Cerebrocerebellum: planning & programming movements cerebellar cortex (3 layers & 5 types of neurons)

Cerebellum in motor planning & execution: perkinje cells receive strong excitatory input from climbing fibers (oliviary nucleus) and weak excitatory input from mossy fibers (body/cerebral cortex) and project to golgi and granule cells output is varied inhibition that goes to deep cerebellar nucleus cells to modify its excitatory output to brainstem and thalamus

PHRM 100 (2015) (Most of) APPP Miriam Ahmed

SOMATOSENSORY SYSTEM: Glabrous = non-hairy Non-glabrous = hairy Epidermis: mechanical protection, barrier to water loss & permeation of soluble substances, innate immune function, UV protection • Keratinocytes: produce keratin • Melanocytes: produce melanin

(transferred to keratinocytes via melanosomes)

• Langerhan cells: antigen-processing and presenting cells

• Merkel cells: slowly adapting mechanoreceptors

Dermis: mechanical injury protection, binds water, thermal regulation, sensory receptors (Meissner’s & Pacinian corpuscles) • Fibroblasts: synthesis &

degradation of connective tissue matrix (wound healing)

• Macrophages: phagocytic cells (immune function)

• Mast cells: release histamine Hypodermis: insulates body, reserve energy supply, cushions & protects skin, allows for mobility • Primarily adipose tissue; contains

large blood vessels, hair follicles & sweat glands

Hair: hair follicles, sebaceous glands, apocrine gland & arrector pili muscle • Hair follicles: surrounding hair

shaft; hair pigmentation (melanosomes)

• Sebaceous glands: lipid-filled sebocytes secrete sebum

Sweat glands: eccrine (body temperature) vs. apocrine (pheromone) Cutaneous slowly adapting (SA): respond to sustained skin deformation with sustained discharge Cutaneous rapidly adapting (RA): respond only during dynamic phase of tissue deformation Hair follicle afferents: RA; detect light touch (Type d = Aδ; Type g = Aβ) Merkel’s Disc: SA Aβ; small receptive field • Spatial resolution & pressure

sensation • Spatial & temporal features • Roughness perception • Respond to cooling Meissner’s Corpuscles: RA; very small receptive fields • Low frequency vibration (2-40 Hz) • Low frequency skin motion • Feedback signals for grip control Ruffini endings: SA Aβ; large receptive fields • Conformation • Skin stretch & changes in hand/

finger shape • Sustained indentation • Lateral forces • Respond to cooling

PHRM 100 (2015) (Most of) APPP Miriam Ahmed

Pacinian corpuscles: RA Aβ; large receptive fields • High frequency vibration (40-500

Hz) • Tissue deformation • Distant events C-tactile afferents: only in hairy skin • Low force, slowly moving

mechanical stimuli • Emotional aspects Non-painful thermal sensation: warm specific (c fibers) or cold specific (a & b fibers; most likely Aδ) Cold afferent fibers: ongoing discharge at room temperature; increase firing rate to cooling High threshold cold fibers: rapid changes in temperature (not ongoing) Rare cold fibers: also activated by noxious heat Warm afferent fibers: ongoing discharge at > 30o C; increase firing rate to warming • Cooling suppresses activity • Max discharge 43-45oC • No firing by 50oC Myelinated axons: • A-fibers; fastest; motor (except Aδ

= pain, temperature, touch) Aα Aβ Aγ Aδ

• B-fibers: preganglionic sympathetic

Unmyelinated axons: C-fibers; slowest • Sympathetic: post ganglionic • Sensory: pain, temperature, touch

PHRM 100 (2015) (Most of) APPP Miriam Ahmed

CONSCIOUSNESS & SLEEP Electroencephalogram (EEG): • Alpha rhythm: 8-13 Hz; relaxation • Beta rhythm: 13-30 Hz; active

concentration • Gamma rhythm: 30-80 Hz Slow wave sleep (NREM): decreased motor tone & loss of awareness to surroundings • Stage 1: low-voltage with theta

rhythm (4-7 Hz) • Stage 2: sleep spindles (12-14 Hz) &

high-voltage waves (K complexes) • Stage 3: delta rhythms (0.5-4 Hz) • Stage 4: larger slow waves Rapid eye movements (REM) sleep: rapid eye movements; motor atonia; dreaming; desynchronized EEG Transition form wakefulness to sleep: 1. Wakefulness: cholinergic,

noradrenergic, histaminergic tone 2. Transition: increase serotinergic

firing, adenosine & prostaglandin D2

3. NREM sleep: increase GABA, decrease noradrenergic, cholinergic & histaminergic tone (VPO: inhibited by monoaminergic nuclei; fires during sleep to inhibit monoaminergic nuclei; builds up adenosine)

4. REM sleep: increase cholinergic tone (pontine reticular formation)

Sleep architecture: sleep progresses from stage 1-4 SWS sleep, then from stage 3/4 SWS into REM sleep • Infants 16h sleeping (mostly REM) • SWS progressively decreases with

age

Circadian rhythm: 24 h cycle; entrainment of neurons in CNS by superchiasmatic nucleus receiving light/dark info from retina Pineal gland: releases melatonin which acts on SNS to promote sleepiness • Darkness increases melatonin • Connected to SNS through

superior cervical ganglion of SNS

PHRM 100 (2015) (Most of) APPP Miriam Ahmed

PAIN: Nociceptive pain: related to tissue injury & protective Inflammatory pain: related to consequences of tissue injury (release of algogens) & is protective Pathophysiological pain: persists in spite of injury resolution Neuropathic pain: abnormal processing of pain signalling in PNS or CNS Nociceptor: peripheral nerve fiber which responds to painful stimuli • Code duration & intensity • “Free endings” • Small receptive fields • Stimulus required (not

spontaneous) Silent nociceptors: only respond to stimulation after an injury Thermo-nociceptors: initial pain (Aδ

fibers) & second longer burning pain (C-polymodal nociceptor) Mechano-nociceptors: slowly adapting responses to mechanical stimuli Central pathway: integration in spinal cord • Lateral thalamus: processes

sensory & discriminative aspect sensory cortex

• Medial thalamus limbic structures (amygdala) – emotional response

Central sensitization: sustained pain input can increase sensitivity of neurons in brain to pain (expansion of receptive fields) • Alterations in NMDA & P2X3

receptors • Neuropathic factors (long-term) Descending pain modulatory circuit: endogenous pain relieving circuit (opioid sensitive) Diffuse noxious inhibitory circuit: pain relief by causing pain somewhere else

PHRM 100 (2015) (Most of) APPP Miriam Ahmed

EYE AND VISION Lacrimal gland: secretes tears Sclera: white, outer protective layer • Conjunctiva: mucous membrane

covers sclera • Cornea: transparent sclera allows

light to enter eye Choroid: vascular layer; provides oxygen & nutrients to eye Retina: neural tissue containing photoreceptors; images projected onto retina are inverted Iris: contains dilator & sphincter muscles to control pupil Pupil: opening in iris; allows light to pass through to retina Crystalline lens: allows light to be focused on retina; modified by ciliary muscle/body Optic disk: point where optic nerve leaves eye (blind spot) Macula: back of eye; contains fovea (cones-only) where visual acuity is greatest Anterior cavity: filled by aqueous humor to nourish cornea & iris Vitreous (posterior) cavity: filled by vitreous humor (gelatinous) Accommodation: ciliary muscle contracts to increase curvature of lens, allowing objects close to eye to be brought into focus

Hyperopia: far sightedness; short eyeball = focus behind eye Myopia: near sightedness; long eyeball = focuses in front of retina Photoreceptors: • Na2+ channels open in dark

depolarizing (depolarize off-centre bipolar cells; hyperpolarize on-centre bipolar cells)

• Light closes some Na2+ channels hyperpolarization (hyperpolarize off-centre bipolar cells; depolarize on-centre bipolar cells)

Rods: extremely sensitive to light (night vision) Cones: allow greater visual acuity & color vision (red, blue, green) Horizontal cells: connect photoreceptors Bipolar cells: synapse with ganglion cells Amacrine cells: connect ganglion cells together & make connections with terminals of bipolar cells Muller cells: bind retinal layers together (glial cell) Pathway of vision: from retina to lateral geniculate body of thalamus (nasal side crosses at optic chiasm); from thalamus continues to occipital cortex

PHRM 100 (2015) (Most of) APPP Miriam Ahmed

VESTIBULAR & AUDITORY SYSTEMS External ear: auricle/pinna • Collects sound waves & funnels

them through external acoustic meatus to tympanic membrane

Middle ear: ossiscles (malleus, incus, stapes) • Transmit & amplify vibrations from

tympanic membrane to inner ear Tympanic membrane: converts energy of sound wave into vibration Inner ear: • Semicircular canals: rotation of

head • Otolith organs (utricle & saccule):

linear movements of head Hair cells: mechanoreceptors respond to mechanical movement of their end processes of hairs; elevated K+ in endolymph flows into cell to cause depolarization (releases glutamate to activate ganglion neurons) • Crista ampularis (semicircular canal

hair): angular acceleration • Organ of Corti (cochlear hair):

vibrated by sound waves traveling through endolymph

• Macula (otolith hair): linear acceleration

Transmission of sound: CN VIII synapse in cochlear nuclei inferior colliculi (brainsteam) medial geniculate body (thalamus) auditory cortex (temporal lobe) Loudness: amplitude; increase firing of Organ of Corti outer hair cells

Pitch: frequency; where sound wave maximally activates membrane of cochlea Timbre: number of harmonic vibrations that give sound its characteristic Mechanism for detection of balance: • Rotation activates cristae

(semicircular hairs) • Horizontal acceleration activates

utricular macula • Vertical acceleration activates

saccular macula Transmission of balance: VIII nerves supplying cristae & maculae vestibular nuclei & cerebellum CN III, IV & VI (eye movements) & somatosensory cortex (perception of movement)

PHRM 100 (2015) (Most of) APPP Miriam Ahmed

CARDIOVASCULAR SYSTEM Heart: • Ventricle wall (myocardium) thicker

than atria (left more) • Pericardium surrounds heart (inner

& outer layer with pericardial fluid) Valves of heart: • Tricuspid: right atrium & ventricle • Bicuspid (mitral): left atrium &

ventricle • Semilunar aortic: left ventricle &

aorta • Semilunar pulmonary: right

ventricle & pulmonary artery Papillary muscles: right ventricle; contract & pull on chordae tendinae which prevent AV valves from inverting into atria Blood flow:

Artery: endothelial cells (inner) – intima (cholesterol accumulation) – internal elastic lamina – media (smooth muscle) – adventitia (outer) Differences between blood vessels: • Walls of artery thickest • Lumen of vein larger • Skeletal muscle milks blood in vein • Walls of capillary 1 cell layer thick

Electrical circuitry of heart: 1) SA node drives HR (60-100 bpm) 2) AV node : delayed ; 40-70 bpm

• Backmann bundle : takes electrical activity from right to left atrium

3) Left & right bundle branches 4) Purkinje fibers: conduct impulse

into ventricles (20-40 bpm) Currents in SA node: 1) Pacemaker current: slow Na+

current; transient Ca2+ channel opens

2) Depolarizing current: long-lasting (slow) Ca2+ channel opens

3) Repolarizing current: outward K+ current

Electrical impermeability: AV fibrous tissue is non-conducting • Moderator band carries impulses

down interventricular septum Intercalated disk: contains gap junctions to connect each cardiac myocyte; important for conductivity (transmitting electrical impulses) Early after-depolarization: Ca2+ channels open = ventricles are always contracting Later after depolarization: Na+ channels open = get APs faster Heart sounds; lub (closing of AV valve) & dub (closing of SL valves)

PHRM 100 (2015) (Most of) APPP Miriam Ahmed

Electrocardiogram: indirect measure of electrical activity of heart • P wave: atrial depolarization • QRS complex: ventricular

depolarization • T-wave: ventricular repolarization

o PR interval: conduction time from atrium to ventricle

o QT interval: duration of ventricular AP

Na+K+-ATPase: 3 Na+ out; 2 K+ in Na+Ca2+-exchanger: 3 Na+ out, Ca2+ in Cardiomyocyte: sarcolemma invaginates into t-tubules which make close contact to sarcoplasmic reticulum (key storage of Ca2+) Excitation-contraction coupling: 1) AP via pacemaker cell to

conduction fibers 2) Calcium-induced calcium release:

Ca2+ channels on t-tubules open and Ca2+ enters cell, opening ryanodine receptors, releasing Ca2+ from sarcoplasmic reticulum

3) Ca2+ binds with troponin, moving the troponin/tropomyosin complex

4) Myosin binds and slides over action Myocardial relaxation: • Ca2+ transported back into SR (ATP) • Ca2+ transported out of cell by NCX • As ICF Ca2+ decreases, myosin and

actin unbind

SNS: releases NE, binds β1 receptor (G-protein cAMP) • cAMP activates PKA

o Binds to I-type Ca2+ channels (more Ca2+ in cell)

o Inactivates PLB = activates Ca2+ ATPase (more Ca2+ in SR)

• cAMP activates HCN channel (increases slow Na+ in SA node)

PNS: vagus nerve releases ACh; binds M2 receptors (inhibit G-protein and decreases cAMP) • Decreases slow Na+

current (HCN channel)

Blood vessels: • Constriction: α1 predominant

(angiotensin II, NE, endothelin) o Increases IP3, releases Ca2+

from SR and activates MLCK • Dilation: β2 Blood pressure = force that blood exerts on blood vessels = cardiac output x total peripheral resistance Cardiac output = amount of blood pumped by each side of the heart in 1 minute = heart rate x stroke volume Stroke volume = volume of blood by each ventricle in one contraction Renin: converts angiotensinogen to angiotensin I angiotensin II (ACE) vasodilator & aldosterone (salt retention) = increases blood pressure

PHRM 100 (2015) (Most of) APPP Miriam Ahmed

RESPIRATORY SYSTEM Conducting airways: conduct air; warm & humidify inspired air • Upper conducting airways: trachea

smaller bronchi o Cartilage, smooth muscle,

ciliated epithelium, goblet cells (mucin)

• Lower conducting airways: bronchioles terminal bronchioles o No cartilage, smooth muscle,

unciliated epithelium Respiratory airways: gas exchanged with blood (O2 in / CO2 out) • Respiratory bronchioles & alveoli • Simple epithelium Functions of pulmonary system: supply O2, remove CO2, maintain physiological Ph Processes of pulmonary system: • Ventilation (inhalation & exhalation) • Perfusion (regulation of blood flow) • Gas exchange (max 2 cells) Brain centers for ventilation: • Medulla oblongata: rhythm of

inhalation (inspiratory & expiratory center)

• Pons: timing/speed (apneustic center promotes inspiration; pneumotaxic center is antagonist)

Regulation of ventilation: • Primary: increase ventilation in

response to lower pH (as a result of increased CO2; stored as HCO3

-+ H+) • Exercise: increase ventilation with

cellular energy storage (release H+) • Involuntary control: limbic system,

hypothalamus

• Voluntary control: cerebral cortex • Impaired by: CNS depressants,

airway obstruction, lung restriction Receptors in regulation of ventilation: • Central chemoreceptors: sensitive

to environmental (blood) pH • Peripheral chemoreceptors:

primarily arterial O2; secondary arterial CO2 & pH

• Mechanoreceptors: o Hering-Bruer reflex: prevents

lung over-inflation; terminates respiration ▪ Response of coughing,

airway constriction & hyperventilation

o Upper airway receptors: response of sneezing, coughing, closure of glottis and hiccups

o Spinal cord reflex: activation of compensatory respiratory muscles; increase in breathing frequency & volume ▪ Reflex of gasping, hypo-

ventilation o Nasopumonary & nasothoracic

reflexes: deepening inhale (trigeminal nerve) air flow, quality and nasal pressure

Hypoxemia: drop in arterial blood oxygenation Hypercapnia: rise in arterial carbon dioxide Hypoxia: inadequate oxygenated blood supply

PHRM 100 (2015) (Most of) APPP Miriam Ahmed

Ventilation:perfusion ratio: • Normal: lung V/Q = 0.8 • Low V/Q = low arterial O2

o Impaired gas exchange o Bronchitis, asthma,

pulmonary edema • High V/Q = high arterial O2

o Wasted ventilation (unoxygenated blood)

o COPD, pulmonary embolism Forced exhalation volume (FEV1): max air exhaled in 1 second after max inhalation FEV1/FVC % = Tiffenau-Pinelli index • Proportion of vital capacity Spirometry: measuring lung function

Obstructive lung disease = obstruction of airflow in & out of lungs • FEV1 & ratio reduced (< 0.7) • VC, RV decreased; TLC normal

Restrictive lung disease = limit expansion of lung; less ventilation or ore effort to ventilate • FEV1 & FVC equally reduced

(ratio > 0.7) • VC, RV & TLC decreased Chest x-ray: radio dense material Sputum culture: detect & identify infection

Pulmonary angiography: pulmonary blood vessels x-rayed Bronchoscopy: visualize inside of airways Asthma: chronic inflammatory airway disease • Early phase: inflammatory

mediators; bronchoconstriction • Later phase: eosinophils &

neutrophils; inflammation • Diagnosis:

o > 12% improvement in FEV1 from baseline to 15 min post β2 agonist challenge

o Bronchial challenge (measure after inhalation of histamine)

Chronic obstructive pulmonary disease (COPD): progressive respiratory disease • Chronic bronchitis = airway

obstruction • Emphysema = destruction &

enlargement of terminal bronchioles or alveolar sacs (reduced gas exchange)

• Diagnosis: post-bronchodilator FEV1 < 80% predicted; FEV1/FVC <0.7

Airway smooth muscle contraction: controlled by intracellular Ca2+ (activates Ca2+ calmodulin activates MLCK phosphorylates MLC contraction) β2-adrenoreceptor agonists: result in smooth muscle relaxation (activate adenyl cyclase cAMP PKA relaxation)

PHRM 100 (2015) (Most of) APPP Miriam Ahmed

Short-acting beta agonists: onset in 1-3 minutes; duration 2-6 hours Long-acting beta agonists: prolonged bronchodilator effect (12 h) • Enhance anti-inflammatory effect

of corticosteroid Muscuranic ACh receptor antagonists: block ACh from activating M3 receptors (reduces release of Ca2+ from sarcoplasmic reticulum) Inhaled corticosteroids: no direct relaxation; anti-inflammatory Leukotriene receptor antagonists (LTRA): prevent binding of CysLT to CysLT1 receptors • Prevents plasma exudation, mucus

secretion, bronchoconstriction & eosinophil recruitment

PHRM 100 (2015) (Most of) APPP Miriam Ahmed

URINARY SYSTEM Glomerulus: encased in Bowman’s capsule • Blood enters from afferent arteriole

where it passes through endothelial cells (capillary pore) to basement membrane (negatively charged) and through podocytes

• Blood exits via efferent arteriole • Afferent arteriole has a larger

diameter than efferent = pressure gradient to allow filtration

Renal circulation: 2 capillary beds • Glomerular: high pressure causes

filtration (20%) • Peritubular: low pressure permits

absorption (to venous system) Tubular reabsorption: filtered products can be reabsorbed into peritubular capillaries Tubular secretion: reabsorbed products can be filtered Lumen tubular cell: diffusion (passive transport) • Na+ channel • Na+Cl-/Gl co-transport • Na+H+ counter-transport Tubules interstitial fluid = active transport (basolateral Na+K+ATPase) Interstitial fluid peritubular capillary: • Proximal tubule: 65-75%

o Microvilli & mitochondria Into lumen: Na+H+ counter-

transport (NHE3) because of carbonic anhydrase IV

Into blood: sodium bicarbonate co-transporter & Na+K+ATPase

• Descending thin limb of Loop of

Henle: o Permeable to H2O o No transporters

• Ascending thick limb of Loop of Henle: 20-25% o Impermeable to water Into lumen: NKCC2 (Na+K+2Cl-

co-transporter) ▪ K+ diffuses back into lumen

+ve potential repels Mg +Ca & forces into blood

Into blood: Na+K+ATPase • Distal tubule: 4-5%

Into lumen: sodium-chloride cotransporter (NCC) ▪ PTH hormone for Ca2+

Into blood: Na+K+ATPase, NCC, Ca2+H+ATPase

• Collecting ducts: 4-5% Into lumen: Na+ (+ve charge) Into blood: Na+K+ATPase o Under hormonal control

▪ Aldosterone makes more Na+K+ATPase

▪ ADH increases water permeability (aquaporin-2)

o Major site of potassium loss Reabsorption of filtered glucose: key transporter is SGLT-2 (90%) Juxtaglomerular cells: specialized smooth muscle cells responsible for production of renin Renin: converts angiotensinogen angiotensin I angiotensin II (ACE) increase total peripheral resistance or aldosterone (salt & water retention = increases blood volume) increase in blood pressure

PHRM 100 (2015) (Most of) APPP Miriam Ahmed

Release of renin from JG cells: 1. Renal sympathetic nerves (NE on β1

stimulates renin release) 2. Afferent baroreceptors

(prostacyclin PGI2 signals renin secretion)

3. Macula densa cells: senses low Na+ (adenosine releases renin)

Vasopressin = ADH • V1 receptor vasopressin

increases arterial pressure • V2 receptor renal fluid

reabsorption increases blood volume increases arterial pressure

Renal stenosis: decreased renal blood flow

STUDYING RECEPTORS IN LAB Immunocytochemistry/ histochemistry: • Antibodies are key • Native tissue (histo) or dissociated

cells (cyto) Calcium imaging: Ca2+ sensitive dyes Western immunoblotting: molecular weight & antibody detection • Proteins linearized by SDS

detergent Immunoprecipitation: protein complex can be isolated by using an antibody specific for one protein complex Cloning & overexpression: clone specific DNA into expression vector & transfect into cultured cells Electrophysiology: patch-clamp measures currents from ion channels in real time Physiology: physiological studies Pharmacology: can be applied to other studies (effect of drugs)

PHRM 100 (2015) (Most of) APPP Miriam Ahmed

PANCREAS Endocrine pancreas: islets of Langerhans • Beta cells: insulin • Alpha cells: glucagon • Delta cells: somatostatin • Pancreatic acini: polypeptides Insulin secretion: glucose enters beta cell and is metabolized ATP closing of ATP-sensitive K+

channels depolarization Ca2+ moves into cells insulin granules secreted Regulation of insulin secretion: • Triggered: glucose, FA,

sulfonylureas • Inhibited: catecholamines • Enhanced: glucagon-like peptide Insulin: C-peptide chain (fast-acting), A-chain (short-acting) & B-chain (intermediate acting) Insulin leads to: • Uptake of glucose in liver

glycogen • Uptake of glucose in adipose tissue

form triglycerides & prevent lipolysis

• Acts on muscles to convert amino acids proteins

Insulin regulation of glucose transport: insulin binds to receptor which translocate glucose transporters to fuse with plasma membrane allowing glucose to enter cell

Decreased insulin leads to: • Hyperglycemia (glycosuria,

polydipsia, polyuria, polyphagia) • Hyperlipidemia • Ketones (triglyceride breakdown)

ketouria & ketoacidosis Type 1 Diabetes Type 2 Diabetes • Onset < 30

years old • Sudden onset • Usually thin • Severe

symptoms • Ketosis prone • 0% insulin • Complete B-

cell loss • ICA + • 50% in twins • Incidence 10%

• Onset > 20 years old

• Gradual onset • Usually obese • May have

symptoms • Ketosis resistant • < 30% insulin • Varied B-cell

mass • No ICA • 60-80% in twins • Incidence 90%

Biphasic insulin response: 1. Early phase: insulin secreted from

rapidly releasable pool 2. Late phase: insulin comes from

reserve pool which replenishes the rapidly releasable pool

Post-prandial hyperglycemia: type-2 diabetics lose first phase of insulin release

PHRM 100 (2015) (Most of) APPP Miriam Ahmed

LIVER Functions of cholesterol: component of cell membranes; precursor of aldosterone, estrogens & androgens Cholesterol metabolism: acetate HMG coA mevalonic acid (HMG coA reductase*) cholesterol biles (breakdown) * rate limiting step Lipoproteins: outer layer makes protein soluble in blood & hydrophobic inner layer allows cholesterol to be packaged Exogenous cholesterol pathway: 1. In gut, cholesterol packaged into

chylomicrons (lipoprotein) 2. In blood, lipoprotein lipase (LPL)

enzyme reduces size of chylomicron (breaks triglyceride portion)

3. Cholesterol-rich chylomicron remnants enter liver & add to store

Endogenous cholesterol pathway: 1. HMG coA reductase makes

cholesterol endogenously 2. Exogenous + endogenous

cholesterol combined into VLDL 3. VLDL IDL LDL 4. LDL takes cholesterol to liver (75%

receptors) or extrahepatic tissue (25%)

Hepatic lipase: makes LDL even more denser & cholesterol-rich = small LDLs (LDL pattern B) responsible for atherosclerosis

HDL: moves cholesterol in opposite direction (back into liver) inhibit modification of LDL & adhesion molecules LDL receptors: formed in nucleus, enters golgi, then inserted into plasma membrane • LDL binds & LDL receptor

internalizes as endosome • LDL receptor recycled back to

plasma membrane & LDL enters lysozyme (cholesterol separated from protein)

• Cholesterol packaged as cholesterol ester droplet

Drugs that block HMG co-A reductase: block cholesterol synthesis = increases LDL receptors brings more LDL from blood into liver Monochromal antibody drug: binds PCSK9 so it can’t internalize LDL receptors = increases LDL receptors on membrane brings in more LDL from blood Cholesterol recycling: cholesterol broken down into bile acids which are reabsorbed

PHRM 100 (2015) (Most of) APPP Miriam Ahmed

Process of atherosclerosis: 1. Damage in endothelial cell of artery

allows small LDL to enter arterial intima

2. LDL becomes oxidized & releases MCP-1

3. Monocytes enter macrophages 4. Modified LDL taken up my

macrophages & accumulates into foam cell

5. Macrophage releases cytokines adhesion molecules that bring in more monocytes

6. Foam cells allow smooth muscle to proliferate & migrate to site of injury

7. Smooth muscle loses contractile ability = atherosclerosis

8. Pressure increases & endothelial cell ruptures

9. Anticoagulation takes place forming a clot inside blood vessels