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整合課程 課程講義 骨骼肌肉系統 100 學年度第二學期 骨骼肌肉系統之 解剖、組織、胚胎、生理、藥理 及病理學 中國醫藥大學 吳慶祥、曾拓榮、蔡孟宏、吳政訓、顧國棟、 林靜茹、謝文聰、魏一華 編著 1 目錄 Chapter 1 Upper Limbs ------------------------------------------------------------ 3 Chapter 2 Lower Limbs ------------------------------------------------------------27 Chapter 3 The Development of the Skeletal & Muscular Systems -------------37 Chapter 4 Cartilage & Bone ----------------------------------------------------------42 Chapter 5 Muscle Tissue --------------------------------------------------------------43 Chapter 6 Skeletal Muscle Physiology ---------------------------------------------.48 Chapter 7 Synaptic Transmission and the Autonomic Nervous System--------52 Chapter 8 Introduction to Autonomic Pharmacology ------------------------------54 Chapter 9 Cholinoceptor-activating & Cholinesterase-inhibiting Drugs -------66 Chapter 10 Cholinoceptor-blocking Drugs ------------------------------------------72 Chapter 11 Adrenoceptor-activating & Other Sympathomimetic Drugs--------76 Chapter 12 Adrenoceptor Antagonist Drugs -----------------------------------------86 Chapter 13 Skeletal Muscle Relaxants ------------------------------------------------90 2 Chapter 1 Upper Limbs Overview 1) 2) 3) 4) shoulder, arm, forearm, hand shoulder – the pectoral, scapular and deltoid regions of the upper limb pectoral (shoulder) girdle – the scapula, clavicle, the manubrium of the sternum hand – the wrist, palm, dorsum of hand and digits 2. comparison of upper and lower limbs 3. bones of upper limb 1) clavicle (collar bone) a. shaft – medial half convex anteriorly a) sternal end articulates with the manubrium of the sternum (sternoclavicular joint) b) acromial end articulates with the acromion of the scapula (acromioclavicular joint) b. scapulothoracic joint – a physiological “joint” c. cervico-axillary canal – protect the neurovascular bundle supplying the upper limb d. transmit shocks from the upper limb to the axial skeleton e. superior surface – smooth f. inferior surface – rough a) coracoclavicular ligament b) conoid tubercle – conoid ligament c) trapezoid line – trapezoid ligament d) subclavian groove – the attachment of the subclavius muscle e) the impression for the costoclavicular ligament 2) scapula a. overlying the 2nd-7th ribs b. posterior surface a) the spine of the scapula, infraspinous fossa, supraspinous fossa b) the spine of the scapula i. acromion ii. the deltoid tubercle - prominence on the dorsum of the scapular spine, lateral to the root of the spine, to which a flat, triangular tendon from the most inferior part of the middle part of the trapezius (muscle) is attached. c. costal surface – subscapular fossa d. glenoid cavity e. coracoids process f. medial (vertebral), lateral (axillary) and superior border a) suprascapular notch – at the junction of medial 2/3 and lateral 1/3 of superior border g. superior, inferior and lateral angles a) lateral angle of the scapula – the head and neck of the scapula 3) humerus a. proximal end a) the head b) the anatomical neck of the humerus i. separates the head from the greater and lesser tubercles of the humerus ii. indicates the line of attachment of the glenohumeral joint capsule c) the surgical neck of the humerus i. a common site of fracture 3 ii. the narrow part distal to the tubercles d) the greater tubercle is at the lateral margin of the humerus whereas the lesser tubercle projects anteriorly from the humerus. e) Intertubercular (bicipital) groove – the long head of the biceps muscle b. the shaft a) deltoid tuberosity – deltoid muscle b) radial (spiral) groove - groove for radial nerve c) supraepicondylar ridge d) medial and lateral epicondyles c. distal end a) condyle of the humerus i. capitulum for articulation with the head of the radius ii. trochlea for articulation with trochlear notch of the ulna iii. coronoid fossa receives the coronoid process of the ulna iv. olecranon fossa accommodates the olecranon of the ulna v. radial fossa accommodates the edge of the head of the radius 4) bones of forearm a. ulna a) olecranon – a short level for extension of the elbow b) coronoid process c) trochlear notch formed by the olecranon and coronoid process d) tuberosity of the ulna i. inferior to the coronoid process ii. for attachment of the tendon of the brachialis muscle e) radial notch i. on the lateral side of the coronoid process ii. receive the periphery of the head of the radius f) supinator crest inferior to the radial notch g) supinator fossa i. between the crest and the distal part of the coronoid process ii. to which and the crest the deep part of the supinator muscle attaches h) the shaft i) the head of the ulna j) ulnar styloid process b. radius a) the head articulates with the capitulum of the humerus and the radial notch of the ulna b) the neck c) radial tuberosity demarcates the proximal end of the radius from the shaft and attached by the biceps tendon d) the shaft e) distal end i. ulnar notch accommodates the head of the ulna ii. radial styloid process I. the radial styloid process is larger than the ulnar styloid process and extends farther distally - clinical important when fractured iii. dorsal tubercle - lateral to it, a groove for the tendon of the extensor carpi radialis longus and brevis c. interosseous border of the radius or ulna a) interosseous membrane of the forearm i. major fibers run inferiorly from the radius to the ulna 4 ii. transmit forces received by the radius to the ulna 5) bones of hand a. the carpus is composed of 8 carpal bones arranged in proximal and distal rows of 4 a) proximal row i. scaphoid – scaphoid tubercle (gives attachment to the transverse carpal ligament) ii. lunate iii. triquetrum – articulates with the articular disc of the distal radioulnar joint iv. pisiform – on the palmar surface of the triquetrum b) distal row i. trapezium I. tubercle of the trapezium (for the attachment of the abductor pollicis brevis muscle) II. a groove for the tendon of the flexor carpi radialis ii. trapezoid iii. capitate – the largest one in the carpus iv. hamate – hook of the hamate b. the metacarpus a) 5 metacarpal bones (metacarpals) b) base, shaft and head c) the first one is the thickest and shortest, while the third one has a styloid process c. the phalanges a) base, shaft and head 4. surface anatomy of upper limb bones the acromial end of the clavicle – acromioclavicular joint the neurovascular bundle pass posterior to the anterior convexity of the clavicle superior angle of the scapula – T2 vertebra medial end of the root of scapular spine – T3 spinous process inferior angle of the scapula – T 7 vertebra (inferior border of the 7th rib and 7th intercostals space) 6) when the upper limb is abducted and the hand is placed on the back of the head – the medial border of the scapula parallels the 6th rib or the oblique fissure of the lung (a line drawn from the spinous process of the second thoracic vertebra around the side of the thorax to the sixth rib in the mid-clavicular line) 7) the corocoid process of the scapula – the lateral side of the clavipectoral triangle 8) when the elbow joint a. is extended, the tip of the olecranon and the humeral epicondyles lie in a straight line. b. is flexed, the tip and the epicondyles form a triangle 9) the head and styloid process of the ulna 10) the head and styloid process (in the snuff box) of the radius 11) the dorsal tubercle of radius – a pulley for the long extensor tendon of the thumb 12) the pisiform 13) the hook of the hamate – 2 cm distal and lateral to the pisiform 14) the tubercles of the scaphoid and trapezium at the base and medial aspect of the thenar eminence 1) 2) 3) 4) 5) 5. fascia, efferent vessels, cutaneous innervation and myotomes of upper limb 1) fascia of upper limb a. pectoral fascia – invests the pectoralis major b. axillary fascia – the floor of the axilla c. clavipectoral fascia – encloses the subclavius and the pectoralis minor muscles, continuing with the axillary fascia 5 a) costocoracoid membrane i. between the subclavius and the pectoralis minor ii. pierced by the lateral pectoral n. b) the suspensory ligament of the axilla – fascia inferior to the pectoralis minor d. deltoid fascia e. brachial fascia a) medial and lateral intermuscular septa b) anterior (flexor) and posterior (extensor) fascial compartments f. antebrachial fascia a) interosseous membrane b) extensor retinaculum c) palmar carpal ligament d) flexor retinaculum (transverse carpal ligament) g. palmar fascia a) palmar aponeurosis b) superficial transverse metacarpal ligament 2) venous drainage of upper limb a. superficial veins of upper limb a) originate from the dorsal venous network at the dorsum of the hand b) perforating vein c) cephalic vein i. median cubital vein in the cubital fossa ii. between the deltoid and pectoralis major muscles along the deltopectoral groove iii. enter the costocoracoid membrane and join the axillary vein d) basilic vein i. near the middle and inferior 1/3 of the arm, pierces the brachial fascia ii. parallels to the brachial a. then to the axillary vein e) median antebrachial vein (median vein of the forearm) i. highly variable ii. begins at the base of the dorsum of the thumb iii. between the cephalic and basilic veins b. deep veins of upper limb c. lymphatic drainage of upper limb a) superficial lymphatic vessels i. lymphatic plexus in the hand I. accompanying the basilic vein to cubital lymph nodes, proximal to the medial epicondyle humeral (lateral) axillary lymph nodes II. accompanying the cephalic vein i. apical axillary lymph nodes ii. deltopectoral lymph nodes (beside the cephalic vein, between the pectoralis major and deltoideus, immediately below the clavicle) b) deep lymphatic vessels i. from joint capsule, periosteum tendon nerve and muscles ii. accompany the major deep veins iii. terminate in the humeral axillary lymph nodes d. cutaneous innervation of upper limb a) dematomes – much overlap and variable i. limb development (Keegan and Garret, 1948) ii. clinical findings (Foerster, 1933) e. motor innervation (myotomes) of upper limb 6 a) myotome – the unilateral embryological muscle mass receives innervation from a single spinal cord segment or spinal nerve b) the intrinsic muscles of the hand constitute a single myotome (T1) 6. pectoral and scapular regions 1) anterior axioappendicular muscles a. pectoralis major a) anterior axillary fold, deltopectoral groove (for cephalic vein), clavipectoral triangle b) the clavicular and the sternocostal heads c) adduction and medial rotation of the arm b. pectoralis minor a) coracoid process to the anterior end of the 3rd~5th ribs near their costal cartilages b) stabilizes the scapula and elevates the ribs c) depression and downward rotation of the scapula d) a useful anatomical and surgical landmark for structures in the axilla c. subclavius a) inferior to the clavicle b) anchors and depresses the clavicle c) prevent the dislocation of the clavicle from the SC joint d. serratus anterior a) anterior surface of the medial border of the scapula to the lateral surface of 1~8th ribs b) protractor, rotator and anchor of the scapula 2) posterior axioappendicular and scapulohumeral muscles a. superficial posterior axioappendicular (extrinsic shoulder) muscles: trapeziums and latissimus dorsi b. deep posterior axioappendicular (extrinsic shoulder) muscles: levator scapulae and rhomboids c. scapulohumeral (intrinsic shoulder) muscles: deltoid, teres major and four rotator cuff muscles (supraspinatus, infraspinatus, teres minor and subscapularis [SITS]) a) superficial posterior axioappendicular (extrinsic shoulder) muscles i. trapezius I. assists in suspending the upper arm II. three parts have different action at the physiological scapulothoracic joint i. descending (superior) part – elevates the scapula ii. middle part – retracts the scapula iii. ascending part – depress the scapula (lower the shoulder) III. the descending and ascending parts can act together in rotating the scapula IV. drooping of the shoulder ii. latissimus dorsi I. adductor of the humerus and downward rotator of the scapula II. extends, retracts and rotates the humerus medially III. actions in climbing, swimming, chopping the wood, chin-up and paddling a canoe b) deep posterior axioappendicular (extrinsic shoulder) muscles i. levator scapulae I. from the transverse processes of C1~4 to the superomedial border of the scapula II. elevates and rotates the scapula, depresses the glenoid cavity III. extension and lateral flexion of the neck ii. rhomboids (major and minor) I. not clearly separated from each other (minor [C7&T1], major [T2~5]) II. retracts and rotates the scapula, depresses the glenoid cavity 7 c) scapulohumeral (intrinsic shoulder) muscles i. deltoid I. divided into unipennate posterior and anterior parts and a multipennate middle part II. main abductor of the arm (the first 15o of abduction by the supraspinatus) III. posterior and anterior parts – swing the limbs during walking ii. teres major I. from posterior surface of inferior angle of the scapula to medial lip of intertubercular sulcus II. the lower border of the quadrangular space (through which the axillary n. and the posterior circumflex humeral a. pass) III. adducts and medially rotates the humerus IV. innervated by the lower subscapular n. iii. rotator cuff (SITS) muscles I. rotator of the humerus and stabilizes the head of the humerus in the glenoid cavity II. a bursa separates the supraspinatus from the lateral quarter of the supraspinous fossa III. the infraspinatus is a powerful lateral rotator of the humerus IV. the teres minor muscle i. is completely hidden by the deltoid and often not clearly delineated from the infraspinatus ii. innervated by the axillary n. V. the subscapularis crosses the anterior aspect of the scapulohumeral joint 3) surface anatomy of pectoral, scapular and deltoid regions a. the clavicle indicates the division between the deep cervical and the axillary lymph “sheds” [棚]: structures superior to the clavicle drain via the deep cervical nodes and those inferior to the clavicle via the axillary nodes b. infraclavicular fossa – clavipectoral triangle (cephalic v., thoracoacromial trunk, lateral pectoral n.) c. coracoid process a) lateral aspect of the clavipectoral triangle b) bony landmark for brachial plexus block c) in diagnosing shoulder dislocations d. acromial angle - the subcutaneous bony point at which the lateral border becomes continuous with the spine of the scapula e. the spine of the scapula f. the root of the scapular spine – T3 g. the medial border of the scapula – ribs 3~7 h. the inferior angle of the scapula – T7 or 7th rib / intercostal space 7. axilla 1) the apex – cervico-axillary canal 2) the base – axillary fascia (armpit), about at the level of rib 4 3) the anterior wall a. the pectoralis major and minor muscles, and the pectoral and clavipectoral fascia b. anterior axillary fold – formed by the pectoralis major 4) the posterior wall a. the scapula, subscapularis, teres major and latissimus dorsi b. posterior axillary fold – formed by teres major and latissimus dorsi 5) the medial wall – 1~4th ribs and serratus anterior muscle 6) the lateral wall – intertubercular groove 8 7) contents – neurovascular structures ensheathed in the axillary sheath 8) axillary artery a. begins at the lateral border of the 1st rib and ends at the inferior border of the teres major b. the first part – the superior thoracic artery at the 1~2nd intercostal spaces c. the second part – the thoracoacromial and lateral thoracic arteries a) lateral thoracic artery i. has a variable origin ii. along the lateral border of the pectoralis minor b) thoracoacromial artery i. pierces the costocoracoid membrane ii. four brs.: acromial, deltoid, pectoral and clavicular d. the third part – a) subscapular artery i. the greatest diameter ii. along the lateral border of the subscapularis iii. divides into the thoracodorsal and circumflex scapular arteries I. circumflex scapular artery passes between the subscapularis and teres major muscles II. thoracodorsal artery continues to the inferior angle of the scapula and supplies mainly the latissimus dorsi b) anterior circumflex humeral and posterior circumflex humeral arteries i. encircle the surgical neck of the humerus ii. anterior circumflex humeral a. (generally smaller) passes deep to the biceps iii. posterior circumflex humeral a. (large one) passes via quadrangular space with the axillary n. 9) axillary vein a. receives tributaries that generally correspond to brs. of the axillary a. with some exceptions a) the corresponding to the brs. of the thoracoacromial a. do not merge to enter by a common tributary b) receives directly or indirectly the thoracoepigastric veins and constitutes a collateral route in case of obstruction of the inferior vena cava 10) axillary lymph nodes a. pectoral (anterior) nodes – around the lateral thoracic v. b. subscapular (posterior) nodes – along the subscapular vessels c. humeral (lateral) nodes – along the medial and posterior to the axillary v. d. central nodes – in association with the second part of the axillary vessels and its efferents to the apical nodes e. apical nodes – along the medial side of axillary v. and the first part of the axillary a. 8. brachial plexus 1) 5 roots (C5~8 and T1) between the anterior and middle scalene muscles 2) 3 trunks (superior [C5+6], middle [C7], inferior [C8+T1]) 3) each trunk divides into anterior and posterior divisions a. through the cervico-axillary canal posterior to the clavicle b. anterior division – supplies anterior (flexor) compartments of the upper limb c. posterior division – extensor compartments 4) 3 cords – bear the relationship to the second part of the axillary a. a. lateral cord - anterior divisions of the superior and middle trunks b. medial cord - anterior division of inferior trunk c. posterior cord – posterior divisions of all trunks 5) branches 9 a. the supraclavicular part a) arise from the roots and trunks b) dorsal scapular n., long thoracic n., nerve to subclavius, and suprascapular n. c) phrenic n. (C5 root + C3~4) on the anterior surface of the anterior scalene muscle b. the infraclavicular part a) arise from the cords b) table 6.8 9. arm 1) muscles of arm a. 3 flexors (biceps brachii, brachialis and coracobrachialis) and 1 extensor (triceps brachii) b. the flexors are innervated by the musculocutaneous n. and the extensor is supplied by the radial n. c. the flexors is stronger (better puller than pusher) d. the triceps is of importance in elderly or disabled persons ( for raising oneself out of a chair) e. biceps brachii a) usually has two heads – long and short b) a three-joint muscle (at the glenohumeral, elbow and radio-ulnar joints) c) its action and effectiveness are markedly affected by the position of the elbow and forearm d) supinator e) the long head - arising from the supraglenoid tubercle, crossing the humeral head, descending in the intertubercular sulcus and hold by the transverse humeral ligament f) inserts mainly to the radial tuberosity g) bicipital aponeurosis runs from the biceps tendon across the cubital fossa and attaches the subcutaneous border of the ulna f. brachialis a) the only pure flexor b) primarily responsible for sustaining the flexed position g. coracobrachialis a) a useful landmark for locating other structures in the arm i. pierced by the musculocutaneous n. ii. distal part of its attachment – nutrient foramen of the humerus iii. shunt muscle – resisting downward dislocation of the humeral head h. triceps brachii a) three heads: lateral, medial and long i. long head – stabilizes the adducted glenohumeral joint and serves as a shunt muscle ii. medial head – the workhorse of forearm extension iii. lateral head – acts primarily against resistance i. anconeus – help the triceps extend the forearm 2) brachial artery a. begins at the inferior border of the teres major muscle and ends at the neck of the radius b. branches a) deep artery of arm i. accompanies the radial n. along the radial groove ii. terminates by dividing into the middle and radial collateral arteries b) superior ulnar collateral artery i. arises near the middle of the arm and accompanies the ulnar n. ii. anastomoses with the posterior ulnar recurrent artery 10 c) inferior ulnar collateral artery i. arises at 5 cm proximal to the elbow crease ii. anterior to the medial epicondyle and anastomoses with the anterior ulnar recurrent artery 3) veins of arm 4) nerves of arm a. musculocutaneous nerve a) arises opposite the inferior border of the pectoralis minor b) pierces the coracobrachialis c) continues distally between the biceps and the brachialis d) emerges lateral to the biceps tendon as the lateral cutaneous nerve of the forearm b. radial nerve a) descends with deep brachial a. in the radial groove b) continues between the brachialis and the brachioradialis to the lateral epicondyle c) then divides into the deep and superficial branches of the radial n. c. median nerve a) proximally runs on the lateral side of the brachial a. b) near the middle of the arm, crosses to the medial side of the brachial a. c) at the cubital fossa, lies deep to the bicipital aponeurosis and median cubital v. d) no branches in the arm d. ulnar nerve a) arises anterior to the insertion of the teres major on the medial side of the brachial a. b) around the middle of the arm, accompanies with the superior ulnar collateral a. c) passes posterior to the medial epicondyle as the “funny bone” d) no branches in the arm 10. cubital fossa 1) boundaries a. superiorly, a line connecting the medial and lateral epicondyles b. medially, the pronator teres c. laterally, the brachioradialis d. the floor, the supinator and brachialis muscles 2) contents a. the brachial a. lies between the biceps tendon and the median n. b. the radial n. deep between the brachiaradialis and the brachialis c. the median cubital v. d. the medial and lateral antebrachial cutaneous ns. 11. surface anatomy of arm and cubital fossa 1) 2) 3) 4) 5) the attachment of the deltoid the long, lateral and medial heads of the triceps; the triceps tendon the olecranon – olecranon bursa, resulting in the mobility of the overlying skin the biceps brachii tendon, the bicipital aponeurosis the medial and lateral bicipital grooves a. indicate the location of the medial and lateral intermuscular septa b. the basilic and cephalic vs. run superiorly in the grooves respectively c. the brachial a. deep to the medial bicipital groove 6) the head and epicondyles of the humerus 12. forearm 1) compartments of forearm a. flexor-pronator one innervated by the median n. (except the flexor carpi ulnaris and the flexor digitorum profundus [medial half to digits 4 and 5]) supplied by the ulnar n.) b. extensor-supinator one innervated by the radial n. 11 c. the anterior compartment is exceptional for the spreading of fluids and infections because it communicates with the central compartment of the palm through the carpal tunnel 2) muscles of forearm a. the flexor muscles a) superficial layer i. pronator teres, flexor carpi radialis, palmaris longus, flexor carpi ulnaris ii. common flexor tendon to the medial epicondyle b) intermediate layer – flexor digitorum superficialis c) deep layer – flexor digitorum profundus, flexor pollicis longus, pronator quadrates a) the more distally placed a muscle’s distal attachment lies, the more distally placed is its proximal attachment (except the pronator quadratus) b) the brachioradialis, a flexor but located at the extensor compartment and innervated by the radial n. c) the long flexors of the digits i. also flex the metacarpophalangeal and wrist joints ii. when the wrist is flexed, the contraction of these flexors is consequently weaker and vice versa d) pronator teres (PT) i. the most lateral of the superficial forearm flexors ii. has two heads - humeral and ulnar I. the humeral head - arises from the medial supracondylar ridge and from the common flexor tendon II. the ulnar head - arises from the medial side of the coronoid process of the ulna iii. inserted into a rough impression at the middle of the lateral surface of the body of the radius, just below the insertion of the supinator iv. the median nerve enters the forearm between the two heads of the muscle, and is separated from the ulnar artery by the ulnar head e) flexor carpi radialis (FCR) i. produces flexion and abduction (radial derivation) of the wrist ii. originates on the medial epicondyle of the humerus and inserts on the anterior aspect of the base of the 2nd (and 3rd) metacarpals and trapezial tuberosity iii. its tendon through the flexor retinaculum and a groove in the trapezium iv. has it own tendinous sheath v. a good mark for the location of the radial a. lying just lateral to it at the wrist f) palmaris longus (PL) i. variable existence, passes superficial to the flexor retinaculum to the palmar aponeurosis ii. a useful guide to the median n. at the wrist, the nerve lying just lateral to it g) flexor carpi ulnaris (FCU) i. flexes and adducts the hand at the wrist ii. arises by two heads - humeral and ulnar, connected by a tendinous arch (cubital tunnel) beneath which the ulnar nerve and ulnar artery pass I. the humeral head arises from the medial epicondyle of the humerus by the common flexor tendon II. the ulnar head arises from the medial margin of the olecranon of the ulna iii. Its insertion is into the pisiform bone and then via ligaments into the hamate bone and 5th metacarpal bone iv. a flexor in the anterior comparment of the forearm but innervated by the ulnar n. v. at the wrist, a useful guide to the ulnar n. and a. lying just lateral to it 12 h) flexor digitorum superficialis (FDS) i. the median n. and the ulnar a. enter the forearm by passing between its humeroulnar and radial heads ii. These tendons, along with those of flexor digitorum profundus, are enclosed by a common flexor sheath iii. flexes the middle phalanges of the medial four fingers at the proximal interphalangeal joint and serves independently iv. also flexes he proximal phalanges at the metacarpophalangeal and wrist joints i) flexor digitorum profundus (FDP) i. flexes the distal interphalangeal joints but also the two interphalangeal, metacarpophalangeal and wrist joints ii. the part of the muscle going to the index finger separates early from the rest and is capable of independent contraction j) flexor pollicis longus (FPL) i. has its own tendinous sheath lateral to the common flexor sheath ii. primarily flexes the distal phalanx of the thumb at the interphalangeal joint iii. secondarily flexes the proximal phalanx and the 1st metacarpal at the metacarpophalangeal and carpometacarpal joints respectively k) pronator quadratus (PQ) i. the only muscle that attaches only to the ulna at one end and the radius at the other end ii. the prime mover for pronation iii. initiates pronation and is assisted by the pronator teres b. extensor muscles a) three functional groups i. muscles that extend and abduct or adduct the hand (extensor carpi radialis longus, extensor carpi radialis brevis, extensor carpi ulnaris) ii. muscles that extend the medial four digits (extensor digitorum, extensor indicis, extensor digiti minimi) iii. muscles that extend or abduct the thumb (abductor pollicis longus, abductor pollicis brevis, extensor pollicis longus) b) superficial extensors of the forearm 4 muscles (ECRB, ED, EDM, ECU) attached by a common extensor tendon; 2 muscles (Br, ECRL) to the lateral supraepicondylar ridge the common tendon of the index and little fingers are joined on their medial sides by the respective tendons of the EI and EDM i. brachioradialis (Br) I. attached to the distal styloid process of the radius by way of the brachioradialis tendon, and to the lateral supracondylar ridge of the humerus II. overlies the radial n. and a. but its tendon is covered by the abductor pollicis long and extensor pollicis brevis III. flexes the forearm at the elbow and acts as a shunt muscle resisting subluxation [半脫位] of the radial heads IV. also capable of both pronation and supination, depending on the position of the forearm ii. extensor carpi radialis longus and brevis (ECRL, ECRB) I. ECRL i. originates from the lateral supracondylar ridge of the humerus and inserts into the base of the second metacarpal bone ii. pass under the extensor retinaculum within the tendinous sheath of the 13 extensor carpi radials II. ECRB i. arises from the lateral epicondyle of the humerus by the common extensor tendon and inserts into the base of the third metacarpal bone ii. covered by the ECRL III. at the wrist, the two muscle tendons pass beneath the APL and EPB IV. as synergists to other muscles i. acting with the ECU, they extend the hand and steady the wrist during clenching a fist ii. acting with the FCR, they produce pure abduction iii. extensor digitorum (ED) I. four tendons join the tendon of the extensor indicis and pass deep to the extensor retinaculum through the tendinous sheath of the extensor digitorum and extensor indicis II. intertendinous connection restrict independent extension of the medial digits (especially the ring finger) III. extensor expansion (dorsal expansion/hood) wraps around the dorsum and sides of a head of the metacarpal and proximal phalanx i. the hood formed over the head of the metacarpal and anchored to the palmar ligament ii. palmar ligament, a portion of the fibrous layer of the joint capsule of the metacarpophalangeal joint iii. median band passes to the base of the middle phalanx iv. lateral bands a. pass to the base of the distal phalanx b. the tendon of the interosseous and lumbrical muscles join the bands v. retinacular ligament runs from the proximal phalanx and fibrous digital sheath obliquely cross the middle phalanx and two interphalangeal joints, then joins the extensor expansion iv. extensor digiti minimi (EDM) I. as a partially detached part of the extensor digitorum II. has its own tendinous sheath III. its tendon has two slips but all three attach to the extensor expansion v. extensor carpi ulnaris (ECU) I. has two heads: a humeral head from the common extensor tendon and an ulnar head from posterior border of the ulna II. passes in a groove between the ulnar head and its styloid process III. has its own tendinous sheath, and can extend and adduct the hand IV. also indispensable when clenching the fist vi. supinator (Su) I. lies in the cubital fossa along with the brachialis II. envelops the neck and proximal part of the radius III. pierced by the deep branch of the radial n., which then joins the posterior interosseous a. and becomes the posterior interosseous n. IV. the prime mover for slow, unopposed [無阻抗的] supination versus the biceps brachii against resistance c) deep extensors of the forearm act on the thumb (APL, EPL, EPB) and the index finger (EI) outcropping [露出] muscles of the thumb (APL, EPL, EPB) that emerge from the furrow in the lateral part of the forearm i. abductor pollicis longus (APL) 14 commonly split into two parts: to the trapezium instead of the base of the 1st metacarpal II. can abduct and extend the thumb III. passes deep to the extensor retinaculum in the common tendinous sheath with the tendon of the EPB ii. extensor pollicis brevis (EPB) I. covered partly by APL II. helps extend the 1st metacarpal and extend and abduct the hand III. anatomical snuff box can be seen when the thumb is fully extended iii. extensor pollicis longus (EPL) I. has its own tendinous sheath medial to the dorsal tubercle of the radius II. also adducts the extended thumb and rotates it laterally III. creates the anatomical snuff box with the tendon of the EPB i. radial a. in the floor of the box ii. radial styloid process, the base of the 1st metacarpal, scaphoid and trapezium can be felt in the box iv. extensor indicis (EI) I. lies medial to and alongside the tendon of the EPL II. extends the index finger and also helps extend the hand 3) arteries of the forearm a. ulnar artery a) arises opposite the neck of the radius in the inferior part of the cubital fossa b) can be palpated on the lateral side of the FCU and separated from the FCU by the ulnar n. c) branches i. anterior ulnar recurrent artery I. passes superiorly between the brachialis and pronator teres II. anastomoses mainly with the inferior ulnar collateral a. ii. posterior ulnar recurrent artery I. much larger than the anterior ulnar recurrent a. II. passes superiorly in the interval between the medial epicondyle and the olecranon, it lies beneath the FCU, and ascending between the heads of FCU III. anastomoses mainly with the superior ulnar collateral a. iii. common interosseous artery I. arises immediately below the tuberosity of the radius II. passing backward to the upper border of the interosseous membrane, it divides into two branches, the anterior interosseous and posterior interosseous arteries iv. anterior interosseous artery I. runs on the anterior aspect of the interosseous membrane with anterior interosseous n. II. at he upper border of the ponator quadrates, it pierces the interosseous membrane and reaches the back of the forearm, where it anastomoses with the dorsal interosseous a. III. then descends, in company with the terminal portion of the dorsal interosseous nerve, to the back of the wrist to join the dorsal carpal network v. posterior interosseous artery I. relatively small, passes backward between the oblique cord and the upper border of the interosseous membrane in accompany with the posterior interosseous n. I. 15 at the lower part of the forearm it anastomoses with the termination of the anterior interosseous artery, and with the dorsal carpal network III. gives off, near its origin, the recurrent interosseous artery vi. recurrent interosseous artery I. ascends to the interval between the lateral epicondyle and olecranon II. anastomoses with the medial/middle collateral artery b. radial artery i. can be felt throughout the forearm ?? ii. proximally covered by the brachioradialis, distally covered only by skin and fascia where radial pulse can be felt iii. the course represented by a line joining the midpoint of the cubital fossa to a point just medial to the radial styloid process iv. crosses the floor of the anatomical snuff box braches i. radial recurrent artery I. ascends between the branches of the radial nerve, lying on the supinator and then between the brachioradialis and brachialis II. anastomoses with the radial collateral a. from the deep brachial a. ii. dorsal carpal branch of the radial artery (posterior radial carpal artery) I. arises beneath the extensor tendons of the thumb II. crosses the carpus transversely toward the medial border of the hand III. anastomoses with the dorsal carpal branch of the ulnar artery iii. palmar carpal branch of the radial artery I. arises near the lower border of the pronator quadratus II. runs across the front of the carpus III. anastomoses with the palmar carpal branch of the ulnar artery. c. veins of forearm – deep venous palmar arch d. nerves of forearm a) median nerve in forearm the principal nerve of the anterior compartment of the forearm supplies all muscles of the anterior compartment except the FCU and the medial part of the FDP via the anterior interosseous nerve braches i. anterior interosseous nerve I. runs distally on the interosseous membrane with the anterior interosseous a. II. then deep to and supplies the pronator quadratus ii. palmar cutaneous branch of the median nerve I. arises just proximal to the flexor retinaculum II. distributed to skin of the central part of the palm b) ulnar nerve in forearm supplies only the FCU (by passing between its two heads of proximal attachment) and the medial part of the FDP (sending the tendons to the 4th and 5th digits) becomes superficial just proximal to the wrist and passes superficial to the flexor retinaculum enter the hand via a groove between the pisiform and the hook of the hamate, then divided into superficial and deep branches ulnar canal (Guyon canal) - a fibrous band bridges the abovementioned groove branches: i. palmar cutaneous branch arises about five 5 cm above the wrist from where the ulnar nerve splits into palmar and dorsal branches II. 16 the distribution, origin and course are still uncertain ii. dorsal cutaneous branch - passes backward beneath the FCU, perforates the deep fascia, and, running along the ulnar side of the back of the wrist and hand c) radial nerve in forearm appears in the cubital fossa between the brachialis and the brachioradialis branches i. posterior cutaneous nerve of the forearm I. runs along the radial groove II. pierces the deep fascia below the insertion of the deltoideus, and descends along the back of the forearm to the wrist ii. superficial branch of the radial nerve – emerges from the brachioradialis and crosses the floor of the anatomical snuff box iii. deep branch of the radial nerve I. becomes the nerve after the radial n. piercing the supinator II. accompany with the posterior interosseous a. and referred to as the posterior interosseous nerve III. supplies all muscles in the posterior compartment of the forearm d) lateral and medial cutaneous nerve of forearm 4) surface anatomy of forearm a. the medial and lateral epicondyles b. the olecranon c. the head of the radius a) in the hollow located posterolaterally when the forearm is extended b) can be left when supinate and pronate your forearm d. the posterior border of the ulna a) being subcutaneous along the entire length of the bone b) demarcates the posteromedial boundary separating the anterior and posterior compartment of the forearm e. the cubital fossa a) a line demarcates the course of the radial a. i. from the cubital fossa to the radial styloid process ii. demarcates the anterolateral boundary separating the anterior and posterior compartment of the forearm f. the head of the ulna g. the ulnar styloid process h. the radial styloid process – located about 1 cm more distal than the ulnar styloid process 13. hand 1) fascia and compartment of palm a. palm fascia a) thenar and hypothenar fascia b) palmar aponeurosis c) fibrous digital sheath b. medial fibrous septum a) from the medial border of the palmar aponeurosis to the 5th metacarpal b) hypothenar compartment is medial to the septum c. lateral fibrous septum a) from the lateral border of the palmar aponeurosis to the 3th metacarpal b) thenar compartment is lateral to the septum d. central compartment between the thenar and hypothenar compartments e. adductor compartment f. two potential spaces between the flexor tendons and the fascia covering the deep palmar 17 muscles a) thenar space b) midpalmar space – continuous with the anterior compartment of the forearm via the carpal tunnel 2) muscles of hand a. intrinsic muscles in five compartments: thenar, hypothenar, adductor, central and interosseous compartments b. thenar muscles a) form the thenar eminence and chiefly responsible for opposition of the thumb b) the 1st metacarpal is independent with mobile joints at both ends c) movements: extension, flexion, abduction, adduction, opposition d) opposition i. begins with the thumb in extended position ii. initial abduction and medial rotation of the 1st metacarpal at the carpometacarpal joint iii. then flexion at the metacarpophalangeal joint e) abductor pollicis brevis (APB) – assists during the early stages of opposition by rotating its proximal phalanx slightly medially f) flexor pollicis brevis (FPB) - has two bellies i. larger superficial head I. inserts unto the radial side of the base of the proximal phalanx of the thumb; in its tendon of insertion there is a sesamoid bone. II. innervated by the recurrent branch of the median n. ii. smaller deep head I. inserts into the ulnar side of the base of the first phalanx with the adductor pollicis II. innervated by the deep branch of the ulnar n. g) opponens pollicis i. the most important movement – oppose the thumb ii. flexes and rotates the 1st metacarpal medially c. adductor pollicis a) a fan-shaped muscle has two heads of origin that separated by the radial a. i. oblique head from the bases of 2nd and 3rd metacarpals and the carpals ii. transverse head from the shaft of the 3rd metacarpal b) adducts the thumb d. hypothenar muscles a) abductor digiti minimi i. from the pisiform to the base of the proximal phalanx of the 5th digit ii. abducts the 5th digit and assists in flexion of its proximal phalanx b) flexor digiti minimi brevis i. form the hook of the hamate and the flexor retinaculum to the base of the proximal phalanx of the 5th digit ii. flexes the proximal phalanx of the 5th digit c) opponens digiti minimi i. form the hook of the hamate and the flexor retinaculum to the medial border of the 5th metacarpal ii. draws the 5th metacarpal anteriorly and rotates it laterally e. palmar brevis a) in the subcutaneous tissue of the hypothenar eminence b) attaches to the medial border of the palmar aponeurosis c) wrinkles the skin of the eminence thereby aiding the palmar grip 18 d) covers the ulnar a. and n. f. short muscles of hand a) lumbricals i. the 1st and 2nd ones as unipennate muscle from the tendon of the FDP to the extensor expansions ii. the 3rd and 4th ones as bipennate muscle from the tendon of the FDP to the extensor expansions iii. flex the fingers at the metacarpophalangeal joints and extend the interphalangeal joints b) interossei i. dorsal interossei, as bipennate muscle from the adjacent side of two metacarpals to the bases of proximal phalanges and extensor expansions of the 2nd ~ 4th digits ii. palmar interossei, as unipennate muscles from the palmar surface of the 2nd, 4th and 5th metacarpals to the bases of proximal phalanges and extensor expansions of the 2nd, 4th and 5th digits iii. acting together with the lumbricals, the interossei produce flexion of the fingers at the metacarpophalangeal joints and extension of the interphalangeal joints (z-movement) 3) long flexor tendons and tendon sheaths in hand a. common flexor sheath (FDS and FDP) b. digital synovial sheath c. tendinous chiasm d. fibrous digital sheath a) osseofibrous tunnel b) annular and cruciform parts (pulleys) 4) arteries of hand a. supplied with an abundance of highly branched and anastomosing arteries b. ulnar artery in hand a) lie lateral to the ulnar n. b) anterior to the flexor retinaculum, runs between the pisiform and the hook of the hamate via the ulnar canal c) superficial palmar arch – the main terminal branch i. common palmar digital arteries I. anastomose with the palmar metacarpal as. from the deep palmar arch ii. proper palmar digital arteries along the side of the 2nd~4th digits c. radial artery in hand a) enters the palm by passing between the heads of the 1st dorsal interosseous muscle b) then passing between the head of the adductor pollicis c) anastomoses with the deep br. of the ulnar a. to form the deep palmar arch i. formed mainly by the radial a. ii. lies across the metacarpals just distal to their bases iii. gives rise to I. the palmar metacarpal arteries anastomosing with common palmar digital arteries II. the principal pollicis artery i. arises from the radial artery just as it turns medially towards the deep part of the hand ii. descends between the first dorsal interosseous muscle and the oblique head of the adductor pollicis iii. along the medial side of the first metacarpal bone to the base of the 19 proximal phalanx III. the radial indicis artery i. arises close to the princeps pollicis artery, and descends between the first dorsal interosseous muscle and the transverse head of the adductor pollicis ii. runs along the lateral side of the index finger to its extremity 5) nerves of hand a. median nerve in hand a) through the carpal tunnel – between the tubercles of the scaphoid and trapezoid bones on the lateral side and the pisiform and the hook of the hamate on the medial side b) innervates the thenar muscles except the adductor pollicis and the deep head of the flexor pollicis brevis and the lateral two lumbricals (digit 2 and 3) c) recurrent br. loops around distal to the flexor retinaculum and innervates the thenar muscles d) palmar cutaneous br. i. arises just proximal to the flexor retinaculum to which runs superficial ii. passes between tendons of palmaris longus and flexor carpi radialis b. ulnar nerve in hand a) deep to the tendon of the FCU and continues to the wrist via ulnar canal b) the palmar cutaneous branch arises about 5 cm proximal to the flexor retinaculum, crosses the latter on the lateral side of the pisiform bone c) the dorsal cutaneous branch passes backward beneath the flexor carpi ulnaris d) the superficial branch i. arises at the wrist as passes between the pisiform and hamate bones ii. supplies the palmaris brevis and the skin on the ulnar side of the hand, iii. then divides into a proper palmar digital nerve and a common palmar digital nerve. e) the deep branch i. passes between the abductor digiti minimi and the flexor digiti minimi brevis ii. then perforates the opponens digiti minimi and follows the course of the deep palmar arch beneath the flexor tendons c. radial nerve in hand a) the superficial branch i. entirely sensory ii. runs deep to the brachioradialis iii. in the middle third of the forearm, it lies behind the same muscle, close to the lateral side of the artery iv. quits the artery about 7 cm. above the wrist, passes beneath the tendon of the brachioradialis, and, piercing the deep fascia, divides into two branches: lateral and medial 6) surface anatomy of hand a. radial artery pulse – lateral to the FCR tendon at the wrist b. the tendons of the FCR and palmaris longus for marking the radial a. and medial n. respectively c. the FCU tendon for marking the pisiform and the ulnar a. and n. d. the FDS tendons e. the anatomical snuff box a) the anterior boundary – tendons of the APL and EPB b) the posterior boundary – the tendon of the EPL c) the floor of the box – the radial a., scaphoid and trapezium 20 f. the dorsal venous network g. the superficial palmar arch – at the level with the distal border of the fully extended thumb h. the deep palmar arch – at about 1 cm proximal to the superficial one (the base of the metacarpals) i. flexion creases a) wrist creases i. proximal, distal, middle ii. the distal one indicates the proximal border of the flexor retinaculum b) palmar creases i. radial longitudinal crease – “life line”, encircles the thenar eminence ii. proximal (transverse) palmar crease iii. distal (transverse) palmar crease c) transverse digital flexion creases 14. joints of upper limb 1) 2) 3) movement of the pectoral girdle a. involves the sternoclavicular (SC) , acromioclavicular (AC) and glenohumeral (GH) joints b. all moving simultaneously c. the clavicle a) forms a strut that holds the scapula and the GH joint away from the thorax b) establishes the radius [軸] where the shoulder rotates at the SC joint c) the 15-20o movement of the AC joint permits positioning the glenoid cavity d. scapulohumeral rhythm a) the motions of the scapula, clavicle, and humerus working together to achieve full elevation of the arm b) supraspinatus initiates first few degrees of shoulder abduction c) 2:1 ratio of glenohumeral to scapulothoracic movement sternoclavicular joint a. a saddle synovial joint but functions as a ball-and-socket joint b. the articular disc is firmly attached to the anterior and posterior sternoclavicular ligaments, the fibrous layer of the joint capsule and the interclavicular ligament c. the only articulation between the upper limb and the axial skeleton d. articulation – the sternal end articulates with the manubrium and the 1st costal cartilage e. joint capsule f. ligaments - the anterior and posterior sternoclavicular ligaments, the interclavicular ligament and the costoclavicular ligament g. movements – significantly mobile h. blood supply and innervation – internal thoracic and suprascapular as., the medial suprascapular n. and nerve to the subclavius acromioclavicular joint a. a plane type of synovial joint b. articulation – the acromial end articulates with the acromion of the scapula and separated by an incomplete articular disc c. ligaments a) the acromioclavicular ligament b) the coracoclavicular ligament the (vertical) conoid ligament attaches to the root of the coracoid process and the conoid tubercle of the clavicle the (horizontal) trapezoid ligament attaches to the superior surface of the coracoid process and the trapezoid line of the clavicle 21 d. 4) movement a) AP gliding of acromion during protraction & retraction of scapula b) tilting of acromion during abduction & adduction of arm c) rotation of the clavicle d) rotation occurs during abduction & adduction of shoulder e. blood supply and innervation – the suprascapular and thoracoacromial as., the lateral pectoral, axillary and lateral supraclavicular ns. glenohumeral joint a. a ball-and-socket joint, wide range of movements, relatively unstable b. articulation a) large humeral head articulates with shallow glenoid cavity of the scapula b) glenoid labrum c) held by the tonus by SITS c. joint capsule a) from the margin of the glenoid cavity to the margin of the anatomical neck of the humerus b) superiorly, encroaches [進犯] on the root of the coracoid process and encloses the tendon of long head of the biceps to the supraglenoid tubercle c) inferiorly, the weakest area without the coverage of SITS d) two apertures one between two tubercles of the humerus for passage of the tendon of the long head of the biceps the other situated anteriorly and inferior to the coracoid process, communicating with the subscapular bursa d. ligaments a) anteriorly, the glenohumeral ligaments evidence only on the internal aspect of the capsule radiate medially and inferiorly from the glenoid labrum at the supraglenoid tubercle to the anatomical neck of the humerus b) superiorly, the coracohumeral ligament – from the base of the coracoid process to the greater tubercle of the humerus c) transverse humeral ligament bridges over the intertubercular sulcus d) coraco-acromial arch formed by the acromion, the coracoid process and the coraco-acromial ligament a protective arch overlies the humeral head and prevents its superior displacement the supraspinatus muscle passes the subacrominal bursa separates the arch from the supraspinatus tendon and the greater tubercle e. movements (see fig. 6.96, table 6.17) a) flexion-extension, abduction-adduction, medial and lateral rotation of the humerus, circumduction b) full abduction of the arm needs lateral rotation of the humerus c) circumduction at the GH joint an orderly sequence: flexion abduction extension adduction accompanied by movements at the two other joints of the pectoral girdle f. blood supply and innervation – the anterior and posterior circumflex humeral as., the suprascapular a.; the supra scapular, axillary and lateral pectoral ns. g. bursae around GH joint a) subscapular bursa 22 5) 6) between the tendon of the subscapularis and the humeral neck communicates with the GH joint cavity – an extension of the joint cavity b) subacromial/subdeltoid bursa - between the acromion, coraco-acromial ligament and deltoid superiorly and the supraspinatus tendon and joint capsule of the GH joint inferiorly elbow joint a. a hinge type of synovial joint b. articulation - the trochlea and capitulum of the humerus with the trochlear notch of the ulna and the head of the radius: humeroulnar and humeroradial articulations c. ligaments a) radial collateral ligament from the lateral epicondyle of the humerus to the annular ligament of the radius and the lateral margin of the ulna b) ulnar collateral ligament from the medial epicondyle of the humerus to the coracoid process and olecranon of the ulna anterior band to the tubercle on the coronoid process posterior band to the medial margin of the olecranon oblique band bridges across the notch between the olecranon and the coronoid process d. movements a) extension and flexion b) carry angle - ~ 170o made by the fully-extended ulna and the humerus c) the obliquity of the ulna – 10o more in female than in men e. muscles moving elbow joint a) 17 muscles, have some potential to affect elbow movement; in turn, their function and efficiency in other movements are affected by elbow position b) The chief flexor of the elbow joint: the brachialis and the biceps c) The brachioradialis and pronator teres assist the chief flexors in producing slow flexion d) The chief extensor of the elbow joint: the triceps, especially the medial head f. blood supply and innervation – anastomoses around the joint; the musculocutaneous, radial and ulnar ns. g. bursae around elbow joint a) olecranon bursae intratendinous bursa in the tendon of the triceps subtendinous bursa between the olecranon and the triceps tendon subcutaneous bursa in the subcutaneous CT over the olecranon b) bicipitoradial bursa separates the biceps tendon from the anterior part of the radial tuberosity proximal radio-ulnar joint a. a pivot type of synovial joint b. articulation - the head of the radius articulates with the radial notch of the ulna c. ligaments a) annular ligament of radius b) sacciform recess of the proximal radio-ulnar joint on the radial neck d. movements a) supination and pronation b) the axis through the center of the radial head to the styloid process of the ulna c) the movements are accompanied by synergistic movements of GH and elbow joints, except when the elbow is flexed e. muscles moving the joint 23 supination – the supinator (when resistance is absent), biceps (due to resistance), EPL and ECRL (assistance) b) pronation – the pronator quadratus (primarily), pronator teres (secondarily), FCR, palmaris longus and brachioradialis (assistance) f. blood supply and innervation a) the radial portion of the periarticular arterial anastomosis of the elbow joint (radial and middle collateral as. and the radial and recurrent interosseous as.) b) the musculocutaneous, median and radial ns. distal radio-ulnar joint a. a pivot type of synovial joint b. articulation a) the ulnar head articulates with the ulnar notch of the radius b) articular disc (triangular ligament) from the medial edge of the ulnar notch to the base of the ulnar styloid process the proximal surface of the disc articulates with the ulnar head c) L-shaped joint cavity d) the sacciform recess of the distal radio-ulnar joint c. blood supply and innervation – by the anterior and posterior interosseous as. and ns. wrist (radiocarpal) joint a. a condyloid (ellipsoid) type of synovial joint b. a line joining the styloid processes of the ulna and radius (the proximal wrist crease) c. articulation a) the distal end of the radius and the articular disc of the distal radioulnar joint articulate with the proximal row of carpal bones (except the pisiform) b) the pisiform, as a sesamoid bone for the FCU and articulates with only the triquetrum d. ligaments a) palmar radiocarpal ligaments b) dorsal radiocarpal ligaments c) ulnar collateral ligament attached to the ulnar styloid process and triquetrum d) radial collateral ligament attached to the radial styloid process and scaphoid e. movements a) flexion-extension, abduction-adduction (radial deviation-ulnar deviation), circumduction b) flexion > extension, adduction (at the wrist joint) > abduction (at the midcarpal joint) c) circumduction: flexion adduction extension abduction f. muscles moving wrist joint a) produced primarily by the “carpi” muscles of the forearm, which attach to the base of the metacarpals b) pisohamate ligament, a continuation of the FCU tendon c) most activities require a small amount of wrist flexion (but tight grip requires extension at the wrist) d) the mildly extended position is the most stable and the “rest” position a) flexion: FCR and FCU (assistance from the flexor muscles of the fingers and thumb, the palmaris longus and the APL) b) extension: ECRL, ECRB and ECU (assistance from the extensor muscles of the fingers and thumb) c) abduction: the APL, FCR, ECRL and ECRB; only 15O, due to the projecting radial styloid process a) 7) 8) 24 d) adduction: ECU and FCU g. blood supply and innervation – dorsal and palmar carpal arch; anterior and posterior interosseous ns. and dorsal and deep branches of the ulnar n. 9) intercarpal (IC) joints a. plane synovial joints a) joints between the carpal bones of the proximal row b) joints between the carpal bones of the distal row c) midcarpal joint between the proximal and distal rows of the carpal bones d) pisotriquetral joint between the pisiform and triquetrum b. a continuous, common articular cavity is formed by the IC and carpometacarpal joint (except the carpometacarpal joint of the thumb) c. ligaments – anterior, posterior and interosseous ligaments d. movements a) initiates the flexion and extension of the hand at the midcarpal joint b) most flexion and adduction occur mainly at the wrist joint, whereas extension and abduction at the midcarpal joint c) movements with the proximal row are more mobile than the distal row e. blood supply and innervation – the dorsal and palmar carpal arches; the anterior interosseous n. and the dorsal and deep braches of the ulnar n. 10) carpometacarpal (CMC) and intermetacarpal (IM) joints a. are the plane synovial joint except the CMC joint of the thumb, which is a saddle synovial joint b. articulation a) generally, the distal surface of the carpals of the distal row articulates with the carpal surface of the base of the metacarpals b) except the CMC joint of the thumb that is between the trapezium and the base of the 1st metacarpal c) the IM joint between the bases of the metacarpals c. a common joint capsule, except the independent CMC joint of the thumb d. ligaments a) the palmar and dorsal CMC and IM ligaments b) the interosseous IM ligaments c) the superficial and deep transverse metacarpal ligaments e. movements a) the CMC joint of the thumb moves in any plane, essential to opposition of the thumb b) no movement occurs at the CMC joints of the 2nd and 3rd digits, slightly the 4th digit, moderately the 5th digit f. blood supply and innervation – the dorsal and palmar carpal arches, deep palmar arch and metacarpal as.; the anterior and posterior interosseous n. and the dorsal and deep braches of the ulnar n. 11) metacarpophalangeal (MP) and interphalangeal (IP) joints a. metacarpophalangeal joints, the condyloid synovial joint for flexion-extension and adduction-abduction b. interphalangeal joints, the hinge synovial joint for flexion-extension c. ligaments a) medial and lateral collateral ligaments denser cord-like part from the metacarpal or phalangeal heads to the phalangeal base thinner fan-like part from the metacarpal or phalangeal heads to the palmar ligament, which forms the palmar aspect of the joint capsule 25 d. e. the cord part is slack during extension and taut during flexion – the fingers cannot be spread (adducted) when the MP joints are fully flexed b) deep transverse metacarpal ligaments united by the palmar ligaments of the 2nd-5th MP joints movements a) the 2nd-5th MP joints – flexion-extension, abduction-adduction and circumduction b) the MP joint of the thumb - flexion-extension c) all IP joints - flexion-extension blood supply and innervation – deep digital as. from the superficial palmar arch; digital ns. from the median and ulnar ns. 26 Chapter 2 Lower Limbs 學習目標 (Learning objectives): 1. 骨盆的骨性結構與聯接關節,依附骨盆的臀部肌肉與其功能,臀部的神經血管走向與分布。 2. 大腿股骨的骨性結構與聯接關節,依附股骨的大腿肌肉與其功能,大腿的神經血管走向與 分布。 3. 小腿脛、腓骨的骨性結構與聯接關節,依附脛、腓骨的小腿肌肉與其功能,小腿的神經血 管走向與分布。 4. 足部的骨性結構與聯接關節,依附足部的肌肉與其功能,足部的神經血管走向與分布。 Lower Limbs Pelvic girdle: Innominate (hip) bone 1) Pubis: Pubic symphysis/Pubic tubercle/Body of pubis/Sup. & inf. pubic ramus /Obturator crest/Pectineal line/Iliopubic eminence 2) Ilium: Iliac cerst/Iliac spine (Anterior superior iliac spine, Anterior inferior iliac spine, Posterior superior iliac spine, Posterior inferior iliac spine)/Greater sciatic notch/Body of ilium/Iliopubic eminence/Gluteal surface(Anterior gluteal line/Posterior gluteal line/Inferior gluteal line)/Arcuate line/Articular surface for sacrum/Iliac fossa/Iliac tuberosity 3) Ischium: Body of ilium/Ischial spine/Lesser sciatic notch/Ischial tuberosity/Ramus of ischium/Obturator forame Anatomical position: a.s.i.s. and symphysis pubis on the same vertical plane Acetabulum: Lunate surface/Acetabular notch/Margin (Limbus) Sacro-iliac joint: Ant. & post. sacroiliac ligaments/Sacrospinous ligament/Sacrotuberous ligament (Greater & lesser sciatic foramen) Femur Proximal end: Head: Fovea Neck: Greater & lesser trochanter/Trochanteric fossa/Intertrochanteric crest/Intertrochanteric line Shaft: Linea aspera/Gluteal tuberosity/Nutrient forament Distal end: Med. & lat. condyle/Med. & lat. epicondyle/Adductor tubercle/Intercondylar fossa/Patellar surface Hip joint Acetabular labrum Transverse acetabular ligament: Vessels, n. to head run deep Round ligament: Acetabular notch fovea (head of femur) Joint capsule:Attaches ant. to intertrochanteric line; post. to smooth neck Joint capsule Ilio-femoral ligament (Y): a.i.i.s. (ilium) intertrochanteric line Pubo-femoral ligament Ischio-femoral ligament med. aspect of greater trochanter Tibia Proximal end: Med. & lat. condyle/Ant. & post. intercondylar area/Med. & lat. intercondylar tubercles/Sup. articular surface /Articular surface for fibula/Oblique line/Tibial tuberosity/Gerdy’s tubercle (Iliotibial tract)/Groove for tendon of semimembranosus Shaft: Soleal line/Borders: Ant., med. & interosseous/Surface: Ant., med. & lat./Nutrient foramen 27 Distal end: Medial malleolus/Inferior & Malleolar articular surface/Groove for tendon of tibialis post. & flexor digitorum longus Fibula Proximal end: Apex/Head/Neck/Articular surface for tibia Shaft: Borders: Ant., Med. & Interosseous/Surfaces: Post., Med. & Lat. Distal end: Lateral malleolus/ Malleolar articular surface Leg and Foot Palpate patella to find the patellar ligament Structures of the proximal leg: Tibial tuberosity/Lat. & med. condyles of the tibia/Head of the fibula Structures of the distal leg:Medial malleolus/Lateral malleolus Knee Joint Hinge joint: Medial condyle (Femur) + Tibia, Lateral condyle (Femur) + Tibia, Flexion & Extention Arthrodial joint: Patella surface (Femur) + Patella, Sliding Patello-femoral compartment: Infrapatellar synovial fold/Suprapatellar bursa/Ligamentum patellae (Patellar ligament) Extracapsular ligaments Patella lig./Tibial collateral lig./Fibular collateral lig./Oblique popliteal lig./Arcuate popliteal lig. Meniscus Medial meniscus: Wide-C in shape/Lateral meniscus: Circular-O in shape Intra-articular ligaments Ant. cruciate lig./Post. cruciate lig./Transverse lig./Post. meniscofemoral lig. Bursae Prepatellar & infrapatellar bursae/Suprapatellar bursae/Gastrocnemius bursa/Popliteal bursa (Subpopliteal recess) Foot bones Talus Head: Articulate with Navicular Body: Trochlea Sup. articular facet Tibia/Med. articular facet Medial malleolus/Lat. articular facet Lateral malleolus Inferior: Sulcus tali (for interosseous lig.) Ant. part: 2 smaller facet Calcaneus Post. part: 1 large facet Calcaneus= Post. talocalcaneal joint (Inversion/eversion) Calcaneus Sup. surface: Talocalcaneal joint Post. facet/Mid. facet: Sustentaculum tali (Groove: Flexor hallucis longus)/Ant. facet Ant. surface for Cuboid/Calcaneal tuberosity: Calcaneal tendon (Achilles tendon) Navicular Transverse tarsal joint/Tuberosity: Tibialis posterior Cuboid Transverse tarsal joint/Tarsometatarsal joint/Groove: Peroneus longus Cuneiform Tarsometatarsal joint/Med., intermedial. & lat. Metatarsals Transverse metatarsal ligament 28 Phalanges The arches of the foot Longitudinal arch: Med. & lat., Transverse arch Ankle joint: Tibia + fibula Talus (Flexion/extension) Ligaments: Medial (Deltoid) collateral lig.(Post. tibio-talar lig./Tibio-calcaneal lig./Tibio-navicular lig./Ant. tibio-talar lig.) Tibia + fibula Talus (Flexion/extension) Transverse lig.: Ant. & post. tibiofibular lig. Ligaments: Lateral collateral lig.(Post. talo-fibular lig./Calcao-fibular lig./Ant. talo-fibular lig.) Joint of foot Intertarsal joints (Post. talocalcaneal joint/Transverse tarsal joint)/Tarsalmetatarsal joints/Intermetatarsal joints/Metatarsophalangeal joints/Interphalangeal joints Ligament of foot Bifurcate lig.(Calcaneo-navicular lig./Calcaneo-cuboid lig.) Plantar calcaneo-navicular lig. (Spring lig.)/Long plantar lig./Short plantar lig. Sole of the foot Heel (Calcaneus)/Ball of the foot (Metatarsal) Deep fascia: Med. plantar fascia (Great toe)/Lat. plantar fascia (Small toe)/Mid. plantar fascia (Plantar aponeurosis) Muscles moving the hip joint: Flexors of the hip Psoas major O: LI -L5 vertebrae, I: Lesser trochanter Ventral rami. L2,3 Psoas minor O: Detached upper part of psoas major, I: Pubis Ventral rami. L1 Iliacus O: Pelvic surface of ilium, I: Lesser trochanter Femoral n. (L2-4) Gluteal Region Iliac crests/Posterior superior iliac spine/Ischial tuberosities/Greater trochanter of the femur/Located at the lateral hip/Prominences of the buttocks“Cheeks”of the buttocks/Natal cleft (gluteal cleft) Vertical midline groove/Gluteal fold Horizontal fold below Muscles moving the hip joint: Gluteal muscles Gluteal maximus O: Iliac crest, p.s.i.s., sacrum and coccyx, thoracolumbar fascia, sacrotuberal ligament I: Iliotibial tract, gluteal tuberosity Inf. gluteal n. Extensor / Lat. rotation / Abduction Gluteal medius O: Iliac crest, between ant. & post. gluteal line, I: Greater trochanter Sup. gluteal n. Extensor / Med. rotation / Abduction Gluteal minimus O: Iliac crest, between ant. & inf. gluteal line, I: Greater trochanter Sup. gluteal n. Extensor / Med. rotation / Abduction Tensor fasciae latae O: Lat. a.s.i.s., I: Iliotibial tract (Lat. condyle of tibia) 29 Sup. gluteal n. Flexion (Thigh) / Extension (Leg) / Tense iliotibial tract Piriformis O: Pelvic surface of sacrum, I: Greater trochanter Ventral rami. S1-2 (n. to piriformis m.) Extensor / Lat. rotation / Abduction Obturator internus O: Internal obturator membrane, I: Greater trochanter n. to obturator internus m. Lat. rotation Sup. gemellius O: Ischial spine, I: Tendon of obturator internus m. n. to obturator internus m. Lat. rotation Inf. gemellus O: Ischial tuberosity, I: Tendon of obturator internus m. n. to quadratus femoris m. Lat. rotation Quadratus femoris O: Ischial tuberosity, I: Intertrochanteric crest n. to quadratus femoris m. Lat. rotation Obturator externus O: External obturator membrane, I: Greater trochanter (Trochanteric fossa) Obturator n. Lat. rotation Thigh Three groups of muscles: Quadriceps femoris – anterior thigh (Vastus lateralis – injection site) Adductors – medial thigh Hamstrings – posterior thigh The Femoral Triangle Superior border – Inguinal ligament Inferior borders – Sartorius/Adductor longus Popliteal fossa Diamond-shaped hollow on posterior knee Defined by borders of “hamstring” tendons and gastrocnemius Adductor canal Apex of femoral triangle ~ Hiatus of adductor magnus, Ant.: Sartorius, Post.: Adductor longus & adductor magnus, Lat.: Vastus medialis Femoral vessels, Saphenous n. Femoral triangle Roof: Fascia lata, Above: Inguinal ligament, Lat.: Sartorius, Med.: Adductor longus, Floor: Ilopsoas & Pectineus Femoral sheath Fascia of transversalis & iliopsoas, Femoral vessels and lymphatics Saphenous opening Falciform margin, Great saphenous v. Lat. Intermuscular septum Ant. Compartment (Thigh flexion & leg extension, Femoral n.) 30 Med. Intermuscular septum Med. Compartment (Adduction, Obturator n.) Post. Intermuscular septum Post. Compartment (Thigh extension, Sciatic n.) Muscles of the thigh Sartorius O: a.s.i.s., I: Tibia (Upper med. end) Femoral n. Flexion (Thigh), Lat. rotation (Thigh) Quadriceps femoris Rectus femoris: O: a.i.i.s. Vastus lateralis: O: Lat. linea aspera Vastus intermedialis: O: Body of femur Vastus medialis: O: Med. linea aspera I: Tibial tuberosity Femoral n. Flexion (Thigh: Rectus femoris), Extension (Leg: Quadriceps femoris) Articularis genu O: Most distal part of Vastus intermedialis, I: Joint capsule Gracilis O: Inf. ramus of pubis, I: Med. side of tibia Obturator n. (Ant.) Adduction (Thigh), Flexion (Leg), Med. rotation (Leg) Adductor longus O: Inf. ramus of pubis, ramus of ischium, I: Linea aspera Obturator n. (Ant.) Adduction (Thigh), Flexion (Thigh), Lat. rotation (Thigh) Adductor brevis O: Inf. ramus of pubis, I: Inf. to lesser trochanter Obturator n. (Ant.) Adduction (Thigh), Flexion (Thigh), Lat. rotation (Thigh) Pectineus O: Sup. ramus of pubis (Pecteal line), I: Pecteal line of femur Femoral n. Adduction (Thigh), Flexion (Thigh), Lat. rotation (Thigh) Adductor magnus Adductor part O: Inf. ramus of pubis, I: Linea aspera Obturator n. (Post.) Adduction (Thigh) Hamstring part O: Ischial tuberosity, I: Adductor tuberosity Sciatic n. Extension (Thigh), Lat. rotation (Thigh) Obturator externus O: External obturator membrane, I: Trochanteric fossa Obturator n. Lat. rotation (Thigh) Hamstring muscle: Biceps femoris O: Long head: Ischial tuberosity, Short head: Linea aspera, I: Head of fibula 31 Sciatic n. Extension (Thigh), Flexion (Leg), Lat. rotation (Leg) Semitendinosus O: Ischial tuberosity, I: Inf. to med. condyle of tibia Sciatic n. Extension (Thigh), Flexion (Leg), Med. rotation (Leg) Semimembranosus O: Ischial tuberosity, I: Post. to med. condyle of tibia Sciatic n. Extension (Thigh), Flexion (Leg), Med. rotation (Leg) Popliteal fossa Sup. lat. border: Biceps femoris, Sup. med. border: Semitendinosus & Semimembranosus, Inf. lat./med. border: Gastrocnemius, Base: Popliteus Muscle Groups of the Leg Posterior calf muscles Gastrocnemius and soleus/Calcaneal tendon Anterior compartment muscles Tibialis anterior/Extensor digitorum/Fibularis Intermuscular septa: Crural fascia Ant. intermuscular septum/Post. intermuscular septum/Transverse intermuscular septum Muscles of the leg Tibialis anterior O: Lat. condyle, Lat. surface of tibia, Interosseous memb., I: Med. Cuneiform, 1st metatarsal Deep peroneal n. Dorsiflexion (Foot), Inversion (Foot) Extensor digitorum longus O: Lat. condyle of tibia, Ant. fibula, Interosseous memb., I: Extensor expansion, b. Lat.4 digits Deep peroneal n. Dorsiflexion (Foot), Extension (4 toes) Extensor hallucis longus O: Fibula, Interosseous memb., I: Distal phalanx of great toe Deep peroneal n. Dorsiflexion (Foot), Extension (Great toes) Peroneus tertius O: Fibula, I: Base of 5th metatarsal Deep peroneal n. Dorsiflexion (Foot), Eversion (Foot) Peronens longus O: Fibula, Around lat. malleolus (Groove on cuboid), I: Med. Cuneiform, 1st metatarsal Superficial peroneal n. Plantar flexion (Foot), Eversion (Foot) Peronens brevis O: Fibula, Around lat. malleolus, I: Base of 5th metatarsal Superficial peroneal n. Plantar flexion (Foot), Eversion (Foot) Gastrocnemius O: Lat. & med. condyle of femur, I: Calcaneus Tibial n. Flexion (Leg), Plantar flexion (Foot) Soleus O: Soleal line (Tibia), Fibula, I: Calcaneus 32 Tibial n. Plantar flexion (Foot) (Gastrocnemius + Soleus = Triceps surae) Plantaris O: Lat. condyle of femur, I: Calcaneus Tibial n. Flexion (Leg), Plantar flexion (Foot) Popliteus O: Lat. condyle of femur, I: Post. aspect of upper tibia (Above soleal line) Tibial n. Lat. rotation (Thigh), Med. rotation (Leg) Tibialis posterior O: Post. surface of upper end of tibia and fibula, Interosseous memb., Around med. malleolus I: Tuberosity of navicular, Cuneiform (Med. + intermediate), Base of 2nd, 3rd, 4th metatarsal Tibial n. Inversion (Foot), Plantar flexion (Foot) Flexor digitorum longus O: Post. surface of middle end of tibia, Around med. malleolus I: Base of distal phalanx of Lat.4 digits (Extensor expansion) Tibial n. Flexion (4 toes), Plantar flexion (Foot) Flexor hallucis longus O: Post. surface of middle & distal end of fibula, Around med. Malleolus, Groove b. on caleaneum (Sustentaculum tali) I: Distal phalanx of great toe Tibial n. Flexion (Great toes) Retinaculum Dorsum (Superior extensor retinaculum/Inferior extensor retinaculum: Y-shaped) Peroneal retinaculum: (Tendons of pero. long.& brev.) Flexor retinaculum: Restricting those passing behind med. malleolus to the sole (Tibialis post., Flex. dig. long. & Flex. hall. long.) Muscles of the foot (Dorsum) Extensor digitorum brevis O: Calcaneus & inf. extensor retinaculum, I: 2nd, 3rd & 4th phalanges Deep peroneal n. Extension (2nd, 3rd & 4th Toes) Extensor hallucis brevis O: Calcaneus & inf. extensor retinaculum, I: Great toe (Prox. phalanx) Deep peroneal n. Extension (Great toe) Plantar muscles: 4 layers (Med. or Lat. plantar n.) Muscles of the foot (Sole) 1st layer: (All from calcaneus) Flexor digitorum brevis O: Calcaneus, I: 2nd ~ 5th mid. phalanges Med. plantar n. Flexion (2nd ~ 5th toes) Abductor hallucis O: Calcaneus, I: Great toe (Prox. phalanx) Med. plantar n. 33 Abduction (Great toe), Flexion (Great toe) Abductor digiti minimi O: Calcaneus, I: Small toe (Prox. phalanx) Lat. plantar n. Abduction (Small toe), Flexion (Small toe) 2nd layer: 2nd layer: Tendon of Flexor digitorum longus/Flexor hallucis longus Quadratus plantae (Flexor accessories) O: Calcaneus, I: Tendon of flexor digitorum longus Lat. plantar n. Flexion (Toes) Lumbricals O: Tendon of flexor digitorum longus, I: Med. side of extensor expansion Med. plantar n. (1st), Lat. plantar n. (2nd, 3rd, 4th) Flexion (Toes) 3rd layer: (All are short) 3rd layer: Flexor hallucis brevis O: Cuboid, Lat. cuneiform, I: Great toe (Med. & lat. prox. phalanx) Med. plantar n. Flexion (Great toe) Flexor digiti minimi brevis O: 5th metatarsal, I: Small toe (Lat. prox. phalanx) Lat. plantar n. Flexion (Small toe) Adductor hallucis Transverse head: O: Metatarsophalangeal joint Oblique head: O: 3rd ~ 5th metatarsals I: Great toe (Lat. prox. phalanx) Lat. plantar n. Adduction (Great toe), Flexion (Great toe) 4th layer: Plantar interossei : 3 O: 3rd ~ 5th metatarsals, I: 3rd ~ 5th toes (Med. prox. phalanx) Lat. plantar n. Adduction (3rd ~ 5th toes) Dorsal interossei: 4 O: Metatarsal space, I: 2nd toe (Med. prox. phalanx), 2nd ~ 4th toes (Lat. prox. phalanx) Lat. plantar n. Abduction (Toes) Tibialis post. tendon: (Tuberosity of navicular and cuneiform) Inversion Peroneus longus tendon: (1st metatarsal and medial cuneiform) Evertion Lumbar plexus Ventral rami of L1-4 with gray rami communicantes from sympathetic trunk Iliohypogastric n. (L1)/Ilioinguinal n. (L1)/Genitofemoral n. (L1-2)/Lat. femoral cutaenous n. (L2-3)/Femoral n. (L2-4)/Obturator n. (L2-4)/Lumbosacral trunk (L4-5) Supplies: Abdominal wall, External genitals, Anterior/medial thigh Lumbosacral plexus (Lumbosacral trunk + Sacral Plexus (Ventral rami of S1-4)) Superior gluteal n. (L4-S1)/Inferior gluteal n. (L5-S2)/Muscular nerves (n. to piriformis m./n. to 34 obturator internus m./n. to quadratus femoris m.)/Sciatic n. (L4-S3) (Supplies: Post thigh, All below knee)/Pudendal n. (S2-4) Supplies: Buttocks, Perineum, Part of lower limbs Skin innervation of lower limb: Dermatome Principles: Ventral side: Lumbar, Dorsal side: Sacral, Genital / Perineum: Sacral Skin innervation of Gluteal region Sup. clunial n.: Lumbar plexus/Mid. clunial n.: Sacral plexus/Inf. clunial n.: Sacral plexus (Post. femoral cutaneous n. : Sacral plexus) Nerves in lower limb Nerves in Thigh Muscular nerves Ant.–Femoral n., Med.–Obturator n., Post.–Sciatic n. (Fibular (Peroneal) n., Tibial n.), Cutaneous nerves (Post. femoral cutaneous n.) Popliteal fossa Thigh: Sciatic n. Common fibular (peroneal) n. Popliteal fossa Lat. sural cutaneous n. Communicating fibular n. Tibial n. Popliteal fossa Med. sural cutaneous n. Leg: Common peroneal (Fibular) n. Popliteal fossa Superficial peroneal n. Deep peroneal n. Lat. sural cutaneous n. Communicating peroneal n. Tibial n. Popliteal fossa Med. sural cutaneous n. Sural n. Dorsum of foot: Common peroneal (Fibular) n. Popliteal fossa Superficial peroneal n. Deep peroneal n. (Extensor digitorum brevis) Branches of Common iliac arteries Internal iliac a. Posterior trunk Iliolumbar a./Lat. sacral a./ Sup. gluteal a. Superficial br. Deep br. Sup. br. Inf. br. Inf. gluteal a. Anterior trunk Sup. vesical a./Inf. vesical a./Mid. rectal a./Obturator a. Internal pudendal a. (Uterine a., Vaginal a. (female)) 35 External iliac a. Femoral a. Profunda femoral a. Med. femoral circumflex a. Lat. femoral circumflex a. Descending br. Perforating aa. Descending genicular a. Ant. tibial a. Ant. tibial recurrent a. Popliteal a. Sup. med. genicular a. Sup. lat. genicular a. Inf. med. genicular a. Inf. lat. genicular a. Middle genicular a. Dorsum of foot Ant. tibial a. Dorsalis pedis a. Deep plantar a. Arcuate a. Perforating aa. Sole of foot Post. tibial a. Med. plantar a. Lat. plantar a. Plantar arch Common Iliac Vein Internal iliac v. Sup. gluteal v./Inf. gluteal v./Obturator v./Internal pudendal v. Rectal plexus/Vesical plexus/Prostatic plexus or uterine plexus, vaginal plexus External iliac v. Superficial v.: Great saphenous v./Small saphenous v. Deep v.: Femoral v./Popliteal v./Ant. tibial v./Post. tibial v./Peroneal v./Med. & Lat. plantar v./Venous arch Inferior vena cava Common iliac v. External iliac v. Femoral v. Great saphenous v. Popliteal v. Small saphenous v. Ant. tibial v. Peroneal v. Post. tibial v. Med. plantar v. Lat. plantar v. Venous arch 36 Chapter 3 Development of the Skeletomuscular system Learning Objective 本課程主要讓同學能瞭解: 1. 脊柱(vertebral column)是如何發育來的? 2. 肢芽(limb bud)的發育來自何處? 何構造誘導它們生成? 3. 何謂 AER?它於四肢發育時扮演和重要角色? 4. 四肢發育時有三個重要的軸心,它們如何建立四肢的 3D 結構? 5. 有哪些訊息傳遞分子(factors signal)主導肢芽的產生? 6. 三種不同種類的肌肉(骨骼肌、平滑肌、心肌)的發育過程。 7. 骨骼肌肉組織於發育過程中所常見的異常疾病(malformation)。 1. Mesoderm revision: 1) Paraxial mesoderm: a. The area immediately lateral to the notochordal process becomes thickened as paraxial mesoderm b. Lateral to paraxial mesoderm is a zone of intermediate mesoderm c. The peripheral layer which enters to the margins of germ disc and becomes continuous with extraembryonic mesoderm is the lateral plate mesoderm 2) Development of somites a. About the 17th day --- development the paraxial mesoderm b. About the 20th day --- somites c. 42 to 44 somites are formed (8 cervical , 12 thoracic , 5 lumbar , 5 sacral, 8(10) coccygeal ) 2. Development of vertebrae 1). The formation of bone involves: a. the mesenchymal cells differentiating and migrating from the sclerotome to the region of the presumptive vertebrae and ribs b. During 4 wks cells from sclertomes migrate in 3 directions: a) Ventromedially: around the notohord forms the vertebral body b) Dorsally: around the neural tube forms the vertebral arch c) Ventrolaterally: into the body wall forms the costal process (ribs) c. During 6 wks chondrification centers appear in each vertebrae 2). Development of vertebrae body Cervical region: 8 somites form only 7 vertebrae 37 a) Cranial half of the 1st sclerotome fuses with the cranial mesenchymal tissue to form the occipital bone. b) The caudal half of the 1st sclerotome fuses with the cranial half of the 2nd sclerotome to form the first vertebra. c) The caudal half of the second vertebra fuses with the cranial half of the third vertebra to form the second vertebra. d) This pattern continues until the caudal part of the 8th sclerotome fuses with the cranial portion of the first thoracic sclerotome to form the first thoracic vertebra. 3. Development of intervertebral discs a. Densely packed cell move cranially to the middle part of each segments b. Form peripheral part – annulus fibrosus c. Enclosed notochord expands and undergo mucoid degeneration d. Form central part –nucleus pulposus 4. Process of chondrification a. 2 centers of chondrification in each centrum appear b. Fuse together at the end of embryonic period (8th week) form cartilaginous centrum – Centers of chondrification appear in neural arhes and fuse with each other and centrum – Chondrification spreads until a cartilaginous vertebral column formed c. Ossification of vertebral column Comprises of 2 stages: a). primary ossification center b). secondary ossification center d. Primary ossification center: a). Time of development at the end of 8th week b). Number: Ⅰ. 3 ossification centers are present by the end of embryonic period Ⅱ. one in the centrum Ⅲ. one in the neural arch e. Secondary ossification center a). Time of development: after puberty b). Number: the 5 secondary ossification center appears at: - tip of spinous process - tip of each transverse process - superior rim of the vertebral body - inferior rim of the vertebral body 38 @ Clinical Considerations: Spina bifida: - is a developmental birth defect caused by the incomplete closure of the embryonic neural tube - the most common location of the malformations is the lumbar and sacral areas - The terms spina bifida and myelomeningocele are usually used interchangeably Lumbar sacralization/ sacral lumbolization - A developmental abnormality in which the first sacral vertebra becomes fused with the fifth lumbar veterbra § Development of Appendicular Skeleton A. Limbs development time frame: 1. At about day 28 (4 weeks), limb buds appear as a paddle-shaped mesenchymal condensation. The mesenchyme is derived from the somatic mesoderm and is overed by a layer of ectoderm. 2. The arm buds develop opposite the lower six cervical and upper two thoracic segments. 3. The leg buds develop opposite the lower four lumbar and upper three sacral segments. 4. The ectoderm at the apex of the limb bud becomes thickened and is known as the apical ectodermal ridge. The apical ridge exerts its inductive influence on the loose mesenchyme of the limb bud which rapidly begins to grow and differentiate into cartilaginous elements. 5. As the limb bud elongates, its distal portion becomes flattened to form hand or foot plates which further develop radial grooves. 6. The tissue in the radial grooves disappears (programmed cell death; Apotosis), resulting in the separation of the fingers. Meanwhile, constrictions appear in the proximal part of the limb to divide it into two portions. 7. Limb rotation at 7th week. 8. The cartilaginous models formed (at 6 weeks) in the limbs undergo endochondral ossification to give rise to the bones at 8th week. 9. The primary ossification centers of the limb bone appear at 12 weeks. B. What Directs Limb Development? Without the AER the limb will not develop. If the AER is removed surgically, only the parts that have been determined already develop limbs development 1. The upper limbs earlier than lower limbs (1day) 2. The upper limbs develop opposite the lower six cervical and upper two thoracic segments. 39 3. The lower limbs develop opposite lower four lumbar and upper three sacral segments. 4. 3 developmental axes decide the directions of limb. proximal/distal (base of limb / digits): by AER; FGF8, FGF4, 23 different Hox genes ventral/dorsal (palm/ dorsum of hand): by ectoderm; Wnt-7a gene anterior/posterior (1st to 5th digits): by ZPA ; Sonic Hedgehog (SHH) @ Clinical Considerations: Amelia: complete absence of one or more limbs Meromelia: partial absence of one or more limbs Micromelia: All of the segments of the limbs are present, the limbs are very short Polydactyly: the presence of extra digits Syndactyly: fusion of the digits Cleft foot: one or more central digits are missing. 3. Development of Skeletal muscle The skeletal muscle is derived from the mesenchyme of myotomes, somatic mesoderm, and the branchial arches. 1. Myotomes 1) Myotomes, which are separated from the dermomyo tomes, increase in thickness and their cells differentiate into myoblasts. Myoblasts elongate, aggregate into parallel bundles, and fuse to form large fibers. 2) The nuclei, which are initially situated in the center, move to the periphery of the cell. Meanwhile, myofibrils appear and by the third month cross striations are evident. 3) Some muscles remain segmental (intercostals), but most myoblasts migrate away from the myotomes to form non-segmented muscles. 4) This muscular tissue, as yet undifferentiated, splits into small dorsal epaxial division (epimere) and large ventral hypaxial division (hypomere) components. 5) Myoblasts from the epaxial division form the extensor muscles of the neck, the extensor muscles of the vertebral column, and the extensor muscles of the lumbar region. 6) Myotomes from the hypaxial division give rise to the following: In the neck, myotomes form scalene, prevertebral, and genohyoid muscles. In t he thorax they form vertebral flexor muscles, which lat er split to form the internal and external intercostal, and transverse thoracic muscle. In the abdominal region the mesenchyme fuses to form three muscle layers: External oblique, Internal oblique, Transverse abdominis In the lumbar region myoblasts again fuse to form quadratus lumborum. From the ventral tip of the hypomere a longitudinal muscular column arises 40 which forms the infrahyoid in the cervical region, the sternalis (which normally disappears later) in the thoracic region, and the rectus abdominis in the abdominal region. 7) Subsequently, epaxial divisions are innervated by dorsal primary rami and the hypaxial divisions receive the primary ventral rami of the nerves. 4. DEVELOPMENT OF SMOOTH MUSCLES 1) Differentiate from splanchnic mesenchyme surrounding the endoderm of the primordial gut and its derivatives 2) the walls of many blood and lymphatic vessels arises from somatic mesoderm 3) The muscles of the iris(sphinicter and dilator pupillae) and the myoepithelial cells in mammary and sweat glands from ectoderm 4) The first sign of differentiation of smooth muscle is the development of elongated nuclei in spindle- shaped myoblasts 5. DEVELOPMENT OF CARDIAC MUSCLES 1). It is from the lateral splanchnic mesoderm surrounding the developing heart tube 2). Cardiac myoblasts: differentiate from the primordial myocardium. 3). Heart muscle is recognizable in the 4th week. 4). Cardiac muscle fibers arise by differentiation and growth of single cells. 5). These atypical cardiac muscle cells(purkinje fibers) form the conducting system of the heart. 41 Chapter 4 Bone & Cartilage 1. Cartilage 1) Structural components: a. Cartilage cells (chondrocytes from chondroblast) b. Cartilage matrix(intercellular matrix) a) Fibers: Collagen fibers and elastic fibers. b) Ground substance c. Types of cartilage: a) Hyaline cartilage b) Elastic cartilage c) Fibrous cartilage. 2) Perichondrium a. Composed of 2 layers: a) Outer fibrous layer- Dense fibroelastic tissue, more cellular adjacent to cartilage, rich in blood vessel. b) Inner cellular layer b. Functions: a) Supply the nuttiest to the cartilage from it blood vessel. b) Regeneration. 3) Histogenesis of hyaline cartilage 2. Bone(骨) 1) Structural components of the bone tissue (osseous tissue) a. Bone cells-osteocytes, cell body in lacuna. b. Bone matrix-organic and inorganic substance. 2) Types of bone tissue a. Based on macroscopic structure (gross observation) of a bone of the adult a) Spongy bone (cancellous bone or trabecular bone) b) Compact bone (dense bone) b. Based on microscopic structure a) Immature bone b) Mature bone 4 types: a. Outer circumferential lamellae b. Haversian system c. Inner circumferential lamellae d. Interstitial lamellae 3) Associated connective tissue a. Periosteum b. Endosteum 4) Blood supply: blood vessel etc. trapped within bone. 5) Bone formation Essential method of bone formation (during embryonic period) a) Intramembranous ossification- In mesenchyme, ossification centers appear. b) Endochondral ossification-Cartilagenous model. 42 Chapter 5 Muscle Tissue Types: 1. Skeletal muscle 2. Cardiac muscle 3. Smooth muscle Structural components : 1. Muscle cells (fibers) 2. Connective tissue containing blood vessels and nerves. Skeletal muscle Connective tissue: 1. Endomysium - delicate layer of reticular fibers that surrounds individual muscle fiber. 2. Perimysium - dense connective tissue that surrounds a group of fibers to form a bundle or fascicle. 3. Epimysium - dense connective tissue that surrounds the collection of fascicles that form a muscle. Skeletal muscle fibers: 10 to 100 um, cyclindrical, multinucleate, striations. 1. Plasma membrane (sarcolemma) Covered by external (basal) lamina. Transverse (T) tubules: Tubular invaginations of sarcolemma at A-I junctions that penetrate deep into the interior of fibers crossing many myofibrils. Two per sarcomere. Spread excitation impulse of muscle contraction. 2. Sarcoplasm All of the common organelles are found. - Mitochondria (sarcosomes) congregate in juxtanuclear sarcoplasm; few in white fiber, many in red fibers. - Endoplasmic (sarcoplasmic) reticulum: A specilized smooth endoplasmic reticulum, form a tubular network surrounds the myofibrils. i. Longitudinal sarcotubules Parallel with myofibrils. Transport calcium from the sarcoplasm back into the lumen of reticulum during muscle relaxation. ii. Junctional reticulum 43 Expanded transverse cisternae (terminal cisternae) formed by lateral anastomose of longitudinal sarcotubules. Storage of calcium. 2 parallel terminal cisternae and an intervening T-tubule form triad at A-I junction. - Myofibrils: Contractile elements of skeletal muscle fibers. Show cross striations, which responsible for the striated, appearance of a striated muscle fibers. Bound to one another side by side by desmin intermediate filaments, anchored to the sarcolemma by various proteins, e.g., dystrophin. Each fibril consists of a chain of sarcomeres, which show light and dark bands. Adjacent sarcomeres are joined at Z line. Each sarcomere is composed of two sets of parallel and partly overlapping myofilaments; thick filaments and thin filaments (the ratio is 1 to 2 or 1 to 4). Thick filaments are in the center of sarcomere, thin filaments externd partway into thick filament from two ends (Z line) of sarcomere. Dark (anisotropic, A) band - the region where thick and thin filaments overlap. Light (isotropic, I) band - both sides of dark band where consist of only thin filaments. Thick filaments: 15 nm in diameter. Composed of myosin. Held in the center of the sarcomere and anchored their ends to the Z line by titin protein. Isolated thick filament shows: central smooth segment (forms the H-band in the center of A-band); lateral short projections known as cross bridges (each sorresponds to the head of myosin molecule). Thin filaments: 8 nm in diameter. Composed of actin, tropomyosin, and troponin. Anchored their ends to Z line by α-actinin. Innervation: 1. Motor innervation Motor end plate - the contact made by a terminal branch of axon with a muscle fiber (described, in nervous tissue). Motor unit - formed by a motor neuron (a single nerve fiber) and all the muscle fiber or fibers it innervates. 2. Sensory innervation i. Interstitial endings in the connective tissue between muscle fibers. 44 ii. Neuromuscular (muscle) spindles (described in the nervous tissue). iii. Neurotendinous organs (Golgi tendon organs). Regeneration: The new cells may be derived via mitotic activity of existing smooth muscle cells, as in gastrointestinal and urinary tracts, or from undifferentiated pericytes accompanying some blood vessels. Muscle-tendon (myotendinous) junction: Connective tissue elements of the muscle cells are continuous with the tendon. 1. at junction, the end of the muscle cells become large numbers of folds and tapering processes that interdigitate with the collagen fibers of the tendon (collagen fibers connect with reticular fibers of endomysium). 2. at end of muscle cells, fine filaments from the external lamina transverse the sarcolemma and mixed with subsarcolemmal cytoskeletal filaments in which thin filaments anchored. Cardiac muscle Found in the wall of the heart (myocardium) and the base of the large veins that empty into the heart. 3 kinds: 1. Myocardial contraction tissue 2. Myocardial conduction tissue 3. Myocardiac endocrine cells Myocardial contraction tissue Formed by branching and anastomosing fibers (cardiac myocytes). cardiac muscle fibers (cardiac myocytes): 1. Sarcolemma Covered by external lamina. - Transverse (T) tubules are located at Z- lines, larger than those in skeletal muscle fibers. Only one per sarcomere. For influx of extracellular calcium. - Intercalated disk: Junctional complex between cardiac muscle fibers. i. Transverse portion Desmosomes (macula adherens), sites of anchorage of intermediate filaments. Fascia adherens, sites of anchorage of thin filaments, form the greater part of the disk. (ribbon-like adhesions) ii. Longitudinal portion Gap junction. 2. Sarcoplasm More abundant, cell organelles and inclusions are concentrated at the pole of the 45 nucleus. - Sarcoplasmic reticulum: Not well developed, has no terminal cisternae. Junctional saccules - small flattened saccules that make junctional contact with T-tubules forming diad at Z-lines. Storage of calcium. Copular reticulum - small cisternae of superficial reticulum that connected directly to sarcolemma. Storage of calcium. - Myofibrils: Have the same types and arrangement of the contractile filaments as skeletal muscle fibers, but without clearly defined limits. 3. Nucleus: One or two, ovoid, centrally located. Innervation: 1. Motor nerve endings Synapse end passant (synapse by pass) (described in nervous tissue). 2. Sensory endings Nerve fibers ramify in connective issue between bundles of muscle fibers and end near the surface of the muscle fibers without specialized contact. Myocardiac endocrine cells: Specialized myocytes located mainly in the atria. Presence of membrane-bounded dense granules (atrial granules) in the pole of the nucleus. The granules contain the precursors of hormone, atrial natriuretic peptides (ANP). The hormone causes vasodilatation, lowing of blood pressure and decrease blood volumn. Myocardial conducting tissue (described in cardiovascular system) Regeneration Cardiac muscle cells have no regenerative capacity Smooth muscle Types: 1. Visceral smooth muscle (single unit smooth muscle) Forms sheets or bundles in the wall of intestine and uterus ect. Not every cell is innervated by efferent nerve ending. 2. Multi-unit smooth muscle Such as sphincter pupillae, in the wall of vas deferens. Each cell is innervated by efferent nerve ending. Smooth muscle fibers: Spindle-shaped cells, an elongated nucleus situated in central portion. 1. Sarcolemma 46 Covered by external lamina. - Gap junctions, provide the cell to cell communication, (nexus). - Dense plaques, the sites achoring of contractile actin filaments and cytoskeletal filaments; formed mainly of α-actinin. - Sarcolemmal vesicles (caveolae) - may function in release and sequestering of calcium ions. 2. Sarcoplasm Organelles are at the pole of the nucleus. - Myofilaments: Thin filaments: composed of actin and tropomyosin (absence of troponin) Thick filaments: Composed of myosin molecules, but they appear to form only when necessary for contraction. Single myosin molecule have folded into a compact configuration, they are not able to assemble into filaments efficiently. Light-chain kinase catalyzes the phosphorylation of myosin molecules to assemble into filaments. Thin and thick filaments do not form distinct myofibrils. The organization of the thin and thick filaments is poorly understood. - Dense bodies, the sites of anchoring of thin filaments and intermediate filaments, composed of α-actinin. - Sarcoplasmic reticulum, few reticulum lying just beneath the sarcolemma are associated sarcolemmal vesicles. Innervation: 1. Motor endings Synapse end passant 2. Sensory endings Nerve fibers ramify in connective tissue between bundles of muscle fibers and end near the surface of the muscle fibers without specialized contact. Regeneration Skeletal muscle cells have no regenerative capacity, the tissue can regenerate by mitotic activity of satellite cells. 47 Chapter 6 Skeletal Muscle Physiology 1. Classification of muscles 1). Skeletal muscle: attached to skeleton, striated, voluntary, controlled by motor neurons 2). Cardiac muscle: heart, striated, involuntary, controlled by Autonomic nervous system (ANS), hormones and stretch. 3). Smooth muscle: hollow organs, nonstriated, involuntary, controlled by ANS, hormones, local chemicals and stretch 2. Structure of the Contractile Unit in Skeletal Muscle 1). Skeletal muscles and structures: a. Formed by Multinucleated muscle fibers(多核肌纖維). b. Diameter: 10-l00μm; length: up to 20 cm 。 c. Tendon (肌腱):a bundle of collagen fibers by which muscle are linked to bones. d. have light and dark bands under the microscope --- Striated muscles (橫紋肌) e. Myofibrils (肌原纖維) :the cylindrical bundles (1-2 μm in diameter) form by parallel arrangement of thick filaments (粗絲 ) and thin filaments (細絲) (Fig. 9-2). f. Fig. 9-2: A band (暗帶), I band (明帶), Z line (間板), H zone, M line (中線) and Sarcomere(肌節). g. Scaffold(支架) proteins: Titin, actinin and dystrophin (Duchennec Muscular Dystrophy; Fig. 9-31) h. Contractile proteins: 1). Thin filaments (細絲): Actin (肌動蛋白) + Tropomyosin (肌旋蛋白); with regulatory protein Troponin (親肌球蛋白) in between. Transmit force. 2). Thick filaments (粗絲): formed by Myosin (Myosin II; 肌凝蛋白); able to Generate force. i. Cross bridges (連接橋): the thick filament called myosin is actually a polymer of myosin molecules, each of which has a flexible cross-bridge that binds ATP and actin. Cross bridges have opposite orientations on two sides (reverse polarity) 2). Molecular Mechanisms of Skeletal Muscle Contraction (骨骼肌收縮的機 制) --- Sliding-Filament Mechanism (肌絲滑動機制) a. Contraction (收縮): myosin binds to actin, and slides it, pulling the Z-lines closer together, and reducing the width of the I-bands. (Note that filament lengths have not changed.) b. During the process, the lengths of thin and thick filaments do not change, but the overlapping length of thin and thick filaments increases. A band length: no change; I band length : shorten; H zone length: shorten; Sarcomere: shorten c. Cross bridge cycle (連接橋週期) Fig. 9-8: Step 1: The myosin-binding site on actin becomes available, so the energized cross-bridge binds. Step 2: The full hydrolysis and departure of ADP + Pi causes the flexing of the bound cross-bridge. Step3: Binding of a “new” ATP to the cross-bridge uncouples the bridge. Step 4: Partial hydrolysis of the bound ATP energizes or “re-cocks” the bridge. 48 Each cross-bridge undergoes its own cycle of movement independently of the other cross bridges. ★ The Roles of ATP in the Cross-Bridge Cycle and Rigor Mortis (屍僵) Table 9-1 3. Transmission at the neuro-muscular junction (神經肌肉交接處) (Figs. 9-13, 14 &15) a. Motor units b. Neuromuscular junction and Motor end plate (運動終板) c. Events at the neuromuscular junction: Motor neuron stimulated action potentials Acetylcholine(ACh; 乙醯膽鹼)released at the neuromuscular junction; binds to ACh receptors Endplate potential (EPP; 終板電位) Action Potentials in sarcolemma (肌纖維膜) Synchronous contraction in ALL the muscle fibers in that motor unit 4. Roles of Tropnin(親肌球蛋白) , Tropomyosin (肌旋蛋白), and calcium in contraction. a. Transverse –tubule (T-tubular ) network(橫管)and Sarcoplasmic reticulum (肌漿網)(Fig. 9-11) b. In relaxed skeletal muscle, tropomyosin blocks the cross-bridge binding site on actin. Contraction occurs when calcium ions bind to troponin; this complex then pulls tropomyos in away from the cross-bridge binding site. c. Release and uptake of calcium by the sarcoplasmic reticulum during contraction and relaxation of a skeletal muscle fiber. (Fig. 9-12) d. E-C coupling; 興奮與收縮 Clinical Considerations: E). Disruption of neuromuscular signaling: i). Curare (箭毒): strongly binds to nicotinic ACh receptors, but it dose not open their ion channels and is not destroyed by Acetylcholinesterase, no EPP, no muscle contraction; antagonist. ii). Clostridium botulinum (肉毒桿菌): block the release of ACh from nerve terminal; flaccid paralysis (鬆弛性麻痺); correction of strabismus (斜視). iii). Acetylcholinesterase inhibitor (抑制乙醢膽胺酯化酵素的物質) F). Defects in musculoskeletal system: i). Myasthenia gravis (重症肌無力): An autoimmune disease. Antibodies against ACh receptor (the number of released ACh is normal, but numbers of receptors decreased) weakness of muscles. ii). Denervation atrophy (去敏性萎縮): When motor neurons or fibers are injured, muscle will become decrease in size ( muscle fibers replaced by fat and connective tissues). E.g. Poliomyelitis. iii). Hypertrophy (肌肉肥大): Doubling the myofibril’s diameter by adding more sarcomeres. Increase force generation iv). Muscle cramp or spasm (肌肉痙擊): Muscle tetanus contraction because of abnormal firing of the action potential (300 times/per second, hyperactivity). Eg. Defects in central or peripheral motor system, or tetanus toxin (破傷風). v). Hypocalcemic tetany (低血鈣性肌肉強直): When the blood calcium is lower than 40% of normal value more Na+ channels opens membrane depolarization spontaneous action potential muscle 49 cramp. 3. Biophysics of the Contractile System A. Terminology: Tension (張力); Load (承受力); Passive tension (passive elastic property) and Active tension B. Three types of muscle contraction a). Isometric contraction (等長收縮):When a muscle develop tension but dose not shorten. Fig. 9-8 step 2, no shortening of cross bridges. (No thin filament sliding) b). Isotonic contraction (等張收縮):A contraction in which muscle shortens, while the load remains constant. Step 2, sarcomere shortens (thin filaments slide). c). Lengthening contraction (增長收縮) :When the unsupported load on a muscle is greater than the tension being generated by the cross-bridges. Eg. Keen extensors C. Load-Velocity Relation (肌肉承受力-速率的關係) Fig. 9-18 The velocity at which a muscle fiber shortens decreases with increasing loads. The shortening velocity is maximal when there is no load; and is zero when the load is equal to the maximal isometric tension. D. Frequency-Tension Relation: Fig. 9-19 and 9-20 a).Spatial summation and temporal summation b). Tetanus (強直): fused and unfused tetanus E. Length-Tension Relation: Fig. 9-21 Optimal Length (最佳長度, Lo): the length at which the fiber develop the greatest isometric active tension. Muscle tension decrease at both lengths bigger and smaller than Lo. 4. Skeletal muscle Energy Metabolism A. The three sources of ATP production during muscle contraction (Fig. 9-22): a). Phosphorylation of ADP by creatine phosphate (need creatine kinase 肌酸激酶): rapid supply of ATP at onset of contraction b). Oxidative phosphorylation in mitochondria (aerobic glycosis): first 30 min of moderate muscular activity. c). Glycolysis: exercise intensity bigger than 70% ATP breakdown; anaerobic conditions. B. Types of muscle fibers and their characteristics (Table 9-3): a). Maximal velocity of shortening— Slow or fast Slow fibers : Type II vs. Fast fibers : Type I b). ATP forming— Oxidative or glycotic Oxidative fibers: red muscle fibers, myoglobin Glycolytic fibers: white muscle fibers; larger 5. Smooth and Cardiac Muscle A. Structure of smooth muscle (Fig. 9-32 and 9-33) Thick (myosin-based) and thin (actin-based) filaments Tropomyosin : present; Troponin: absent; Dense bodies (緻密體)~ Z-line Sliding filament mechanisms B. Smooth muscle contraction (Fig. 9-34 and 9-35) Calcium ions play major regulatory roles in the contraction of both smooth and skeletal muscle, but the calcium that enters the cytosol of stimulated smooth muscles binds to calmodulin, forming a complex that activates the enzyme that phosphorylates myosin, permitting its binding interactions with actin. 50 C. Inputs that influence smooth muscle contractile activities (Table 9-5) D. Generation of action potential potentials in smooth muscle fibers(Fig. 9-36) Rhythmic membrane potential changes – Pacemaker potential. E). Excitation-Contraction coupling in the cardiac muscle (Fig. 9-40) F). Characteristic of muscle fibers (Table 9-6) Comparing the structures and physiological functions among the skeletal, the smooth and the cardiac muscles. References: 1.Widmaier E.P. et al., 2006, Human Physiology 11th edition. Ch. 9. 授課教材(藝軒)。 2. Ganong WF. 2005, Review of Medical Physiology. 22th edition; Ch. 3. 授課教材(合記代理)。 51 Chapter 7 Synaptic Transmission and the Autonomic Nervous System Learning Objective (Synaptic Transmission): 1). To understand the types of synapses in the human body. 2). To understand the process of synaptic transmission at the chemical synapses, including both chemical and electrical events happening at the pre-synaptic and the post-synaptic structures. 3). To learn the types of the neurotransmitters, the receptors and their functions. 4). The modification of synaptic transmission strength. 1. Synapse: Where neurons talk 1). Synaptic transmission: the process of information transfer at a synapse. Presynaptic vs. Postsynaptic 2). Types of Synapses: electrical synapse vs. chemical synapse 2. Structure and Function of the Chemical Synapses 1). Chemical Synapse: a. Need neurotransmitters (神經傳遞物質) for transmission, influenced by drugs, account for 99% of the synapses at central nervous system (CNS) b. Neuromuscular junction (NMJ): a typical chemical synapse at peripheral nervous system (PNS ) c. Three parts: a). The terminal of presynaptic axon(突觸前神經末梢): Synaptic vesicles; Active zone b). The postsynaptic density(突觸後膜) Receptors c). The synaptic cleft(突觸裂隙): 10-20 nm Unidirectional, synaptic delay (突觸延遲) : 0.2 sec 2). The process of synaptic transmission (Fig. 6-27) a. Neurotransmitter is released through exocytosis a). Vesicle docking: SNAREs proteins -- Synaptotagmin: (Ca++ sensor -- fusion) Clinical Considerations: * Clostridium botulinum (botulism toxin);( 肉 毒 ; flaccid paralysis; “botox”) * Tetanus toxin (spastic paralysis; inhibitory interneurons) b). Ca++ influx c). Fuse of vehicle membrane and neuron plasma membrane: neurotransmitters release d). Membrane recycled by endocytosis b. Vehicle docking and exocytosis proteins: a). v-snare = synaptobrevin; 2). t-snare = Syntaxin and 3). Synaptotagmin 52 3). Electrical Events in Postsynaptic Neurons (Fig. 6-28) a. EPSP: An excitatory postsynaptic potential (EPSP) is a graded depolarization that moves the membrane potential closer to the threshold for firing an action potential (excitement). b. IPSP: An inhibitory postsynaptic potential (IPSP) is a graded hyperpolarization that moves the membrane potential further from the threshold for firing an action potential (inhibition). c. Synaptic Summation: The net post-synaptic membrane potential changes depend on the summation of all synaptic activities affecting the postsynaptic neuron at that time window. Spatial Summation (空間的總合) vs. Temporal Summation (時間的總合) d. Presynaptic facilitation vs. Post-synaptic inhibition 3. Neurotransmitters and neuromodulators 1. Acetylcholine (ACh,乙醯膽鹼類) a. In PNS: NMJ b. In ANS: all preganglionic neurons and postganglionic parasympathetic neurons c. In CNS: e.g. basal ganglion and other pathways; cholinergic neurons defects--- Alzheimer’s disease d. The life cycle of ACh: AChE: Acetylcholinesterase (乙醯膽鹼酯化酵素) • AChE inhibitor : nerve gas or insecticides (parathion) --- decrease in heart rate and blood pressure, respiratory paralysis. e. Receptors fo ACh: a). Nicotinic cholinergic receptors: receptors respond to both ACh and nicotine;ion channels; curare as antagonist (blocker) b). Muscarinic cholinergic receptors:receptors respond to both ACh and muscarine; coupled with G proteins; atropine (阿托品) as antagonist (blocker) 2). Amines or Biogenic Amines (醯胺類) a. Tyrosine derivatives : dopamine (多巴胺, DA)、epinephrine(腎上腺素, Epi) and norepinephrine (正腎上腺素, NE). *Catecholamine:mood (情緒) and blood pressure (血壓) regulation. • Receptors for norepinephrine and epinephrine:α receptors and β receptors. Monoamine oxidase (MAO; 單胺氧化酶) b. Serotonin (血清張力素, 5-HT) and histamine (組織胺). 3). Amino Acids(胺基酸類) a. Excitatory amino acid:glutamate(麩胺酸鹽; in CNS 75% )、aspartate(天門冬酸鹽; visual cortex) Glutamate receptors: a). Ionotropic glutamate receptor: ion channels; AMPA receptors and NMDA receptors; Kinate receptors --- Long-term potentiation (LTP;長期增益效應) b). Metabotropic glutamate receptor: G-protein coupled ; hippocampus and cerebellum; spatial learning c). Inhibitory amino acid:γ-GABA(γ-丁胺酸; in CNS 20%)、glycine(甘胺酸) 53 4). Neuropeptides(胜 肽) Peptidergic; Endogenous opioids (Analgesic): enkephalin(腦啡), Beta-endorphin----jogger’s high; Substance P: pain sensation 4. Modification of synaptic transmission by drugs (synaptic strength) Fig. 6-34 Possible drug effects on synaptic effectiveness: 1). release and degradation of the neurotransmitter inside the axon terminal. 2). increased neurotransmitter release into the synapse. 3). prevention of neurotransmitter release into the synapse. 4). inhibition of synthesis of the neurotransmitter. 5). reduced reuptake of the neurotransmitter from the synapse. (e.g. Prozac) 6). reduced degradation of the neurotransmitter in the synapse. (e.g AChE inhibitor) 7). agonists (evoke same response as neurotransmitter) (e.g curare or atropine) or antagonists (block response to neurotransmitter) (nicotine or muscarine) can occupy the receptors. 8). reduced biochemical response inside the dendrite 5. The Autonomic Nervous System (ANS) 1) Learning Objectives (ANS) a. To understand the functional organization of the nervous system. b. To understand the structural and functional differences between the somatic nervous system and the autonomic nervous system. c. To understand the structural and functional differences between the sympathetic and parasympathetic divisions (including neurotransmitters and receptors.) 2). Differences between sympathetic and parasympathetic divisions a. They leave the CNS at different levels: -- Sympathetic fibers: thoracic (chest) and lumbar regions -- Parasympathetic fibers: brainstem (cranial nerves III, VII, IX, and X) and 54 sacral regions b. The location of ganglia: -- Sympathetic: most lie close to the spinal cord (sympathetic trunk); collateral ganglia -- Parasympathetic: lie within or very close to the organs c. Major neurotransmitters (Fig. 6-46) -- To understand the neurotransmitters used in the ANS and receptor involved. d. Physiological functions (Table 6-11) Fight or Flight vs. Rest and Digest References: 1. Widmaier E.P. et al., 2006, Human Physiology 11th edition. Ch. 6. 授課教材(藝軒)。 2. Ganong WF. 2005, Review of Medical Physiology. 22th edition; Chs. 4 and 13. 授課教材(合記 代理)。 55 Chapter 8 Introduction to Autonomic Pharmacology 自主神經系統簡介 一.神經系統之結構 神經系統主要分為兩類: 1. 包含大腦及脊髓之中樞神經系統; 2. 中樞神經系統以外的神經元,就是周邊神經系統。 周邊神經系統又分為兩種: 1. 第一種是傳入神經,也就是感覺神經系統; 2. 第二種是傳出神經,中樞神經藉由傳出神經來控制身體各個部分。 由中樞傳至周邊的神經可分為兩種: 3. 第一種是可以用意志控制的,例如骨骼肌是經由體神經來控制,也就是體神經系 統。 4. 另一種是無法用意志控制的,例如心跳,血壓,胃腸道的運動。這一部份的功能 就是透過自主神經系統來控制,因為這些神經有自主性,不受意志的控制,所以 叫做自主神經系統。 56 二.自主神經系統 A. 兩種不同型態的傳出神經元將中樞神經傳出的神經脈衝傳送到作用器官上: 1. 節前神經元,神經節前的神經元; 2. 節後神經元,神經節後的神經元。 *、神經節指的是在周邊組織,神經細胞聚集的地方。 **、神經元與神經元交接的地方或者是神經元與作用器官交接的地方叫做 Synapse(突觸)。 突觸可分為前後,突觸前的神經纖維釋放出神經傳遞物質(neurotransmitter),由突觸後的受 體(receptor)來接收。細胞以此方式來傳遞訊息;表達作用。 B. 在解剖學的基礎上分為兩類(注意:解剖學的分類就是一種位置上的分類) 5. 交感神經(Sympathetic):其節前神經元從脊髓胸段的第一段到腰段的第三段傳出來[節 前神經元的細胞體(cell body),位於脊髓內,神經纖維(axon)傳至神經節]。傳出的纖 維不是很長,在神經節與節後神經元相接。節後神經元的細胞體位於神經節內,其神 57 經纖維傳到作用的器官,也就是內臟。 副交感神經(Parasympathetic):其節前神經元是從延腦內或者是脊髓薦骨的 2,3,4 段傳出,神經纖維很長,一直傳至位於內臟附近的神經節與節後神經元相接。節後神 經元再傳至內臟。 C. 交感神經及副交感神經在體內分布的位置不一樣,他們在體內的作用也不一樣,他們的 作用大體上可以說是互相對抗。 1. 交感神經的作用在當受到驚嚇想逃時就會顯現出來。而且顯現出一種整體性的反應。 這些作用包括 瞳孔擴張使更多的光線進入視網膜* 支氣管擴張 (使肺部的換氣量增加) 心跳加快,心收縮力增強、血壓上昇 胃腸道的運動降低 體表及內臟器官的血管收縮,但骨骼肌的血管擴張 (使骨骼肌有充分的血流供 應) 增加肝醣的分解,而增加血糖的濃度 2. 副交感神經大部份的作用和交感神經的作用相反。剛剛所說的交感神經興奮作用的反 向就是副交感神經的作用。 3. 雖然大部分的器官都受到兩種神經支配但亦有少數的器官只受一種神經支配, 例如 副交感神經沒有支配血管;而二種神經系統的作用也不全相反,例如二種系統皆增加 唾液腺的分泌。 4. 交感神經與副交感神經在體內保持一種平衡的狀態,一有失調就會造成疾病。通常在 白天或警覺性高時交感神經的活性會較高;夜晚、飯後或睡覺時,副交感神經系統的 活性較高。 *、瞳孔的收縮由兩種肌肉控制,第一種是放射肌, 第二種是環狀肌,當交感神經興奮使放 射肌收縮,瞳孔就會放大。副交感神經興奮則使環狀肌收縮,造成瞳孔縮小。此外,交感調 控遠距離的對焦;副交感則負責近物的對焦。 6. 三.自主神經系統: A. Cholinergic neuron (膽鹼素性神經元): 神經纖維所釋放的傳遞物質為 Acetylcholine (ACh, 58 乙醯膽鹼) B. Adrenergic neuron (腎上腺素性神經元): 神經纖維所釋放的傳遞物質為 Norepinephrine(NE, 正腎上腺素) 自主神經系統透過這兩種神經元來發揮作用。將自主神經系統與上面這二種神經元配合 在一起,(參照圖 3-2) 1. 一般說來,交感節後神經元釋放的傳遞物質為 NE(屬於 Adrenergic neuron);副交感神 經節後神經元釋放的物質為 ACh(屬於 Cholinergic neuron)。因此影響 NE 作用的藥 物,會影響交感神經系統;影響 ACh 作用的藥物則會影響副交感系統。 2. 汗腺的分泌由交感神經系統(解剖名稱)控制,但傳至汗腺的交感節後神經元所釋放的 傳遞物質為 ACh(亦即屬於 cholinergic neuron),因此影響 ACh 作用的藥物,會影響汗 腺的分泌。 3. 整理如下: a. 屬於 Adrenergic Neuron 的神經元有: - 交感神經節後神經元 b. 屬於 Cholinergic Neuron 的神經元有: - 傳至神經節之節前神經元(交感及副交感) - 副交感節後神經元 - 交感傳至腎上腺髓質之神經元* - 交感傳至汗腺之節後神經元 - 體神經元 *、交感神經興奮後會活化腎上腺髓質使其釋放 Epinephrine(腎上腺素),Epinephrine 進入血液 循環分布至全身各處。因此,交感神經興奮後會活化(1)受交感神經元支配的器官;(2)不受神 經元支配但有腎上腺素性受體的器官。 Table 6–1. Some of the Transmitter Substances Found in Autonomic Nervous System (ANS), Enteric Nervous System (ENS), and Nonadrenergic, Noncholinergic Neurons. 1 Substance Pro able Roles Acetylcholine (ACh) The primary transmitter at ANS ganglia, at the somatic neuromuscular junction, and at parasympathetic postganglionic nerve endings. A primary excitatory transmitter to smooth muscle and secretory cells in the ENS. Probably also the major neuron-to-neuron ("ganglionic") transmitter in the ENS. Adenosine triphosphate (ATP) Acts as a transmitter or cotransmitter at many ANS-effector synapses. Calcitonin gene-related peptide (CGRP) Found with substance P in cardiovascular sensory nerve fibers. Present in some secretomotor ENS neurons and interneurons. A cardiac stimulant. Cholecystokinin (CCK) May act as a cotransmitter in some excitatory neuromuscular ENS neurons. Dopamine A modulatory transmitter in some ganglia and the ENS. Probably a postganglionic sympathetic transmitter in renal blood vessels. Enkephalin and related opioid peptides Present in some secretomotor and interneurons in the ENS. Appear to inhibit ACh release and thereby inhibit peristalsis. May stimulate secretion. Galanin Present in secretomotor neurons; may play a role in appetite-satiety mechanisms. GABA ( -aminobutyric acid) May have presynaptic effects on excitatory ENS nerve terminals. Has some relaxant effect on the gut. Probably not a major transmitter in the ENS. Gastrin-releasing peptide (GRP) Extremely potent excitatory transmitter to gastrin cells. Also known as mammalian bombesin. Neuropeptide Y (NPY) Found in many noradrenergic neurons. Present in some secretomotor neurons in the ENS and may inhibit secretion of water and electrolytes by the gut. Causes long-lasting vasoconstriction. It is also a cotransmitter in some parasympathetic postganglionic neurons. Nitric oxide (NO) A cotransmitter at inhibitory ENS neuromuscular junctions; may be especially important at sphincters. Norepinephrine (NE) The primary transmitter at most sympathetic postganglionic nerve endings. 59 Serotonin (5-HT) An important transmitter or cotransmitter at excitatory neuron-to-neuron junctions in the ENS. Substance P (and related "tachykinins") Substance P is an important sensory neuron transmitter in the ENS and elsewhere. Tachykinins appear to be excitatory cotransmitters with ACh at ENS neuromuscular junctions. Found with CGRP in cardiovascular sensory neurons. Substance P is a vasodilator (probably via release of nitric oxide). Vasoactive intestinal peptide (VIP) Excitatory secretomotor transmitter in the ENS; may also be an inhibitory ENS neuromuscular cotransmitter. A probable cotransmitter in many cholinergic neurons. A vasodilator (found in many perivascular neurons) and cardiac stimulant. 60 四.受體(receptor) 突觸後有受體( receptor)來接收突觸前神經纖維所釋放的傳遞物質,這樣子,norepinephrine 或者是 acetylcholine 的作用才能表現出來。 A. 自主神經的受體可分為二大類: 1. Cholinoceptor(cholinergic receptor,膽鹼性受體):與 ACh 結合的受體,可再分為二類: a. Nicotinic receptor (菸鹼受體):因為尼古丁(菸鹼),與這種受體的結合比 acetylcholine 與這種受體的結合強,因此稱此類受體為 nicotinic receptor,。這類 受體位於神經肌肉接合處及自主神經節。 b. Muscarinic receptor (蕈毒鹼受體):Muscarine 為一種毒菇內含的物質,其與這種 receptor 的結合比 acetylcholine 強。位於副交感節後神經元所支配的器官上。 2. Adrenoceptor(adrenergic receptor,腎上腺素受體):與 NE 結合的受體。位於交感節後 神經元所支配的器官上。 B. 受體是一種蛋白質,當傳遞物質與受體結合後,就會活化受體,受體被活化後可能會打 開一些管道(Channel)或者會增加第二轉訊物(second messenger)的產生,進而造成一些細 胞內的反應。 C. 交感神經或副交感神經釋放的物質只有兩種,Acetylcholine 或者是 Norepinephrine,但是 他們產生的作用非常的複雜,非常的多樣性。例如,當交感神經興奮的時候,體表的血 管會收縮,然而供應骨骼肌的血管會放鬆(使更多的血液可以供應骨骼肌的活動,所以可 以應付突發狀況)。交感節後神經元都是一樣釋放 Norepinephrine,但卻使不同部位的血管 產生不一樣的作用! 為什麼會這樣,很簡單,因為受體不一樣。受體不一樣所傳遞的作用 也就不一樣。前述受體(膽鹼性受體、蕈毒鹼受體、腎上腺素受體)皆可再細分為數個亞型, 每個亞型活化後所呈現出的反應不同。 61 Table 6–2. Major Autonomic Receptor Types. Receptor Typical Locations Name Result of Ligand Binding Cholinoceptors Muscarinic M1 CNS neurons, sympathetic postganglionic neuron sites , some presynaptic Formation of IP3 and DAG, increased intracellular calcium Muscarinic M2 Myocardium, smooth muscle, some presynaptic sites; CNS neurons Muscarinic M3 Exocrine glands, vessels (smooth muscle and endothelium); CNS neurons Like M1 receptor-ligand binding Muscarinic M4 CNS neurons; possibly vagal nerve endings Like M2 receptor-ligand binding Muscarinic M5 Vascular endothelium, especially cerebral vessels; CNS neurons Like M1 receptor-ligand binding Nicotinic NN Postganglionic neurons, some presynaptic cholinergic terminals Opening of Na+, K+ channels, depolarization Nicotinic NM Skeletal muscle neuromuscular endplates Opening of Na+, K+ channels, depolarization Alpha1 Postsynaptic effector cells, especially smooth muscle Formation of IP3 and DAG, increased intracellular calcium Alpha2 Presynaptic adrenergic nerve terminals, platelets, lipocytes, smooth muscle Inhibition of adenylyl cyclase, decreased cAMP Beta1 Postsynaptic effector cells, especially heart, lipocytes, brain; presynaptic Stimulation of adenylyl cyclase, increased adrenergic and cholinergic nerve terminals, juxtaglomerular apparatus of cAMP renal tubules, ciliary body epithelium Beta2 Postsynaptic effector cells, especially smooth muscle and cardiac muscle Stimulation of adenylyl cyclase and increased cAMP. Activates cardiac Gi under some conditions. Beta3 Postsynaptic effector cells, especially lipocytes; heart Opening of potassium channels, inhibition of adenylyl cyclase Adrenoceptors Stimulation of adenylyl cyclase and increased cAMP1 Dopamine receptors D1 (DA1), D5 Brain; effector tissues, especially smooth muscle of the renal vascular bed Stimulation of adenylyl cyclase and increased cAMP D2 (DA2) Brain; effector tissues, especially smooth muscle; presynaptic nerve terminals Inhibition of adenylyl cyclase; increased potassium conductance D3 Brain Inhibition of adenylyl cyclase D4 Brain, cardiovascular system Inhibition of adenylyl cyclase 1 Cardiac beta3-receptor function is poorly understood, but activation does not appear to result in stimulation of rate or force. 62 五.自主神經受體及其活化後所呈現的反應 當交感神經或副交感神經興奮,在某一器官活化某一類的受體後,會產生各種不同的生 理作用。 7. Muscarinic receptor 在器官上的受體可以分為 M1、M2、M3。M1 存在於胃壁細胞, M2 見於心臟及平滑肌細胞,M3 於外泌腺及平滑肌上發現,這些亞型受體皆存在於 神經元上。 8. Nicotinic receptor 的受體分為 NM、NG、NB。 9. Adrenergic receptor 的受體大體上可分為1、2、1、2。1 受體主要位於血管平滑 肌上;2 受體位於突觸前;1 受體位於心臟;2 位於支氣管平滑肌上。 交感神經或是副交感神經作用的多樣性就是因為這些不同的受體造成的。而且有很多藥 物是藉由作用在專一的受體上來發揮他的藥效;如果有一個藥物屬於1 adrenoceptor 的 作用劑,那麼這一個藥物應該是一個具有選擇性,只會作用在心臟,增加心跳及收縮力 的藥物。 體內不同器官所具有的腎上腺素及膽鹼素性受體的類型不同,因此當交感或副交感神經 系統興奮時,體內各器官就呈現出多樣性的生理作用(參照表 3-4)。 63 六.影響自主神經系統的藥物 只要會影響 Cholinergic 或 Adrenergic neuron 傳導的藥物,就會影響自主神經系統。因此 介紹藥物之前,需先了解 cholinergic 及 adrenergic neuron 的傳導 相關的名稱,以影響 cholinergic neuron 傳導的藥物為例 a. 作用與 acetylcholine 類似的藥物: - cholinergic agonists(膽鹼性致效劑); - cholinoceptor stimulants(膽鹼性受體刺激劑); - cholinomimetic drugs(擬膽鹼性藥物); - parasympathomimetics(擬副交感神經藥物) b. 阻斷 acetylcholine 作用的藥物: - cholinergic antagonists (膽鹼性拮抗劑); - cholinergic blockers(膽鹼性阻斷劑); - cholinoceptor antagonists (膽鹼性受體拮抗劑); - anticholinergic drugs(抗膽鹼性藥物); - parasympatholytics(副交感神經抑制劑) Table 6–4. Autoreceptor, Heteroreceptor, and Modulatory Effects in Peripheral Synapses.1 Transmitter/Modulator Receptor Type Neuron Terminals Where Found Acetylcholine M2, M1 Adrenergic, enteric nervous system Norepinephrine Alpha2 Adrenergic Dopamine D2; less evidence for D1 Adrenergic 5-HT1, 5-HT2, 5-HT3 Cholinergic preganglionic ATP and adenosine P2 (ATP), P1 (adenosine) Adrenergic autonomic and ENS cholinergic neurons Histamine H3, possibly H2 H3 type identified on CNS adrenergic and serotonergic neurons Enkephalin Delta (also mu, kappa) Adrenergic, ENS cholinergic Neuropeptide Y Y1, Y2 (NPY) Adrenergic, some cholinergic Prostaglandin E1, E2 EP3 Adrenergic Epinephrine Beta2 Adrenergic, somatic motor cholinergic Acetylcholine NM Somatic motor cholinergic Angiotensin II AT1 Adrenergic Inhibitory effects Serotonin (5-HT) Excitatory effects Table 6–5. Steps in Autonomic Transmission: Effects of Drugs. Process Affected Drug Example Site Action Action potential propagation Local anesthetics, tetrodotoxin,1 saxitoxin2 Nerve axons Block sodium channels; block conduction Transmitter synthesis Hemicholinium Cholinergic nerve terminals: membrane Blocks uptake of choline and slows synthesis -Methyltyrosine (metyrosine) Adrenergic nerve terminals and adrenal medulla: cytoplasm Blocks synthesis Vesamicol Cholinergic terminals vesicles Prevents storage, depletes Transmitter 64 storage Reserpine Adrenergic terminals vesicles Transmitter release Many3 Nerve terminal membrane receptors Modulate release -Conotoxin GVIA4 Nerve terminal calcium channels Reduces transmitter release Cholinergic vesicles Prevents release Cholinergic and adrenergic vesicles Causes explosive transmitter release Tyramine, amphetamine Adrenergic nerve terminals Promote transmitter release Cocaine, tricyclic antidepressants Adrenergic nerve terminals Inhibit uptake; increase transmitter effect on postsynaptic receptors Receptors at adrenergic junctions Binds receptors; causes contraction Receptors at adrenergic junctions Binds receptors; prevents activation Isoproterenol Receptors at adrenergic junctions Binds receptors; activates adenylyl cyclase Propranolol Receptors at adrenergic junctions Binds Nicotine Receptors at nicotinic cholinergic junctions (autonomic ganglion, neuromuscular end plates) Binds nicotinic receptors; opens ion channel in postsynaptic membrane Tubocurarine Neuromuscular end plates Prevents activation Bethanechol Receptors, parasympathetic effector Binds and activates muscarinic cells (smooth muscle, glands) receptors Atropine Receptors, parasympathetic effector Binds muscarinic receptors; prevents cells activation Neostigmine Cholinergic synapses (acetylcholinesterase) Inhibits enzyme; prolongs and intensifies transmitter action Tranylcypromine Adrenergic nerve terminals (monoamine oxidase) Inhibits enzyme; increases stored transmitter pool Botulinum toxin -Latrotoxin Transmitter uptake after release 5 Receptor Norepinephrine activation or blockade Phentolamine Enzymatic inactivation of transmitter Prevents storage, depletes 65 receptors; prevents activation Chapter 9 Cholinoceptor-Activating & Cholinesterase-inhibiting Drugs 膽鹼性神經作用藥物 一、Cholinergic Neuron 的神經傳導: 可分為六個步驟 1. 首先 choline 膽鹼被運入細胞內,然後與 Acetyl CoA 反應產生 acetylcholine 2. 之後 acetylcholine 進入儲存小泡(vesicle) 3. 當有動作電位傳至神經末梢時,神經末梢細胞膜上的鈣通道打開,增加胞內鈣離子的 濃度,使突觸小泡與細胞膜結合而釋放 acetylcholine。acetylcholine 的釋放可被 Botulinum Toxin(肉毒桿菌毒素)或 aminoglycoside 抗生素阻斷。 4. 釋放出的 acetylcholine 與突觸後的受體結合藉由改變離子的流動或第二傳訊物的量來 產生作用。 5. Acetylcholine 會被位於突觸的 acetylcholinesterase 水解成 choline 及 acetate 6. 最後,choline 被回收到神經纖維,被再利用。 影響其中任何一個步驟,都會影響 Cholinergic Neuron 的傳導。目前臨床上使用的藥物以影響 第三個步驟為主。 66 二.Cholinergic agonist (膽鹼性致效劑) 1. 就是那些具有與 acetylcholine 相同作用的藥物。當一個藥物與 acetylcholine 的作用類似時,它可以作用在很多地方。它會作用在副交感節後神經纖維 支配的器官、汗腺、肌肉以及交感或副交感神經的神經節等,影響之範圍, 視濃度之高低而定。就藥理學的觀點,藥物最好能專一性(選擇性)的作用 在標的器官。怎樣能使藥物只作用於副交感節後神經纖維所支配的器官而 不影響肌肉或神經節呢? 第一:在器官上,與 acetylcholine 結合的受體是 muscarinic receptor, 但肌肉或神經節上 acetylcholine 的受體是 Nicotinic receptor,所以一個只作用在 muscarinic receptor 的藥物,就具有選擇性。 第二:如果一個藥物對二種 receptor 皆有作用,或是會增加 acetylcholine 的釋放量,則這個藥物不具專一性;但是只要局部給藥就可以限定藥物的 作用範圍,而達到作用的選擇性。 D. 膽鹼性致效劑分類 1. 直接作用型: - 直接對 muscarinic receptor 或/及 nicotinic receptor 作用的藥物 - 藥物稱為 muscarinic agonist 或/及 nicotinic agonist 2. 間接作用型: - 抑制 acetylcholinesterase 的藥物,acetylcholinesterase 被抑制後,神經末梢釋 放出的 acetylcholine 不能被水解,在突觸的量就會增多,作用就會加強。 - 藥物稱為 cholinesterase inhibitors(膽鹼脂抑制劑)或 anticholinesterase drugs(抗膽鹼脂藥物) E. 直接作用劑:作用與活化副交感神經後的作用相同,如增加胃腸道蠕動,縮瞳等 Acetylcholine a. 作用部位太多,而且很快被 acetylcholinesterase 水解掉,臨床上的用途不大 Carbachol A. 對 Muscarinic 及 Nicotinic receptor 皆有作用, B. 不易被乙醯膽鹼水解 C. 用於眼科之縮瞳劑 Bethanechol 1. 只對 Muscarinic receptor 有作用 2. 不會被乙醯膽鹼水解 3. 對胃腸道及膀胱的作用較具特異性 67 4. 用於無張力狀態的膀胱及增加手術後的胃腸蠕動 Pilocarpine 3. 由毛果芸香的樹葉提煉出的生物鹼 5. 只對 Muscarinic receptor 有作用 4. 局部使用可快速降低眼內壓。用於青光眼的治療 Table 7–1 Some Pharmacological Properties of Choline Esters and Natural Alkaloids MUSCARINIC ACTIVITY MUSCARINIC Susceptibility Cardio- GastroUrinary Eye Antagonism NICOTINIC AGONIST to vascular intestinal Bladder (Topical) by Atropine ACTIVITY Cholinesterase Acetylcholine +++ ++ ++ ++ + +++ ++ Methacholine + +++ ++ ++ + +++ + Carbachol – + +++ +++ ++ + +++ Bethanechol – ± +++ +++ ++ +++ – Muscarine – ++ +++ +++ ++ +++ – Pilocarpine – + +++ +++ ++ +++ – Table 7–3. Effects of Direct-Acting Cholinoceptor Stimulants. Only the Direct Effects Are Indicated; Homeostatic Responses to These Direct Actions May Be Important (See Text). Organ Response Eye Sphincter muscle of iris Contraction (miosis) Ciliary muscle Contraction for near vision Heart Sinoatrial node Decrease in rate (negative chronotropy) Atria Decrease in contractile strength (negative inotropy). Decrease in refractory period Atrioventricular node Decrease in conduction velocity (negative dromotropy). Increase in refractory period Ventricles Small decrease in contractile strength Blood vessels Arteries Dilation (via EDRF). Constriction (high-dose direct effect) Veins Dilation (via EDRF). Constriction (high-dose direct effect) Lung Bronchial muscle Contraction (bronchoconstriction) Bronchial glands Stimulation Gastrointestinal tract Motility Increase Sphincters Relaxation 68 Secretion Stimulation Urinary bladder Detrusor Contraction Trigone and sphincter Relaxation Glands Sweat, salivary, lacrimal, nasopharyngeal Secretion F. 間接作用劑:此類藥物依抑制乙醯膽鹼脂的方式分為可逆性及不可逆性 可逆性 Neostigmine 2. 為四級胺化合物,不能透過血腦障壁,無中樞神經系統作用。對眼角膜滲 透力差,不應用於眼科 3. 刺激膀胱及胃腸道的蠕動,治療手術後尿滯留、腹脹 4. 能改善重症肌無力(myasthenia gravis)的症狀 Edrophonium 5. 作用與 neostigmine 類似 6. 作用時間極短 (可逆性作用且腎臟能迅速清除此藥) 7. 靜脈注射用於重症肌無力的診斷(若注射此藥無法改善症狀,則可能是其他 因素導致肌肉收縮無力) Physostigmine,毒扁豆鹼 d. 可通過血腦障壁,產生中樞神經興奮作用 e. 用於青光眼的治療 (pilocarpine 較佳) f. Table 7–4. Therapeutic Uses and Durations of Action of Cholinesterase Inhibitors. Uses Approximate Duration of Action Myasthenia gravis, ileus, arrhythmias 5–15 minutes Alcohols Edrophonium Carbamates and related agents Neostigmine Myasthenia gravis, ileus 0.5–2 hours Pyridostigmine Myasthenia gravis 3–6 hours Physostigmine Glaucoma 0.5–2 hours Ambenonium Myasthenia gravis 4–8 hours Demecarium Glaucoma 4–6 hours Organophosphates Echothiophate Glaucoma 100 hours 69 10. 不可逆性:有機磷化合物 Isoflurophate 3. 與 acetylcholinesterase 形成不可逆性的共價結合 4. 用於青光眼,作用時間 7 天 農藥(Parathion),神經毒氣(Sarin) 中毒症狀(表 4-7): - 蕈毒鹼性(副交感過度興奮的症狀):腹瀉、縮瞳、支氣管痙攣、流涎、盜汗、 心博減慢等 - 菸鹼性:肌肉麻痺 - 中樞:興奮、顫抖、意識混亂 11. 乙醯膽鹼之再活化- Pralidoxime(PAM) G. 復活膽鹼酯 Table 8–1 Chemical Classification of Representative Organophosphorus Compounds of Particular Pharmacological or Toxicological Interest General formula Group A, X = halogen, cyanide, or thiocyanate leaving group; group B, X = alkylthio, arylthio, alkoxy, or aryloxy leaving group; group C, thionophosphorus or thio-thionophosphorus compounds; group D, pyrophosphates and similar compounds; group E, quaternary ammonium leaving group. R1 can be an alkyl (phosphonates), alkoxy (phosphorates) or an alkylamino (phosphoramidates) group. GROUP STRUCTURAL FORMULA COMMON, CHEMICAL, AND OTHER NAMES COMMENTS A DFP; Isoflurophate; diisopropyl fluorophosphate Potent, irreversible inactivator Tabun Extremely toxic "nerve gas" Ethyl N-dimethylphosphoramidocyanidate Sarin (GB) Extremely toxic "nerve gas" Isopropyl methylphosphonofluoridate Soman (GD) Extremely toxic "nerve gas" Pinacolyl methylphosphonofluoridate B Paraoxon (MINTACOL), E 600 Active metabolite of parathion O,O-Diethyl O-(4-nitrophenyl)-phosphate Malaoxon Active metabolite of 70 C O,O-Dimethyl S-(1,2-dicarboxyethyl)-phosphorothioate malathion Parathion Employed as agricultural insecticide, resulting in numerous cases of accidental poisoning; phased out of agricultural use in 2003. O,O-Diethyl O-(4-nitrophenyl)-phosphorothioate Diazinon, Dimpylate O,O-Diethyl O-(2-isopropyl-6-methyl-4-pyrimidinyl) phosphorothioate Chlorpyrifos O,O-Diethyl O-(3,5,6-trichloro-2-pyridyl) phosphorothioate Malathion D Insecticide in wide use for gardening and agriculture; now banned for indoor use and being phased out of all outdoor use in 2005 Insecticide with restricted use in consumer products and limited to nonresidential settings O,O-Dimethyl S-(1,2-dicarbethoxyethyl) phosphorodithioate Widely employed insecticide of greater safety than parathion or other agents because of rapid detoxification by higher organisms TEPP Early insecticide Tetraethyl pyrophosphate E Echothiophate (PHOSPHOLINE IODIDE), MI-217 Diethoxyphosphinylthiocholine iodide 71 Extremely potent choline derivative; employed in treatment of glaucoma; relatively stable in aqueous solution Chapter 10 Cholinoceptor Blocking Drugs 擬膽鹼素性拮抗劑 (Cholinergic antagonist): 阻斷 acetylcholine 作用的藥物,此類藥物可細分成三類 I. 第一類藥物阻斷副交感節後神經元釋放的 acetylcholine 對 muscarinic receptor 的作用,此類藥物叫做 antimuscarinic agent(抗毒蕈素性藥物)或 muscarinic antagonists(蕈毒鹼性拮抗劑) II. 第二類藥物是阻斷節前神經元與節後神經元在神經節接合處的傳導,稱為 ganglionic blocker (神經節阻斷劑) III. 第三類藥物是阻斷神經與肌肉間的傳導,稱為 neuromuscular blocker(神經肌 肉阻斷劑)或 skeletal muscle relaxants(骨骼肌鬆弛劑) 72 IV. v. 抗毒蕈素性藥物:或稱 parasympatholytics(副交感神經解藥;副交感神 經抑制劑) atropine, scopolamine 是從顛茄等植物抽取出的生物鹼。這類藥物可以與 muscarinic receptor 結合,進而減少 acetylcholine 與 muscarinic receptor 結合的機率。這二種 藥物除了作用在副交感神經外,皆可進入中樞神經,這增加他們作用的複雜性。 Atropine(阿托品) Atropine 阻斷副交感神經的傳導,副交感神經興奮後所產生作用的反面作用,就 是 atropine 的作用。 藥理作用非常的廣泛,但不同器官對此藥物所產生的阻斷作用具有不同的敏感 度: - 低劑量:作用在唾液腺、汗腺及支氣管 – 造成口乾、抑制流汗,以及支氣管 鬆弛 - 較高劑量:造成瞳孔擴張、視力調節麻痺(近物看不清)、心跳加速 - 更高劑量:抑制胃腸及膀胱的蠕動 – 造成便秘、尿滯留;此劑量也會抑制胃 酸的分泌。 - 中毒劑量:幻覺,昏迷 12. Scopolamine (Buscopan, Hyoscine) - 在周邊自主神經系統的作用類似 atropine - 自有特色:經作用在中樞神經來的鎮靜作用及止吐作用 - 是目前用於 motion sickness(動暈病)最有效的藥物 13. Pirenzepine - M1 選擇性拮抗劑,用於胃潰瘍的治療 14. Ipratropium - 鬆弛支氣管平滑肌,以噴霧劑投予,用於治療氣喘 15. Tropicamide - 眼科用藥,用來治療假性近視,以及散瞳以供眼底檢查 有許多藥物,如抗組織胺藥物、抗精神病藥,及三環抗憂鬱劑等藥物(以後的課程會提 及),其化學結構式與 atropine 類似,因此常有口乾、便秘等副作用,又稱類阿托品作 用(atropine-like effects) Table 8–1. Muscarinic Receptor Subgroups and Their Antagonists. Subgroup Property M1 M2 M3 Primary locations Nerves Heart, nerves, smooth muscle Glands, smooth muscle, endothelium Dominant effector system IP3, Antagonists DAG cAMP, current Pirenzepine, telenzepine, dicyclomine,2 trihexyphenidyl3 K+ channel IP3, Gallamine,1 methoctramine, AF-DX 1164 4-DAMP, darifenacin, solifenacin, oxybutynin, tolterodine Approximate dissociation constant5 Atropine 1 1 1 Pirenzepine 25 300 500 AF-DX 116 2000 65 4000 73 DAG Darifenacin 70 55 74 8 H. 神經節阻斷劑 此類藥物阻斷交感及副交感神經神經節的 nicotinic receptor,作用複雜且難以預 測,臨床上極少使用。 同時受交感及副交感神經支配的器官,常有一方佔優勢。如交感神經控制血管平滑 肌,副交感控制胃腸道。神經節阻斷劑會拮抗這些優勢作用。 Trimethaphan - 靜脈注射用於治療舒張壓高於 150mmHg 的高血壓危象。 Figure 8–6. Some ganglion-blocking drugs. Acetylcholine is shown for reference. 75 Chapter 11 Adrenergic Agonists 擬腎上腺素性作用藥物 一.Adrenergic neuron 的傳導 Adrenergic neuron 的傳導與 Cholinergic neuron 的傳導很類似 I. Tyrosine(酪胺酸,是胺基酸的一種)被送入 adrenergic neuron 內,然後受到 tyrosine hydroxylase 的水解形成 Dopa。這個步驟是合成 NE 的速率決定步驟。然後 DOPA 再被 DOPA decarboxylase 去掉酸基而形成 dopamine J. 第二步驟:dopamine 被運送入突觸小泡(synaptic vesicle)內,在此被 dopamine hydroxylase 氫化形成 norepinephrine。在腎上腺髓質,norepinephrine 會再被酵素甲基化形成 epinephrine,當腎上腺髓質受刺激時會釋放出約 85%的 epinephrine,15%的 norepinephrine K. 第三步驟:當動作電位傳達神經末梢時,NE 從儲存小泡釋放出來 L. 第四步驟:釋放出的 NE 與受體結合 M. 第五步驟:NE 會擴散出突觸間隙而進入全身循環,或者是被再回收進入神經元 (acetylcholine 會被先水解成 choline 與 acetate,然後 choline 被回收),這個過程稱為再回 收(uptake)。再回收分為 uptake1[發生於交感神經纖維末梢(sympathetic nerve terminal)] 以 及 uptake 2(發生於周邊組織)。當 NE 被 uptake 1 攝入神經元後,會再被運送進入儲存小 泡。或者被代謝。 N. 第六步驟:代謝。NE 可被位於神經元內粒腺體表面上的 MAO(monoamine oxidase)及位於 突觸後細胞膜上的 COMT(catechol-O-methyltransferase)代謝。MAO 不僅可以氧化 NE,也 可以氧化其它單胺類的化合物,如 dopamine,5-HT。COMT 是一種分布廣泛的酵素,神 經或非神經組織皆含有此酵素。這二種酵素皆參與 norepinephrine 的代謝成最後的代謝 物。Norepinephrine 及 epinephrine 在體內的代謝物有很多種,但最主要的是 VMA (vanillylmandelic acid)。可藉由代謝物的多寡知道 norepinephrine 及 epinephrine 在體內的 產生量是否正常。 作用在第四步驟的藥物最多。 二.腎上腺素性受體 Adrenergic receptor 至少可分成四種 (1、2、1、2),每一種在體內所扮演的角色都不 一樣。而影響 adrenergic neuron 的藥物中,有些具有選擇性,只作用在一種受體;但有些 作用在一種以上的受體。這造成藥物作用的複雜性。 自主神經突觸前的神經纖維有2 及2 受體上。Norepinephrine 與其結合後會調控 NE 自 己的釋放。當 NE 的釋放量太少,就會作用在2 受體來增加 NE 的釋放;當 NE 的釋放量 太多,會作用在2 受體來抑制自己的釋放。此作用稱為負迴饋性抑制(negative feedback inhibition)。 Table 9–1. Adrenoceptor Types and Subtypes. Receptor Agonist Antagonist Effects 1 type Phenylephrine Prazosin Gene on Chromosome IP3, DAG common to all 1A C5 1B C8 76 C20 1D 2 type Clonidine 2A Oxymetazoline Yohimbine cAMP common to all C10 2B Prazosin C2 2C Prazosin C4 type 1 2 Isoproterenol Propranolol cAMP common to all Dobutamine Betaxolol C10 Albuterol Butoxamine C5 C8 3 Dopamine type Dopamine D1 Fenoldopam cAMP C5 D2 Bromocriptine cAMP C11 cAMP C3 cAMP C11 D3 D4 D5 Clozapine ↑ cAMP C4 77 Table 9–3. Distribution of Adrenoceptor Subtypes. Type Tissue Actions Most vascular smooth muscle (innervated) Contraction Pupillary dilator muscle Contraction (dilates pupil) Pilomotor smooth muscle Erects hair Prostate Contraction Heart Increases force of contraction Postsynaptic CNS adrenoceptors Probably multiple Platelets Aggregation Adrenergic and cholinergic nerve terminals Inhibition of transmitter release Some vascular smooth muscle Contraction Fat cells Inhibition of lipolysis Heart Increases force and rate of contraction Respiratory, uterine, and vascular smooth muscle Promotes smooth muscle relaxation Skeletal muscle Promotes potassium uptake Human liver Activates glycogenolysis Fat cells Activates lipolysis D1 Smooth muscle Dilates renal blood vessels D2 Nerve endings Modulates transmitter release 1 2 1 2 3 78 三.Adrenomimetics(擬腎上腺素藥物) 依作用機轉可分成三類: O. 直接作用 P. 間接作用 Q. 混合型作用 此類藥物對心血管的作用,因體內自我調節機制的參與(感壓受體及中樞神經控制),而造 成作用的複雜性。 R. 直接作用型藥物 Catecholamine 類:不能口服,作用期短 - Epinephrine:對及受體均具有活化的作用。在低劑量時,對血管系統的 受體作用較明顯;高劑量時受體的作用較明顯。 - Norepinephrine:在使用劑量下,主要影響受體。 - Isoproterenol:1 及2 受體作用劑。 - Dobutamine:選擇性1 受體作用劑。增強心臟收縮力,用於心衰竭 - Dopamine:可作用於1、dopamine 受體 16. 非 Catecholamine 類:大部份可口服,作用期較長 Figure 10–2 Classification of adrenergic receptor agonists (sympathomimetic amines) or drugs that produce sympathomimetic-like effects. 79 Table 9–2. Relative Selectivity of Adrenoceptor Agonists. Relative Receptor Affinities Alpha agonists Phenylephrine, methoxamine 1 > 2 >>>>> Clonidine, methylnorepinephrine 2 > 1 >>>>> Norepinephrine 1 = 2; 1 >> Epinephrine 1 = 2; 1 = Dobutamine1 1 > 2 >>>> Isoproterenol 1 = 2 >>>> Terbutaline, metaproterenol, albuterol, ritodrine 2 >> Mixed alpha and beta agonists 2 2 Beta agonists 1 >>>> Dopamine agonists Dopamine D1 = D2 >> Fenoldopam D1 >> D2 >> 3. 作用於 受體 b. 作用於1 受體:用於血管收縮劑,治療鼻充血,上心室跳動過速,低血壓 - Phenylephrine、naphazoline、methoxamine:主要活化1 受體 c. 作用於2 受體:用於治療高血壓 - Clonidine:活化血管運動中樞的2 受體,減少交感神經的活性。介紹高血壓 藥物時,會再說明此藥。 Table 10–3 Comparative Information About Prototype Adrenergic Receptor Antagonists * HALOALKYLAMINES IMIDAZOLINES QUINAZOLINES Phenoxybenzamine (DIBENZYLINE) Phentolamine (REGITINE) Prazosin (MINIPRESS) Tolazoline (PRISCOLINE) Terazosin (HYTRIN) Others Doxazosin (CARDURA) Trimazosin (CARDOVAR) Alfuzosin (UROXATRAL) Antagonism Selectivity Hemodynamic effects Actions other Irreversible 1 with some Competitive 2 Decreased PVR and blood pressure Nonselective between Competitive 1 and 2 Similar to PBZ Selective for 1; does not distinguish among 1 subtypes Decreased PVR and blood pressure Venodilation is prominent Veins less susceptible than arteries; thus, postural hypotension less of a problem Cardiac stimulation (cardiovascular reflexes and enhanced NE release due to 2 antagonism) Cardiac stimulation is less (NE release is not enhanced due to 1 selectivity) Some antagonism of ACh, 5-HT, and Cholinomimetic; adrenomimetic; 80 At high doses some direct vasodilator histamine histamine-like actions Blockade of neuronal and extraneuronal uptake Antagonism of 5-HT Routes of administration Intravenous and oral; oral absorption incomplete and erratic Similar to PZB Oral Adverse reactions Postural hypotension, tachycardia, miosis, nasal stuffiness, failure of ejaculation Same as PBZ, plus GI disturbances due to cholinomimetic and histamine-like actions Some postural hypotension, especially with the first dose; less of a problem overall than with PBZ or phentolamine Therapeutic uses Conditions of catecholamine excess (e.g., pheochromocytoma) Same as PBZ Primary hypertension than blockade action, probably due to PDE inhibition Peripheral vascular disease Benign prostatic hypertrophy 作用於2 受體:緩解支氣管痙攣,減少早產時的子宮收縮 - Terbutaline d. Table 10–4 Pharmacological/Pharmacokinetic Properties of DRUG Receptor Blocking Agents MEMBRANE INTRINSIC LIPID EXTENT OF ORAL PLASMA PROTEIN STABILIZING AGONIST SOLUBILITY ABSORPTION BIOAVAILABILITY t½ BINDING ACTIVITY ACTIVITY (%) (%) (hours) (%) Classical non-selective blockers: First generation Nadolol 0 0 Low Penbutolol 0 + High Pindolol + +++ Low >95 Propranolol ++ 0 High <90 Timolol 0 Low to Moderate 0 1-Selective 30 100 30–50 20–24 30 100 5 80–98 100 3–4 40 30 3–5 90 90 75 4 <10 blockers: Second generation Acebutolol + + Low 90 20–60 3–4 26 Atenolol 0 0 Low 90 50–60 6–7 6–16 Bisoprolol 0 0 Low ð90 80 9–12 Esmolol 0 0 Low NA NA 0.15 55 Metoprolol +* 0 Moderate 40–50 3–7 12 85 6 23–30 98 Non-selective 100 30 blockers with additional actions: Third generation Carteolol 0 ++ Low 85 Carvedilol ++ 0 Moderate >90 30 7–10 Labetalol + + Low >90 33 3–4 80 15 50 5 4–5 1-selective 50 blockers with additional actions: Third generation Betaxolol + 0 Moderate Celiprolol 0 + Low >90 74 81 30–70 17. 一些擬交感神經直接作用劑對心血管的影響 受體 血管效應 心臟效應 平均動脈壓 肺效應 臨床應用 備註 Norepine-phrine(N ,,主 收縮 反射性心跳 昇高(收縮壓及 臨床不用 假如在投與 NE 之前先給 E) 過慢 舒張壓皆增加*) 予 atropine,則 NE 會刺激 要是 心臟而增加心跳速率 Epinephrine** 先增加後降低 擴張支 氣喘,過敏 2%溶液可局部用於降低 ,; 收縮 興奮(1) (收縮壓增加;舒 氣管(2) 性休克,心 青光眼的眼內壓(因收縮 > ();擴張 張壓降低) 動停止,與 血管降低眼房水的製造) (2); 局麻共用 Isoproterenol 擴張 降低(稍微增加 擴張支 氣喘 在氣喘的應用上,已被非 興奮(1) 收縮壓,明顯降 氣管(2) catecholamine 類的藥物取 (2), 因擴張血 低舒張壓) 代 管,心跳會再 反射性增加 Dobutamine ---------增加心收縮 增加 休克,鬱血 常與 dopamine 合併用於 1 力,對心跳影 性心衰竭 休克 響較小 Dopamine Dopami 低劑量影 興奮(1) -----增加 休克,鬱血 作用在 Dopamine 受體, ne,1 響小,高 性心衰竭 擴張腎臟及內臟血管,增 劑量收縮 加血流 () 藥物對心跳的影響,除考慮藥物本身對心臟的作用外,還需考慮感壓反射反應。 血壓=心輸出量(心跳及心收縮力)X 周邊阻力(血管的管徑)。心輸出量對收縮壓影響較 大;周邊阻力對舒張壓影響較大。平均動脈壓=舒張壓+1/3(收縮壓-舒張壓) S. 間接作用劑: 結構與 NE 類似,對受體直接的作用極輕微,但可被 uptake 1 運送進入神經末梢,置換 儲存小泡(vesicle)內的 NE,使 NE 由儲存小泡釋出,擴散至突觸,與突觸後的受體結合 Amphetamine(安非他命) - 自主神經作用:收縮血管、增加心收縮力、心跳,及支氣管擴張等作用 - 中樞神經作用:興奮中樞神經,導致警覺性增加、減少疲勞、食慾降低及失 眠等作用 18. Tyramine(酪胺) - 存在於許多發酵的食物,臨床上沒有使用 - 在胃腸道會被 MAO 破壞,無法進入腦部 Table 9–5. Foods Reputed to Have a High Content of Tyramine or Other Sympathomimetic Agents. Food Tyramine Beer (No data) Broad beans, fava beans Negligible (but contains dopamine) Cheese, natural or aged Nil to 130 mg (cheddar, Gruyère, and Stilton especially high) Chicken liver Nil to 9 mg Chocolate Negligible (but contains phenylethylamine) Sausage, fermented (eg, salami, pepperoni, summer sausage) Nil to 74 mg Smoked or pickled fish (eg, pickled herring) Nil to 198 mg Snails (No data) 82 Content of an Average Serving Wine (red) Nil to 3 mg Yeast (eg, dietary brewer's yeast supplements) 2–68 mg 19. Cocaine 古柯鹼 為一局部麻醉劑,可以阻斷 NE 的回收(阻斷 uptake 1),因此在周邊具有擬交感神 經的作用;為局部麻醉藥物中,唯一具有內生性血管收縮作用的藥物。 可以進入腦部,產生中樞興奮作用(類似 amphetamine,但作用較強、持續較短) T. 混合型作用劑 Ephedrine - 不僅能促進神經末梢 NE 的釋放,也可以直接作用在及受體 - 作用類似 epinephrine(但效力較低) - 輕微的中樞神經興奮性 - 臨床用途:用來治療氣喘,鼻充血 Table 10–6 Summary of Adrenergic Agonists and Antagonists CLASS DRUGS Direct-acti Epinephrine ng non-selecti ( 1, 2, 1, ve 2, 3) agonists PROMINENT PHARMACOLOGICAL ACTIONS PRINCIPAL THERAPEUTIC APPLICATIONS Increase in heart rate Open-angle glaucoma Increase in blood pressure Increased contractility Slight decrease in PVR Increase in cardiac output Vasoconstriction (viscera) Vasodilation (skeletal muscle) Increase in blood glucose and lactic acid Norepinephrine ( 1, 2, 1, >> 2) Increase in systolic and diastolic blood pressure With local anesthetics to prolong action Anaphylactic shock Complete heart block or cardiac arrest UNTOWARD EFFECTS COMMENTS Palpitation Not given orally Cardiac arrhythmias Life saving in anaphylaxis or cardiac arrest Cerebral hemorrhage Headache Tremor Restlessness Bronchodilator in asthma Hypotension Similar to Epi Not absorbed orally Hypertension Vasoconstriction Increase in PVR Direct increase in heart rate and contraction Reflex decrease in heart rate Receptor Agonists Non-select Isoproterenol IV administration ive ( 2) Decrease in PVR 1+ Increase in cardiac output Tachyarrhythmias Bronchodilation Dobutamine 1-selective Albuterol 2-selective (intermedi ate acting) Bitolterol Fenoterol Isoetharine Metaproterenol Procaterol Bronchodilator in asthma Complete heart block or cardiac arrest Shock Palpitations Tachycardia Headache Flushed skin Cardiac ischemia in patients with CAD Increase in contractility Short-term Increase in blood treatment of pressure and heart Some increase in heart rate cardiac rate. decompensation Increase in AV conduction after surgery, or patients with CHF or MI Relaxation of bronchial smooth muscle Relaxation of uterine smooth muscle Activation of other 2 receptors after systemic administration Administered by inhalation in asthma Bronchodilators for treatment of asthma and COPD Short/intermediate -acting drugs for acute bronchospasm Ritodrine, to stop premature labor Terbutaline 83 Skeletal muscle tremor Use with caution in patients with hypertension or cardiac arrhythmias Used only IV Use with caution in patients with CV disease (reduced by inhalational administration) Tachycardia and other cardiac effects Minimal side effects seen after systemic administration (much less with inhalational use) Ritodrine (Long acting) Formoterol Formoterol and salmeterol best choice for prophylaxis due to long action Salmeterol Receptor agonists 1-selective Methoxamine Vasoconstriction Phenylephrine Nasal congestion (used topically) Postural hypotension Mephentermine Metaraminol Midodrine 2-selective Clonidine Apraclonidine Guanfacine Guanabenz Brimonidine -methyldopa Indirect-ac Amphetamine ting Methamphetami ne Methyphenidate (releases NE peripherally; NE, DA, 5-HT centrally) Mixed-acti ng Dopamine ( 2, 1, 1, D1; releases NE) Hypertension Reflex bradycardia Dry mouth, sedation, rebound hypertension upon abrupt withdrawal Decrease sympathetic Adjunctive therapy in shock outflow from brain to periphery resulting in decreased PVR and blood Hypertension pressure To reduce sympathetic Decrease nerve-evoked response to release of sympathetic withdrawal from transmitters narcotics, alcohol, Decrease production of and tobacco aqueous humor Glaucoma Mephentermine and metaraminol also act indirectly to release NE Midodrine is a prodrug converted in vivo to an active compound Apraclonidine and brimonidine used topically for glaucoma and ocular hypertension Methyldopa is converted in CNS to -methyl NE, an effective 2 agonist CNS stimulation Treatment of ADHD Restlessness Schedule II drugs Increase in blood pressure Narcolepsy Tremor Marked tolerance occurs Obesity (rarely) Insomnia Chronic use leads to dependence Myocardial stimulation Anxiety Tachycardia Hypertension Vasodilation (coronary, renal mesenteric beds) Increase in glomerular filtration rate and natriuresis Cardiogenic shock Congestive heart failure Can result in hemorrhagic stroke in patients with underlying disease Cardiac arrhythmias Long-term use can cause paranoid schizophrenia High doses lead to vasoconstriction Important for its ability to maintain renal blood flow Administered IV Treatment of acute renal failure Increase in heart rate and contractility Increase in systolic blood pressure Ephedrine ( 2, 1, 2; releases NE) 1, Similar to epinephrine but longer lasting CNS stimulation Bronchodilator for treatment of asthma Nasal congestion Treatment of hypotension and shock Restlessness Tremor Insomnia Anxiety Administered by all routes Not commonly used Tachycardia Hypertension Blockers Postural hypotension Non-select Phenoxybenzam Decrease in PVR and blood Treatment of ine pressure ive catecholamine Failure of ejaculation (classical excess (e.g., Phentolamine Venodilation pheochromocytoma blockers) ) Tolazoline 1-selective Prazosin Terazosin Doxazosin Trimazosin Decrease in PVR and blood Primary pressure hypertension Relax smooth muscles in Increase urine flow neck of urinary bladder and in BPH in prostate Postural hypotension when therapy instituted Cardiac stimulation due to initiation of reflexes and to enhanced release of NE via 2 receptor blockade. Phenoxybenzamine produces long-lasting -receptor blockade and at high doses can block neuronal and extraneuronal uptake of amines Prazosin and related quinazolines are selective for 1 receptors but not among 1subtypes Alfuzosin Tamsulosin Tamsulosin exhibits some selectivity for 1A receptors 84 Blockers Non-selectiv Nadolol e (1st generation) Penbutolol Decrease in heart rate Angina pectoris Bradycardia Decrease in contractility Hypertension Pindolol Decrease in cardiac output Propranolol Slow conduction in atria and AV node Cardiac arrhythmias Negative inotropic effect Timolol Decrease in cardiac output CHF Bradyarrhythmias Increase refractory period, Pheochromocytoma AV node Reduction in AV Glaucoma conduction Bronchoconstriction Hypertropic Bronchoconstriction Prolonged hypoglycemia obstructive cardiomyopathy Fatigue Decrease in plasma FFA Hyperthyroidism Sleep disturbances Reduction in HDL (insomnia, cholesterol Migraine nightmares) prophylaxis Increase in LDL cholesterol Prolongation of and triglycerides Acute panic hypoglycemia symptoms Hypokalemia Sexual dysfunction in Substance abuse men withdrawal Pharmacological effects depend largely on degree of sympathoadrenal tone Bronchoconstriction (of concern in asthmatics and COPD) Hypoglycemia (concern in hypoglycemics and diabetics) Membrane stabilizing effect (propranolol, acebutolol, carvedilol, and betaxolol only) ISA (strong for pindolol; weak for penbutolol, carteolol, labetalol, and betaxolol) Variceal bleeding in portal hypertension 1-selective (2nd generation) Acebutolol Atenolol Bisoprolol Esmolol Metoprolol Non-selectiv Carteolol e (3rd generation) Carvedilol vasodilators Bucindolol Labetalol 1-selective (3rd generation) vasodilators (Membrane stabilizing effect) Vasodilation seen in 3rd generation drugs; multiple mechanisms ( 1 antagonism; (ISA) 2 agonism; release of NO; Ca2+ channel blockade; opening of K+ channels;) (Vasodilation) Betaxolol Celiprolol Nebivolol 85 Chapter 12 Adrenoceptor Antagonist Drugs Adrenergic antagonist(擬腎上腺素性拮抗劑) 大體上分為三類 受體阻斷劑 受體阻斷劑 影響 NE 回收或釋放的藥物 -阻斷劑 非選擇性-阻斷劑:對突觸後的1-受體及突觸前的2 受體皆有作用,因為阻斷2 受體, 會增加 NE 的釋放,因此該類藥物常造成心跳加速的副作用 Phenoxybenzamine - 需代謝轉成活性型式後才有作用,因此起始作用慢 - 與受體形成不可逆且非競爭性的結合,因此作用持久(一天) - 藥理作用:逆轉受體作用劑的作用、擴張血管、影響性機能(造成逆行性射 精) - 臨床用途:嗜鉻性細胞瘤(pheochromocytoma)引起的高血壓,排尿不全(例如 良性前列腺肥大) Phentolamine - 與受體的結合為可逆、競爭性,作用時間短 - 臨床上不常使用[可用於嗜鉻性細胞瘤、凍瘡(frostbite)] Ergot alkaloids(麥角生物鹼) - 由寄生在裸麥(rye)之黴菌 claviceps purpurea 分離出許多成分,通稱為麥角生 物鹼。這些成分對許多受體(包括受體)有作用(參照表 5-8) - ergotamine:收縮腦部血管,用於偏頭痛的治療 - ergonovine:收縮子宮,減少產後出血 - bromocriptine:治療高泌乳素症 - lysergic acid diethylamide(LSD):迷幻藥 Table 10–1. Relative Selectivity of Antagonists for Adrenoceptors. Receptor Affinity Antagonists Prazosin, terazosin, doxazosin 1 >>>> Phenoxybenzamine 1 > 2 Phentolamine 1 = 2 Rauwolscine, yohimbine, tolazoline 2 >> 1 = 1 >>> 1 = 2 >>> 2 1 Mixed antagonists Labetalol, carvedilol 2 1 Antagonists Metoprololol, acebutolol, alprenolol, atenolol, betaxolol, celiprolol, esmolol Propranolol, carteolol, penbutolol, pindolol, timolol Butoxamine 86 2 2 1 > 2 Table 10–2. Properties of Several Beta-Receptor-Blocking Drugs. Selectivity Partial Agonist Activity Local Anesthetic Action Lipid Solubility Elimination Half-Life Approximat e Bioavailabili ty Acebutolol 1 Yes Yes Low 3–4 hours 50 Atenolol 1 No No Low 6–9 hours 40 Betaxolol 1 No Slight Low 14–22 hours 90 Bisoprolol 1 No No Low 9–12 hours 80 None Yes No Low 6 hours 85 None No No High 7–10 hours 25–35 Carteolol 1 Carvedilol Celiprolol 1 Yes No Low 4–5 hours 70 Esmolol 1 No No Low 10 minutes 0 Yes Yes Moderate 5 hours 30 No Yes Moderate 3–4 hours 50 Labetalol1 Metoprolol None 1 Nadolol None No No Low 14–24 hours 33 Penbutolol None Yes No High 5 hours >90 Pindolol None Yes Yes Moderate 3–4 hours 90 Propranolol None No Yes High 3.5–6 hours 302 Sotalol None No No Low 12 hours 90 Timolol None No No Moderate 4–5 hours 50 20. 選擇性1-阻斷劑: Prazosin - 降低周邊血管阻力,可有效的用於高血壓的治療 - 副作用較非選擇性-阻斷劑少 21. 選擇性2-阻斷劑: Yohimbine - 該類藥物阻斷突觸前2 受體,可以促進 NE 釋放,增強交感神經活性。該藥 亦阻斷一些位於周邊血管突觸後的2 受體,而造成血管擴張。 - 此藥在台灣被禁用,因其具有催淫作用。 U. 阻斷劑 非選擇性受體阻斷劑:可同時阻斷1 及2 受體 Propranolol: 藥理作用: 心臟:阻斷1 受體,減少心輸出量(降低心收縮力及心跳速率) 血管:阻斷2 受體,使血管收縮 呼吸:阻斷2 受體,使支氣管收縮,所以不可用於氣喘病人 肝臟:阻斷2 受體,抑制醣原分解,造成低血糖 腎臟:阻斷1 受體,抑制 renin(腎素)釋放 其他:阻斷突觸前2 受體,抑制 NE 的釋放 e. 臨床用途: 87 高血壓、青光眼、心絞痛、心肌梗塞及其所引起的心律不整、偏頭痛的預防,以 及因交感神經興奮所造成的症狀(心跳加快、顫抖等)。 f. 禁忌:禁用於氣喘病人 Timolol: - 效用比 propranolol 強 - 主要用於青光眼的治療。臨床上青光眼急性發作時,pilocarpine 為首選藥, 而受體阻斷劑則用於長期治療。受體阻斷劑不影響眼睛對焦的能力,亦不 改變瞳孔的大小。 22. 選擇性1 受體拮抗劑:不影響2 受體 Atenolol,Metoprolol - 用於高血壓的治療,較不會有支氣管收縮的副作用 23. 受體部分作用劑:兼具受體作用劑及阻斷劑二種特性 Pindolol, Acebutolol: - 對1 及2 受體具有微弱的興奮作用,即所謂的內原性擬交感神經活性 (intrinsic sympathomimetic activity, ISA),但可阻斷體內強效性的 epinephrine 及 norepinephrine 的作用。 - 用於高血壓及心絞痛。該類藥物具有內原性擬交感神經活性,但與單純的 受體阻斷劑比較,此類藥物較不會造成心跳過慢及降低對血中脂質的干擾。 V. 影響神經傳遞物質(NE)釋放或回收的藥物 Reserpine 蛇根鹼 阻斷儲存小泡(vesicle)攝入 NE 的能力,進而耗盡 NE 的量 *reserpine 會阻斷中樞及周邊神經元突觸前的 vesicle 攝入及儲存所有的生物胺, 包括 NE, epinephrine, dopamine, 5-HT。. 可用於高血壓的治療(但很少使用,僅用於難治性病例)。 此藥可穿透血腦障壁,影響中樞神經。使用數月後,許多病人會有惡夢,少數病 人會感到沮喪、憂鬱,且有自殺的傾向。亦具有鎮靜作用。 24. Guanethidine 抑制交感神經節後神經纖維末梢 NE 的釋放(對其他神經元的作用極微) 此藥阻斷 adrenergic neuron 傳導的作用很複雜。此藥物可如同 NE,被 uptake 1 運送進入神經纖維末梢,然後進入突觸小泡(vesicle)取代 NE,使 NE 的儲存逐漸 被排空;此藥亦具有局部麻醉作用而阻礙神經傳導。該藥之作用最有可能是蓄積 在突觸小泡內,使突觸小泡無法與細胞膜融合,而阻止胞吐作用(exocytosis)。 用於高血壓的治療(目前少用)。此藥不能穿透血腦障壁,故不影響中樞神經。有 數個類似 guanethidine 的藥物已被發展出,並應用於臨床上 Table 10–3. Drugs Used in Open-Angle Glaucoma. Mechanism Methods of Administration Ci iary muscle contraction, opening of trabecular meshwork; increased outflow Topical drops or gel; plastic film slow-release insert Increased outflow Topical drops Cholinomimetics Pilocarpine, carbachol, physostigmine, echothiophate, demecarium Alpha agonists Unselective 88 Epinephrine, dipivefrin Alpha2-selective Decreased aqueous secretion Apraclonidine Topical, postlaser only Brimonidine Topical Beta-blockers Timolol, betaxolol, carteolol, levobunolol, metipranolol Decreased aqueous secretion from the ciliary epithelium Topical drops Diuretics Dorzolamide, brinzolamide Acetazolamide, dichlorphenamide, methazolamide Decreased aqueous secretion due to lack of Topical HCO3– Oral Prostaglandins Latanoprost, bimatoprost, travoprost, unoprostone Increased outflow 89 Topical Chapter 13 Skeletal Muscle Relaxants 骨骼肌鬆弛劑 W. 神經肌肉阻斷劑:麻醉前用藥 又可分為兩類 競爭性的阻斷劑,又叫做非去極化阻斷劑。 - 此類藥物可以與神經肌肉接合處的 nicotinic receptor 結合,進而減少 acetylcholine 與 nicotinic receptor 結合的機率,而造成肌肉的鬆弛及麻痺。在 全身麻醉時,用於骨骼肌鬆弛。 - 代表藥物是 tubocurarine (箭毒)。此藥除了阻斷神經肌傳導外,尚有其他副作 用如引起組織胺釋放造成支氣管痙攣和蕁麻疹。 - 一些新的藥物(參照表 4-12),例如 gallamine, pancuronium 等,作用機轉與 tubocurarine 類似,較不會促進組織胺釋放。然而,有些藥物會拮抗心臟蕈毒 鹼受體,而引起心跳過速。 - 這些藥物皆需以靜脈注射給與。 25. 去極化阻斷劑 - 此類藥物會活化神經肌肉接合處的 nicotinic receptor 而且不會立刻被突觸的 乙醯膽鹼水解,造成受體持續的受刺激,使局部肌肉暫時性抽搐。但時間 一久受體對乙醯膽鹼的敏感性消失而造成肌肉麻痺。 Succinylcholine - 起始作用時間快,作用時間短(可快速的被血漿中的 cholinesterase 水解),為 氣管插管時的理想用藥 - Succinylcholine 偶爾會在遺傳性敏感性的病人身上造成肌肉抽搐,以及惡性 體溫過高(malignant hyperthermia)的現象。可以以迅速冷卻或投與 dantrolene 的方法來治療。 X. 骨骼肌解痙劑:用於運動傷害或多發性硬化症等疾病 26. Dantrolene:使鈣離子無法由骨骼肌的肌漿網(sacroplasmic reticulum)釋放出來,而干 擾肌肉的收縮 27. Baclofen:為 GABAB receptor agonist,經作用在中樞神經系統的 GABAB 受體而產生 解痙作用,中樞神經系統的課程會再說明 28. 許多鎮靜安眠藥亦有鬆弛骨骼肌的作用,以後的課程會再詳細說明。 90 91