bry's pharmacology 1st semester

- 37 -

14. CHOLINERGIC AGONISTS AND CHOLINESTERASE

INHIBITORS

CHOLINERGIC AGONISTS

Overview

- “muscarinic receptor agonists”

- cholinergic agonists are drugs that act on acetylcholine receptors, thus causing excitation of

the parasympathetic autonomic nervous system

- there are 2 types of acetylcholine receptors

1) NICOTINIC RECEPTORS

- are receptor-mediated ion channels

- 3 types

RECEPTOR TYPE LOCATION

MUSCLE TYPE - neuromuscular junction

GANGLION TYPE - sympathetic autonomic ganglia

- parasympathetic autonomic ganglia

CNS TYPE - CNS

- agonists of nicotinic receptors are discussed later (“depolarizing

neuromuscular blocking agents”, see 16)

2) MUSCARINIC RECEPTORS

- are g-protein coupled receptors

- 3 types

RECEPTOR TYPE LOCATION

M1 - CNS

- exocrine glands (gastric. bronchial-, salivary-,

lacrimal-, and sweat glands)

M2 - CNS

- GI tract smooth muscle

- atria of the heart

M3 - exocrine glands

- GI tract smooth muscle

- 38 -

- genito-urinary tract smooth muscle

- bronchial smooth muscle

- smooth muscle of the eye

- endothelium of blood vessels

General Effects - 8 types

ORGAN EFFECT

CNS - increased skeletal muscle tension

- tremor

- hypothermia

- improved cognition (improved learning)

HEART - decreased heart rate (“bradycardia”)

- decreased force of contraction

BLOOD VESSELS - decreased blood pressure (due to vasodilation)

EYE - myosis (due to contraction of the pupilary sphincter)

- accomodation to near vision (due to contraction of the

ciliary muscle)

- decreased intraoccular pressure (due to opening of the

schlemm canal)

GI TRACT - GI tract emptying (due to increased peristalsis)

GENITO-URINARY TRACT - urinary bladder emptying (due to contraction of the

detrusor muscle)

BRONCHI - bronchoconstriction (due to contraction of bronchial

smooth muscle)

EXOCRINE GLANDS - increased gastric secretion

- increased bronchial secretion

- increased salivation

- increased lacrimation

- increased sweating

Relevant Drugs

- 3 types

- 39 -

DRUG NAME DESCRIPTION

ACETYLCHOLINE General information

- acetylcholine itself

- non-selective acetylcholine receptor agonist (acts on both

nicotinic- and muscarinic receptors)

- not used clinically

PILOCARPINE General information

- selective muscarinic receptor agonist (acts only on muscarinic

receptors)

- selective to the eye and exocrine glands

Clinical uses

- treatment of glaucoma (by reduction of intraoccular pressure)

MUSCARINE General information

- same as pilocarpine (see above)

- found naturally in toadstool

- the causative agent of mushroom poisoning


CHOLINESTERASE INHIBITORS

Overview

- there are 2 types of cholinesterase enzymes

ENZYME NAME DESCRIPTION

PLASMACHOLINESTERASE

- “butyrylcholinesterase”

- located in the blood

- responsible for the breakdown of acetylcholine in

the blood stream

- not discussed further here

ACETYLCHOLINESTERASE - located in the cholinergic synapses

- responsible for the breakdown of acetylcholine in

the cholinergic synapses

- cholinesterase inhibitors ("anticholinesterases") inhibit the degradation of acetylcholine by

acetylcholinesterase at the nicotinic cholinergic synapses, thus prolonging it's effect

- 40 -

General Effects - 2 types

ORGAN EFFECT

PARASYMPATHETIC

POSTGANGLIONIC SYNAPSES

- increased parasympathetic effects (see above)

- large doses may lead to decreased

parasympathetic effects (due to depolarization

block in autonomic ganglia caused by continuous

acetylcholine action)

NEUROMUSCULAR JUNCTION - increased skeletal muscle tension

- large doses may lead to paralysis (depolarization

block)

Relevant Drugs - 2 categories

1) REVERSIBLE

- 3 types


NEOSTIGMINE Clinical uses

- treatment of myasthenia gravis

PYRIDOSTIGMINE Clinical uses

- same as neostigmine (see above)

PHYSIOSTIGMINE General information

- may cross the blood-brain barrier

Clinical uses

- treatment of glaucoma

Side effects

- coma and respiratory failure (due to initial CNS

excitation followed by CNS depression)

2) IRREVERSIBLE

- 2 types


- 41 -

ECOTHIOPATE Clinical uses

- treatment of glaucoma

Side effects

- peripheral nerve neurotoxicity (due to demyelination

and following slowly developing weakness and sensory

loss)

PARATHION General information

- an insecticide

- causes poisoning


Side effects

- same as ecothopiate (see above)

- 42 -

15. MUSCARINIC RECEPTOR ANTAGONISTS

Overview

- muscarinic receptor antagonists are competitive antagonists to acetylcholine on cholinergic

receptors, thus blocking the effect of the parasympathetic nervous system

- they elicit effects opposite to those of muscarinic agonists (see 14, except no vasoconstriction

due to no parsympathetic innervation of vascular smooth muscle (vaodilation is due to

circulating acetylcholine))

Relevant Drugs

- 2 categories

1) TERTIARY AMINES

- are lipophilic

- , thus may cross the blood-brain barrier

- 3 types


ATROPINE General information

- found naturally in nightshade

(“atropa belladonna”)

Clinical uses

- treatment of irreversible

cholinesterase inhibitor poisoning (see

14)

- treatment of bradycardia

- treatment of spasms of the GI tract

- treatment of parkinson’s disease (see

46)

- supplement to anaesthesia (by

reduced exocrine gland secretions)

Side effects

- midriasis (due to relaxation of the

pupillary sphincter)

- cycloplegia (due to relaxation of the

ciliary muscle leading to inhibition of

accomodation)

- urine retention (due to relaxation of

the detrusor muscle)

- dry mouth (due to inhibition of

salivation)

- dry skin (due to inhibition of

sweating)

- 43 -

- restlessness, anxiety and/or

disorientation (due to CNS

stimulation)

SCOPOLAMINE General information

- “hyosciene”

- found naturally in thorn apple

(“datura stramonium”)

Clinical uses

- same as atrophine (see above)

- treatment of motion sickness

(“antiemetic effect”, see 37)

Side effects

- sedation (due to CNS depression)

PIRENZEPINE General information

- selective to GI tract smooth muscle

Clinical uses

- treatment of peptic ulcer (by

decreased gastric secretion, see 37)

2) QUARTERNARY AMINES

- are hydrophilic

- , thus may not cross the blood-brain barrier

- 2 types


ATROPINE METHONITRATE Clinical uses

- treatment of spasms of the GI tract

IPRATROPIUM Clinical uses

- treatment of asthma and bronchitis

(by bronchodilation and reduced

bronchial secretions)

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16. NEUROMUSCULAR BLOCKING AGENTS. DRUGS

ACTING ON AUTONOMIC GANGLIA

NEUROMUSCULAR BLOCKING AGENTS

Overview

- neuromuscular blocking agents are drugs that competitively inhibit nicotinic receptors at the

neuromuscular junction, thus causing flaccid muscle paralysis (however, they do not block

the awareness of pain (!))

Relevant Drugs

- 2 categories

1) NON-DEPOLARIZING

- are nicotinic receptor antagonists

- 4 types (listed from slowest onset and longest duration to fastest onset and shortest

duration)


TUBOCURARINE General information

- onset: 5-10 minutes, duration: 1-2 hours

- found naturally in curare (“south american indian

arrow poison”)

Medical uses

- supplement to anaesthesia (by skeletal muscle

paralysis)

Side effects

- hypotension (due to inhibition of ganglion type

nicotinic receptors)

- bronchoconstriction (due to histamine release from

mast cells due to its strongly basic character)

GALLAMINE Medical uses

- same as tubocurarine (see above)

Side effects

- tachycardia (inhibition of M2 muscarinic receptors

due to muscarinic antagonist activity)

ATRACURIUM Medical uses


- 45 -

MIVACURIUM General information

- onset: 2 minutes, duration: 10 minutes

Medical uses


2) DEPOLARIZING

- are nicotinic receptor agonists (!)

- mechanism of action

A) bind to the active site, thus triggering an initial depolarization leading to

initiation of an action potential and following muscle twitches

B) however, they remain bound to the receptor due to inability of

acetylcholinesterase to degrade them, thus causing inability of the striated muscle

fibers to repolarize and trigger a new action potential

- 1 type


SUXAMETHONIUM General information

- onset: immediately, duration: 10 minutes

Medical uses

- supplement to anaesthesia (by skeletal muscle

paralysis)

Side effects

- bradycardia (muscarinic agonist effect)

- cardiac dysrythmias (due to muscle denervation

leading to nicotinic receptor spread outside the

neuromuscular junction, continuous depolarization,

continously opened k+ channels, and continuous

leakage of k+ out of the skeletal muscle fibers)

- increased intraoccular pressure (due to simultaneous

contraction of extraoccular muscles)

DRUGS ACTING ON AUTONOMIC GANGLIA

Overview

- 46 -

- drugs acting on autonomic ganglia act both on the sympathetic- and parasympathetic

autonomic nervous system, thus giving very complex effects in the body (not discussed

further here)

Relevant Drugs

- 2 categories

1) GANGLION STIMULANTS

- are ganglion-type nicotinic receptor agonists

- 2 types


NICOTINE General information

- causes initial ganglial stimulation, followed by ganglial

block due to continuous depolarization (“depolarization

block”)

- also stimulates sensory- and noradrenergic nerve terminals

of the CNS (not discussed here)


- see 48

LOBELINE General information

- causes ganglial stimulation


2) GANGLION BLOCKERS

- are ganglion-type nicotinic receptor antagonists

- 1 type


TRIMETAPHAN Clinical uses

- emergency treatment of malignant hypertension (by

vasodilation)

- supplement to anaesthesia (minimizes bleeding due to

vasodilation)

- 47 -

17. AGENTS ACTING ON THE BIOSYNTHESIS, STORAGE,

RELEASE AND ELIMINATION OF CATECHOLAMINES

Overview - see 18

- there are 2 types of catecholamines

NEURONTRANSMITTER NAME DESCRIPTION

NORADRENALINE - “norepinephrine”

- secreted by autonomic sympathetic nerve

terminals (and to a smaller extent by the n-cells

of the adrenal medulla)

ADRENALINE - “epinephrine”

- secreted by the a-cells of the adrenal medulla

BIOSYNTHESIS

Overview

- biosynthesis of catecholamines is done in 3 (4) steps

TYROSINE

tyrosine hydroxylase

DOPA

DOPA decarboxylase

DOPAMINE

dopamine beta-hydroxylase

NORADRENALINE

phenylethanolamide N-methyltransferase (“PNMT”)

ADRENALINE

- , thus there are 3 (4) enzymes involved in catecholamine biosynthesis


TYROSINE HYDROXYLASE - the rate-limiting step

- located in the cytoplasm of sympathetic

postsynaptic neurons

- 48 -

DOPA DECARBOXYLASE - general enzyme located in the cytoplasm of

most cells

- catalyses decarboxylation of aromatic amino

acids

DOPAMINE BETA-HYDROXYLASE - located in the synaptic vesicles of

postsynaptic sympathetic nerve terminals

PNMT - located in the a-cells of the adrenal medulla

Relevant Drugs

- 3 types


ALPHA-METHYLTYROSINE General information

- a tyrosine hydroxylase inhibitor

- inhibits tyrosine hydroxylase, thus causing inhibition

of catecholamine synthesis

Clinical use

- treatment of pheochromocytoma (a catecholamine-

producing adrenal medullary tumor)

Side effects

- hypotension (due to vasodilation)

- drowsiness

METHYLDOPA General information

- a central DOPA decarboxylase inhibitor (may cross

the blood-brain barrier)

- alternate substrate for DOPA decarboxylase , thus

displacing DOPA from the active site of DOPA

decarboxylase and following inhibition of

catecholamine synthesis

- is converted by DOPA decarboxylase to

methylnoradrenalin (a selective alpha-2 agonist, see

19)

Clinical use

- treatment of hypertension during pregnancy (by

inhibition of the sympathetic nuclei of the brainstem)

Side effects

- same as alpha-methyltyrosine (see above)

- 49 -

- impotency

- hypersensitivity reactions

CARBIDOPA General information

- a peripheral DOPA decarboxylase inhibitor (may not

pass the blood-brain barrier)

Clinical use

- treatment of parkinson’s disease (by inhibition of the

use of DOPA for catecholamine synthesis in

peripheral neurons, thus freeing it for restorement of

the dopaminergic pathways of the brain, see 46)

STORAGE

Overview

- noradrenaline is stored in synaptic vesicles of noradrenergic nerve terminals as a complex

with 4 ATP molecules

- both initial uptake of dopamine for synthesis of noradrenaline and re-uptake of noradrenaline

for re-use is done by a vesicular monoamine transporter (“VMAT”) located in the synaptic

vesicular membrane

Relevant Drugs

- 1 type


RESERPINE General information

- found naturally in rauwolfia

- blocks VMAT, thus depleting noradrenaline stores


RELEASE

Overview

- noradrenaline is released into the synaptic cleft by fusion of the synaptic vesicles with the

neuron cell membrane upon arrival of a nerve impulse

Relevant Drugs

- 3 categories

- 50 -

1) PRESYNAPTIC NORADRENERGIC NEURON-BLOCKING DRUGS

- blocks noradrenaline release upon arrival of a nerve impulse by interaction with

presynaptic receptors in the noradrenergic nerve terminals

- 7 types


ADRENALINE/NORADRENALINE

ACETYLCHOLINE

HISTAMINE

ENKEPHALIN

DOPAMINE

SEROTONIN

- “5-Hydroxytryptamine, “5-HT”

PROSTAGLANDIN E - “PGE”

2) NORADRENERGIC NEURON-BLOCKING DRUGS

- blocks noradrenaline release upon the arrival of a nerve impulse by local anaesthetic

action (see 22)

- 1 type


GUANETHIDINE

3) INDIRECTLY-ACTING SYMPATHOMIMETIC DRUGS

- evokes noradrenaline release independently from the arrival of a nerve impulse

- mechanism

A) enters the postsynaptic sympathetic nerve terminal by the way of uptake 1

(see below) located in the neuron cell membrane in exchange for cytoplasmic

noradrenaline into the synaptic cleft

B) enters the synaptic vesicles by the way of VMAT in exchange for vesicular

noradrenaline into the cytoplasm

- 3 types


AMPHETAMINE General information

- 51 -


- also causes release of dopamine and

serotonin in the CNS


- see 48

EPHEDRINE General information

- an amphetamine analogue (see above)

Clinical uses

- treatment of nasal congestion (by

vasoconstriction)

Side effects

- same as amphetamine, though less

pronounced (see above)

TYRAMINE General information

- found naturally in mature cheese and

wine

- usually metabolized by monoamine

oxidase (“MAO”, see below) in the

enterocytes

- may reach the blood stream upon

MAO inhibition

ELIMINATION

Overview

- elimination of catecholamines may be done by 2 mechanisms

MECHANISM DESCRIPTION

REUPTAKE

DEGRADATION

REUPTAKE

Overview

- most important form of ELIMINATION

- 52 -

- reuptake of catecholamines is done by 2 types of membrane transporters

TRANSPORTER NAME DESCRIPTION

UPTAKE 1 - located in the neuronal cell membrane

- has a high affinity to catecholamines

- transports only noradrenaline

UPTAKE 2 - located in the cell membrane of the target tissues

- has a low affinity to catecholamines

- transports both adrenaline and noradrenaline

Relevant Drugs

- 2 types


TRICYCLIC ANTIDEPRESSANTS General information

- blocks uptake 1

- also has an atropine-like effect (see 15)

- see 42

COCAINE General information

- blocks uptake 1


- see 48

DEGRADATION

Overview

- degradation of catecholamines is done by enzymes located in the cytoplasm of most cells

- degradation differs in the periphery and in the CNS

1) PERIPHERY

- 3 steps

NORADRENALINE

alimentary monoamine oxidase (“MAO-A”)

NORADRENALINE ALDEHYDE

aldehyde dehydrogenase

DIHYDROXYMANDELIC ACID (“DOMA”)

- 53 -

cathecol-O-methyl transferase (“COMT”)

VANYLYLMANDELIC ACID (“VMA”)

2) CNS

- 3 steps

NORADRENALINE

brain monoamine oxidase (“MAO-B”)

NORADRENALINE ALDEHYDE

aldehyde reductase

DIHYDROXYPHENYLGLYCOL (“DOPEG”)

cathecol-O-methyl transferase (“COMT”)

METOXY-HYDROXYPHENYLGLYCOL (“MOPEG”)

- , thus there are 2 (3) important enzymes involved in catecholamine degradation


MAO-A - located in the periphery

MAO-B - located in the CNS

COMT

- see 42

- 54 -

18. PHARMACOLOGICAL EFFECTS OF CATECHOLAMINES

19. ADRENERGIC RECEPTOR AGONISTS

Overview

- catecholamines are neurotransmitters that work on adrenergic receptors, thus causing

excitation of the sympathetic autonomic nervous system

- activation of adrenergic receptors usually elicits effects opposite to those of parasympathetic

muscarinic receptor activation (see 14)

- there are 2 types of adrenergic receptors

1) ALPHA RECEPTORS

- 2 types

RECEPTOR TYPE EFFECT

ALPHA-1 - increased blood pressure (due to vasoconstriction)

- midriasis (due to contraction of the radial fibers of the

pupilary sphincter)

- loss of accommodation (due to contraction of the radial

fibers of the ciliary muscle)

- decreased GI tract emptying (due to decreased peristalsis)

- decreased urinary bladder emptying (due to contraction

of the urinary bladder sphincter)

- ejaculation (due to contraction of the seminal tract)

- cardiac- and prostate hypertrophy (due to increased

smooth muscle proliferation)

- hyperglycemia (due to increased glycogenolysis in the

liver)

ALPHA-2 - decreased blood pressure (due to inhibition of the

sympathetic vasomotor center in the brain stem and of the

sympathetic- and parasympathetic ganglia, and following

vasodilation)

- decreased GI tract emptying

- thrombosis (due to increased platelet aggregation)

- hyperglycemia (due to decreased insulin secretion by the

pancreas)

2) BETA RECEPTORS

- 3 types

RECEPTOR TYPE EFFECT

BETA-1 - increased heart rate (“tachycardia”)

- increased force of heart contraction

- 55 -

BETA-2 - decreased blood pressure (due to vasodilation)

- decreased GI tract emptying

- decreased urinary bladder emptying (due to relaxation of

the urinary bladder detrusor muscle)

- distension of the uterus during pregnancy (due to

relaxation of uterine smooth muscle)

- bronchodilation (due to relaxation of bronchial smooth

muscle )

- bronchodilation (due to decreased histamine release from

mast cells in the lungs)

- increased skeletal muscle contraction strength (due to

skeletal muscle hypertrophy)

- increased skeletal muscle contraction speed (due to

increased tension of fast-twitch skeletal muscle fibers)

- hyperglycemia (due to increased glycogenolysis in the

liver)

- decreased proliferation, activity, and cytokine release of

lymphocytes (decreased immune defense system)

BETA-3 - increased thermogenesis from skeletal muscle and

adipose tissue (due to uncoupling of oxidative

phosphorylation)

- decreased fat stores (due to increased beta-oxidation)

General Effects - see above

Relevant Drugs

- “directly acting sympathomimmetic drugs”

- 5 categories

1) NON-SELECTIVE AGONISTS

- act on both alpha- and beta receptors

- 2 types


NORADRENALINE General information


ADRENALINE Clinical uses

- supplement to local anaesthesia (by

vasoconstriction and following increased

- 56 -

duration of action)

- treatment of anaphylactic shock (due to

vasoconstriction)

- treatment of cardiac arrest (by increased

heart rate and increased force of contraction)

- treatment of asthma (by bronchodilation)

Side effects

- hypertension (due to vasoconstriction)

- reflex bradycardia (due to activation of

vascular baroreceptors as a response to

hypertension)

- tachycardia (due to increased heart rate)

- ventricular dysrythmias (due to increased

heart rate)

2) ALPHA-1 AGONISTS

- 2 types


PHENYLEPHRINE Clinical uses

- treatment of hypotension (by

vasoconstriction)

- treatment of rhinitis (by vasoconstriction and

following decreased nasal congestion)

Side effects

- hypertension

- reflex bradycardia

METHOXAMINE General information

- same as phenylephrine (see above)

3) ALPHA-2 AGONISTS

- 2 types


CLONIDINE Clinical uses

- treatment of hypertension (by vasodilation)

- treatment of diarrhea (by decreased

peristalsis)

- treatment of migraine (by cerebral blood

vessel vasodiation)

- 57 -

Side effects

- orthostatic hypotension (due to vasodilation)

- rebound hypertension (due to abrupt seizure

of administration and following

vasoconstriction)

- oedema (due to vasodilation)

- drowsiness

METHYLNORADRENALINE General information

- see 17

- same as clonidine (see above)

4) BETA-1 AGONISTS

- 2 types


ISOPRENALINE Clinical uses

- treatment of cardiogenic shock (by increased

heart rate and increased force of heart

contraction)

Side effects

- ventricular dysryhmias (due to increased

heart rate)

DOBUTAMINE General information

- same as isoprenaline (see above)

5) BETA-2 AGONISTS

- 2 types


SALBUTAMOL General information

- also has a weak beta-1 agonist activity

Clinical uses

- treatment of asthma (by bronchodilation)

- prevention of premature labor (by relaxation

of the uterine smooth muscle)

Side effects

- tachycardia (beta-1 agonist activity)

- 58 -

- ventricular dysrythmias (beta-1 agonist

activity)

- hypotension (by vasodilation)

- tremor (by increased tension of fast-twitch

skeletal muscle fibers)

CLENBUTEROL General information

- same as salbutamol (see above)

- abused as a performance enhancer (increased

muscle mass and contraction speed)

- 59 -

20. ALPHA ADRENERGIC RECEPTOR ANTAGONISTS

General Effects - alpha adrenergic receptor antagonists generally elicit effects opposite to those of alpha

adrenergic receptor agonists (see 18/19)

Relevant Drugs

- 3 categories

1) NON-SELECTIVE ALPHA ANTAGONISTS

- 2 types


PHENOXYBENZAMINE General information

- long-acting, irreversible (binds covalently)

Clinical uses

- treatment of phaeochromocytoma (catecholamine-

secreting tumor of the adrenal medulla)

Side effects

- orthostatic hypotension (due to vasodilation)

- nasal congestion (due to vasodilation)

- reflex tachycardia (due to vasodilation and

following hypotension)

- diarrhea (due to increased peristalsis)

- failure of ejaculation (due to relaxation of the

seminal tract)

PHENTOLAMINE General information

- short-acting, reversible


2) ALPHA-1 ANTAGONISTS

- 2 types


PRAZOSIN Clinical uses

- treatment of hypertension (by vasodilation)

Side effects

- same as phenoxybenzamine, but less reflex

- 60 -

tachycardia (see above)

TAMSOLUSIN General information

- selective for the genito-urinary tract

Clinical uses

- treatment of urinary retention due to prostatic

hypertrophy (by relaxation of the urinary bladder

sphincter)

Side effects

- failure of ejaculation (due to relaxation of the

seminal tract)


- 1 type


YOHIMBE General information

- an aphrodisiac (vasodilation)

- 61 -

21. BETA ADRENERGIC RECEPTOR ANTAGONISTS

General Effects - beta adrenergic receptor antagonists (“beta-blockers”) generally elicit effects opposite to

those of beta adrenergic receptor agonists (see 18/19)

- the effects of beta adrenergic receptor antagonists depend on the degree of sympathetic

activity (weak during rest (low sympathetic activity), stronger during exercise (high

sympathetic activity))

Relevant Drugs

- 3 categories

1) NON-SELECTIVE BETA ANTAGONISTS

- 2 types


PROPANOLOL General information


Clinical uses

- treatment of hypertension (by vasodilation, decreased heart

rate and decreased force of contraction)

- treatment of cardiac dysrythmias (by decreased heart rate)

- treatment of myocardial infarction (by prevention of cardiac

dysrythmias)

- treatment of angina pectoris (by decreased heart rate and

decreased force of heart contraction, and following decreased

myocardial oxygen consumption and increased cardiac blood

supply)

- treatment of tremor (by decreased skeletal muscle twitch

tension)

- treatment of glaucoma (by contraction of the radial fibers of

the ciliary muscle and following opening of the schlemm

canal)

Side effects

- depression (due to CNS stimulation)

- fatigue (due to decreased heart rate and decreased force of

heart contraction, and following decreased oxygenation of the

CNS and skeletal muscle)

- cardiac failure (due to decreased heart rate and decreased

force of heart contraction)

- cold extremities (due to vasoconstriction in cutaneous

thermoregulatory vessels)

- bronchoconstriction (due to constriction of bronchial smooth

- 62 -

muscle)

- hypoglycemia (due to decreased glycogenolysis)

ALPRENOLOL General information

- also has a weak beta agonist activity (, thus increasing heart

rate during rest and decreasing heart rate during exercise)

Clinical uses

- same as propanolol (see above)

Side effects

- same as propanolol (see above)

- increased heart rate during rest and decreased heart rate

during exercise (due to beta agonist activity)

2) BETA-1 ANTAGONISTS

- 1 type


METOPROLOL Clinical uses

- treatment of hypertension

- treatment of caridac dysrythmias

- treatment of angina pectoris

Side effects

- same as propanolol, though less pronounced

bronchoconstriction (see above)


- 1 type


BUTOXAMINE General information


- 63 -

22. LOCAL ANAESTHETICS

Overview

- local anaesthetics block the propagation of nerve impulses by blocking the sodium channels

responsible for initiation and propagation of the nocioceptive action potential

- they are ampiphilic molecules composed of a hydrophilic aromatic group and a basic amine

group joined by an ester- or an amide bond

- the basic amine group is partly ionized at physiological ph, some thing which is important

since only the non-ionized form can penetrate the myelin sheet of the axonal membrane while

only the ionized form can bind to and block the sodium channels

- the importance of partial ionization may provide problems when anaesthetizing inflamed

tissues (acidic pH, thus completely ionizing the basic amine group)

- the sodium channels are more susceptible to blockage in their activated- and in their

inactivated states, and less susceptible in their resting state ("use-dependence")

- mechanism of action

1) penetration of the myelin sheet and axonal membrane in it's non-ionized form

2) binding to activated- or inactivated sodium channels in it's ionized form

- local anaesthetics block propagation of different nerve fibers in the following order

SMALL MYELINATED AXONS

UNMYELINATED AXONS

LARGE MYELINATED AXONS

- , thus nocioception and sympathetic transmission are the first to be blocked

- there are 6 types of local anaesthesia

LOCAL ANAESTHESIA TYPE DESCRIPTION

SURFACE ANAESTHESIA - spray onto the surface of mucous

membranes (not skin)

- used for surgery of the nose,

mouth, bronchi, cornea and urinary

tract

- euretic mixture of local

anaesthetics (“EMLA”), a mixture of

lidocaine and prilocaine (see below),

may be applied on the skin

INFILTRATION ANAESTHESIA - direct injection into tissues to reach

nerve branches and -terminals

- 64 -

- used in minor surgery

- adrenaline may be co-administered

to reduce side effects (see 19)

INTRAVENOUS REGIONAL ANAESTHESIA - intravenous injection distally to a

pressure cuff (arrests blood flow thus

preventing systemic effects)

- used for limb surgery

NERVE-BLOCK ANAESTHESIA - injection close to a nerve trunk (eg.

brachial plexus, intercostal- and/or

dental nerves), thus causing distal

anaesthesia

- used for surgery, dentistry and

analgesia (relief of pain)

SPINAL ANAESTHESIA - injection into the CSF of the

subarachnoidal space

- used for surgery of the abdomen,

pelvis and/or leg when general

anaesthesia can not be used

- often cause severe side effects

EPIDURAL ANAESTHESIA - injection into the epidural space,

thus causing anaesthesia of the spinal

roots

- used for painless labor

- may cause severe side effects

General Side effects - due to escape of local anaesthetics into the SYSTEMIC CIRCULATION

- 3 types

ORGAN SIDE-EFFECT

CNS - confusion (may lead to extreme anxiety)

- tremor (may lead to convulsions)

- depression of the respiratory center (may lead to cessation of

breathing)

HEART - reduced force of contraction (inhibition of sodium-potassium

ATPase, thus depleting intracellular potassium required for

contraction)

BLOOD VESSELS - hypotension (due to vasodilation)

- 65 -

Relevant Drugs

- 5 types (listed from rapid onset, short duration, and good tissue penetration to slow onset,

long duration and poor tissue penetration)


LIDOCAINE Clinical uses

- all types of local anaesthesia

COCAINE Clinical uses

- surface anaesthesia

Side effects

- different side effects than the others due to it's action of blocking

uptake 1 (see 17)

PRILOCAINE Clinical uses

- infiltration-, intravenous regional-, and nerve-block anaesthesia

Side effects

- does not cause vasodilation

- may cause methemoglobinemia (heamoglobin unable to release

oxygen due to covalent binding of prilocaine)

TETRACAINE Clinical uses

- infiltration-, and nerve-block anaesthesia

BUPIVACAINE Clinical uses

- infiltration-, nerve-block-, and epidural anaesthesia

- 66 -

A1. DRUGS, 1ST SEMESTER

14. CHOLINERGIC AGONISTS AND CHOLINESTERASE INHIBITORS

1) CHOLINERGIC (MUSCARINIC RECEPTOR) AGONISTS

- Acetylcholine

- Pilocarpine

- Muscarine

2) CHOLINESTERASE INHIBITORS

A) REVERSIBLE

- Neostogmine

- Pyridostogmine

- Physiostigmine

B) IRREVERSIBLE

- Ecothiopate

- Parathion

15. MUSCARINIC RECEPTOR ANTAGONISTS

1) TERTIARY AMINES

- Atropine

- Scopolamine

- Pirenzepine

2) QUARTERNARY AMINES

- Atropine Methonitrate

- Ipratropium

16. NEUROMUSCULAR BLOCKING AGENTS. DRUGS ACTING ON AUTONOMIC

GANGLIA

1) NEUROMUSCULAR BLOCKING AGENTS

A) NON-DEPOLARIZING

- Tubocurarine

- Gallamine

- Atracurium

- Mivacurium

B) DEPOLARIZING

- Suxamethonium

2) DRUGS ACTING ON AUTONOMIC GANGLIA

A) GANGLION STIMULANTS

- Nicotine

- 67 -

- Lobeline

B) GANGLION BLOCKERS

- Trimetaphan

17. AGENTS ACTING ON THE BIOSYNTHESIS, STORAGE, RELEASE AND ELIMINATION

OF CATECHOLAMINES

1) BIOSYNTHESIS

- Alpha-Methyltyrosine

- Methyldopa

- Carbidopa

2) STORAGE

- Reserpine

3) RELEASE

A) PRESYNAPTIC NORADRENERGIC NEURON-BLOCKING DRUGS

- Adrenaline/Noradrenaline

- Acetylcholine

- Histamine

- Enkephalin

- Dopamine

- Serotonin

- PGE

B) NORADRENERGIC NEURON-BLOCKING DRUGS

- Guanethidine

C) INDIRECTLY-ACTING SYMPATOMIMETIC DRUGS

- Amphetamine

- Ephedrine

- Tyramine

4) ELIMINATION

A) REUPTAKE

- Tricyclic Antidepressants

- Cocaine

B) DEGRADATION

- MAO-A

- MAO-B

- COMT

18./19. PHARMACOLOGICAL EFFECTS OF CATECHOLAMINES. ADRENERGIC

RECEPTOR AGONISTS

1) NON-SELECTIVE AGONISTS

- 68 -

- Noradrenaline

- Adrenaline

2) ALPHA-1 AGONISTS

- Phenylephrine

- Methoxamine

3) ALPHA-2 AGONISTS

- Clonidine

- Methylnoradrenaline

4) BETA-1 AGONISTS

- Isoprenaline

- Dobutamine

5) BETA-2 AGONISTS

- Salbutamol

- Clenbuterol

6) BETA-3 AGONISTS

20. ALPHA ADRENERGIC RECEPTOR ANTAGONISTS

1) NON-SELECTIVE ALPHA ANTAGONISTS

- Phenoxybenzamine

- Phentolamine


- Prazosin

- Tamsulosin


- Yohimbe

21. BETA ADRENERGIC RECEPTOR ANTAGONISTS

1) NON-SELECTIVE BETA ANTAGONISTS

- Propanolol

- Alprenolol


- Metoprolol


- Butoxamine

22. LOCAL ANAESTHETICS

- Lidocaine

- Cocaine

- Prilocaine

- 69 -

- Tetracaine

- Bupivacaine

bry's pharmacology 1st semester

Documents

gi tract smooth muscle

breakdown of acetylcholine

nicotinic cholinergic

degradation of acetylcholine

types organ effect cns

exocrine glands gastric

blood vessels general

blood responsible