- 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
- not used clinically
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
DRUG NAME DESCRIPTION
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
DRUG NAME DESCRIPTION
- 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
- not used clinically
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
DRUG NAME DESCRIPTION
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
DRUG NAME DESCRIPTION
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)
- 44 -
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)
DRUG NAME DESCRIPTION
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
- same as tubocurarine (see above)
- 45 -
MIVACURIUM General information
- onset: 2 minutes, duration: 10 minutes
Medical uses
- same as tubocurarine (see above)
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
DRUG NAME DESCRIPTION
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
DRUG NAME DESCRIPTION
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)
- not used clinically
- see 48
LOBELINE General information
- causes ganglial stimulation
- not used clinically
2) GANGLION BLOCKERS
- are ganglion-type nicotinic receptor antagonists
- 1 type
DRUG NAME DESCRIPTION
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
ENZYME NAME DESCRIPTION
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
DRUG NAME DESCRIPTION
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
DRUG NAME DESCRIPTION
RESERPINE General information
- found naturally in rauwolfia
- blocks VMAT, thus depleting noradrenaline stores
- may cross the blood-brain barrier
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
DRUG NAME DESCRIPTION
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
DRUG NAME DESCRIPTION
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
DRUG NAME DESCRIPTION
AMPHETAMINE General information
- 51 -
- may cross the blood-brain barrier
- also causes release of dopamine and
serotonin in the CNS
- not used clinically
- 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
DRUG NAME DESCRIPTION
TRICYCLIC ANTIDEPRESSANTS General information
- blocks uptake 1
- also has an atropine-like effect (see 15)
- see 42
COCAINE General information
- blocks uptake 1
- may cross the blood-brain barrier
- 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
ENZYME NAME DESCRIPTION
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
DRUG NAME DESCRIPTION
NORADRENALINE General information
- not used clinically
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
DRUG NAME DESCRIPTION
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
DRUG NAME DESCRIPTION
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
DRUG NAME DESCRIPTION
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
DRUG NAME DESCRIPTION
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
DRUG NAME DESCRIPTION
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
- not used clinically
2) ALPHA-1 ANTAGONISTS
- 2 types
DRUG NAME DESCRIPTION
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)
3) ALPHA-2 ANTAGONISTS
- 1 type
DRUG NAME DESCRIPTION
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
DRUG NAME DESCRIPTION
PROPANOLOL General information
- may cross the blood-brain barrier
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
DRUG NAME DESCRIPTION
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)
3) BETA-2 ANTAGONISTS
- 1 type
DRUG NAME DESCRIPTION
BUTOXAMINE General information
- not used clinically
- 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)
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Relevant Drugs
- 5 types (listed from rapid onset, short duration, and good tissue penetration to slow onset,
long duration and poor tissue penetration)
DRUG NAME DESCRIPTION
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
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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
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- 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
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- 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
2) ALPHA-1 ANTAGONISTS
- Prazosin
- Tamsulosin
3) ALPHA-2 ANTAGONISTS
- Yohimbe
21. BETA ADRENERGIC RECEPTOR ANTAGONISTS
1) NON-SELECTIVE BETA ANTAGONISTS
- Propanolol
- Alprenolol
2) BETA-1 ANTAGONISTS
- Metoprolol
3) BETA-2 ANTAGONISTS
- Butoxamine
22. LOCAL ANAESTHETICS
- Lidocaine
- Cocaine
- Prilocaine
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- Tetracaine
- Bupivacaine