Pharmacology
Sites where drugs can act to modulate neurotransmission process & mechanism by which they do it
Drugs that affect ganlionic neurotransmission
Drugs affecting sympathetic system
Review of ANS
Part of peripheral efferent nervous system. Composed of preganlionic & postganglionic
2 arms
Parasympathetic system
Sympathetic system
Rest & digest
Fight or flight
Ach is released from preganglionic fibers then it influences post ganglionic fibers to release NA to influence tissues - Neuroeffector junction= part where post ganglionic fibers infleunces the tissue. The transmitter in this area for this system is NA
Ach is released from preganglionic fibres which activates post gaglionic fibre to release Ach. Hence the neuro-transmitter at the neruoeffector junction is Ach.
- Pupile dilation
- Bronchodilation (but lungs are only affected due to the release of adrenaline)
- Increased rate & force
- Vasoconstriction/vasodilation
- Decreased GI motility
Opposite symptoms to sympathetic. Just addition to increased exocrine secretion
Activates adrenal gland to secrete adrenaline into the blood stream and this dilates or relaxes the bronchi
Tissues are only innervated by 1 side of the ANS
Blood vessels innervated only by symapthetic nervous
Bronchi in lungs=innervated only by the parasympathetic nervous system, but bronchi only responds to adrenaline
Receptors of the ANS
Ach receptors
Nicotininc Ach receptors (nAChRs)
Muscarinic Ach receptors (mAChRs)
Location: on ganglia(start of post ganglionic fibres in both sympathetic & parasympathetic) & skeletal muscle(of the somatic efferent system). And on adrenal medulla
Location: on tissues & responsible for organ effects. Responds to Ach release in that parasympathetic system. Eg of muscles: smooth(glands, gut) and cardiac muscle
Actions: DUMBELLS ie Diarrhoea, Urination, Miosis(constriction of eye), Bradycardia(slow heart rate), Bronchoconstriction, Emesis(vomitting), Lacrimation Lethargy, Salivation
NA receptors
Associated with symapthetic system(sometimes called adregenic)
Alpha receptors
Beta receptors
Location: tissues & responsible for organ effectors. ie eyes, salivary glands, vessels, few in gut.
Location: tissues & responsible for organ effectors. ie smooth & cardiac muscles. Found in heart , few in gut, bladder, lungs
Function: excite & contract. In GIT they close sphincters stop food from moving.
Function: relax & inhibit, except in the heart where they stimulate.
Where
What neurotransmission is: synthesis, storage, release, action @ receptors, termination of action
How does neurotransmission work:
Synthesis: transmitter precursor is pumped into the cell then its acted on by sympathetic enzyme to make the final transmitter
Storage: then its stored in synaptic vesicles
Release: exocytosis allows the migration of synaptic vesicles to the end of the membrane, allowing discharge of contents of vesicles(transmitter) then act on receptor & produce response
Termination: happens in 2 ways. 1st were transmitter is broken by enzymes that are found within synapse. 2nd is transmitter= removed from synapse by being sucked up & recycled back into the nerve terminal
Exocytosis
Preparation for release: Neurotransmitters are stored inside synaptic vesicles within the nerve terminal
Activation of nerve terminal: When the nerve terminal is activated by an AP , various ions, including calcium, enter the cell
Influx of calcium triggers exocytosis, hence what happens
Migration of vesicles: The synaptic vesicles containing neurotransmitters move toward the membrane at the nerve terminal
Fusion with membrane: One of the vesicles fuses with the membrane at the nerve terminal
Release of neurotransmitter: The contents of the vesicle, which include neurotransmitters, are discharged into the synaptic cleft
Interaction with receptors: Once released, neurotransmitters can then bind to receptors on the target tissue (such as muscle cells or other neurons), initiating a response in the receiving cell
Drugs exert their effects by binding to protein molecules
Enzymes: cyclo-oxygenase (COX1 and COX2)
Transporters
Receptors
Occasionally ion channels
Act everywhere in those steps of synthesis, storage, release and termination
How drugs can bind
Mimic the actions of endogenous factors(also called neurotransmitters): most common at receptors taargets where drugs mimic the actions of neurotransmitter
Inhibit the action of endogenous factors:
1) Many drugs are enzyme inhibitors/ transport blockers.
2) Many drugs can also block receptors preventing the action of neurotransmitters
Agents are called agonists. Can be called parasympathoMIMETICS, or sympathoMIMETICS, depnding on which system they target
Agents are called antagonists. They remove the effect of 1 arm of ANS, so either called parasympathoLYTICS, or sympathoLYTICS
Drugs affecting parasympathetic systems
Muscarinic
What effect will muscarinic agonists cause
DUMBBEELS
What effect will muscarinic antagonists cause
Anti-DUMBBELLS ie mydriasis(open up of pupil), dry mouth, speeding of the heart, slowing of GI movement= constipation
Application:
Mydriasis= examination of the retina via the pupil, help of atropine durg derived from belladonna
Decreased bronchial smooth muscles: asthma would be treated as the mucous is dried and bronchial smooth muscle contractions are decreased
Decreased motility= treat diarrhoea
Drugs affecting Ach neurotransmission
Actions of ACh at receptors is terminated by AChE(acetylcholinesterase). AChE breaks down ACh into its constituients ie choline and acetate
Durgs that prevent the breakdown of Ach= anticholinesterase. Hence [Ach] would be increased around the neuroeffector junction=increased tissue responses= further activate parasympathetic system and more DUMBBELLS
Organophosphate insecticide posining results in DUMBBELLS & increased activation of somatic nervous system followed by paralysis
Application: some types of anti-cholinestaerases can help in myasthenia gravis. Which is an auto-immune disorder where there is muscle weakness due to insufficient effects of Ach @ skeletal muscle
Drugs that interferes with Ach release: ie botulininm(botox) toxin=inhibits release of ACh. Observe anti-DUMBBELLS. And progressive muscle weakness & paralysis, observe drooping eyelids, slurre speech, difficulty breathing.
Theraputic uses of botox= mostly related to effects on skeletal muscle neurotransmission. ie bleopharospasm= uncontrolled contractions of eyelids, and cerebral palsy to reduce muscle rigidity & uncontrolled spasms
Clinical uses of drugs targetting NA receptors
Effect of NA agonists: activate alpha & beta transmittors
Stimulation of a receptors leads to vasoconstriction(raising BP), slowing gut, mydraisis
Stimulation of b receptors leads to increasing force & rate of heart contraction, slowing gut, relaxing & dilation of bronchial smooth muscle
Effect of NA antagonist: block a & b receptors
a blockage leads to: vasodilation, lowering BP, speeding gut, miosis
b blockage leads to: decrease force & rate of heart contraction, speeding gut, constriction of bronchial smooth muscle
a adreonceptors (blood vessels)
Agonists at a receptors cause vasoconstriction:
Constrict small blood vessels in nose & eye(clear up redness) acting as nasal decongestants and ocular decongestants. Given "locally" only
Antagonist a receptors cause relaxed blood vessels in circulatory system.
1) Used in hypertension
2)Access all blood vessels
b receptors
Heart
Agonist at b receptors: stimulate the heart (in heart failure)
Antagonists at b receptors: slow heart (used indirectly to help lower BP) ie blockage of b receptors
bronchi/lungs
Agonists: relax & open bronchi(asthma)
Antagonist: contraindicated in asthma (trigger it)
Application: anaphylaxis
Symptoms: closing of airway (shortness of breath), heart pumps less blood
Treatment: give adrenaline cause it targets B receptors hence relax & dilate bronchial smooth muscle. And @ heart it would target B receptors hence increase force & rate of heart contraction. And it causes a receptors to vasoconstrict hence raising BP.
Drugs affecting NA neurotransmission
Actions of NA at receptors= terminated by reuptake. By the nerve terminal sucking it back up into nerve thru a pump called "uptake-1"
NA reuptake blockers: used in depressive disorders (effects are in brain rather than ANS)
Effects of indirectly acting mimetic: ie pseudoephedrine drug, causes vasocinstricition by activating a receptors, constrcit small blood vessels in nose & eye acting as nasal decongestants
Locations of NAChRs: found in ganglia on adrenal medulla & neuromuscular receptors
When activated: response on skeletal muscle, release of adrenaline as the post ganglionic fibers of the sympathetic system and parasymapthetic system. Hence, it is hard to predict what it will exactly do
Effect of blockage/activation of nictotinic receptors: unpredictble effects, as responses are complicated by affecting both the sympathetic & parasympathetic arms
Parasympathetic system