NE

Epi

Dopamine

Serotonin

Histamine

y-aminobutyric acid

ACh

Epi & NE

1. preganglionic fibers terminating at the adrenal medulla

2. the autonomic ganglia for both the psns & sns

3. the postganglionic fibers of the PSNS

4. mm of the somatic system

the 6 steps of neurotransmission in cholinergic neurons

1. synthesis

2. storage

3. release

4. binding of ACh to a receptor

5. degradation in the synaptic cleft

6. recycling of choline

M1-5

M1, 3, and 5 lead to cellular excitation

M2, and 4 inhibit cellular excitability

the largest effect a drug can produce

efficacy implies intrinsic activity

can only use when comparing 2+ drugs

the amount of drug that must be given to elicit an effect

produces less of an effect even if all of the receptors are occupied

antagonist

a drug that binds with a receptor but you don't get an effect, it blocks it

it has no intrinsic activity

ie antihistamine

1. competitive: usually an ionic, reversible bone

2. noncompetitive: usually a covalent bond, its irreversible. the only way to break the bond is to somehow regenerate the receptors

1. CNS: Brain and spinal cord

2. PNS: Somatic motor and autonomic

2 types

1. preganglionic

2. postganglionic

preganglionic fibers arise from the cranial and sacral regions

they synapse in the ganglia near or on the effector organs

the postganglionic fibers extend from the ganglia to the effector organ and are very short

1. regulations of smooth muscle

2. regulation of cardiac muscle

3. regulation of secretory glands

Slows HR, decs contractility

Incs gastric secretions

stimulates bladder emptying

stimulates bowel emptying

incs mm motility and tone

focuses eye for near vision (cont of ciliary mm)

constriction of pupil (iris sph mm)

stimulates erection

contraction of bronchiole smooth mm

increases lung secretions

what nerve is the main nerve that effects the heart?

the PSNS is concerned primarily with...

the housekeeping chores of the body

feed and breathe

or

rest and digest

1. the GI Tract

2. the bladder

3. the eyes

sometimes used for effects and heart and lungs

1. action potential

2. release of NT

3. Interaction of NT with receptor

1. alter axonal conduction: not very selective

ie local and general anesthetics

2. alter synaptic transmission: highly selective bc synapses are different

if the reuptake of ACh is blocked what is inhibited?

1. can increase or decrease the synthesis of transmitters, or can alter the transmitter

2. interfere with transmitter storage (bc if ACh is not stored in a vesicle it will degrade)

3. interfere with transmitter release (promotes or inhibits)

4. act directly on receptors (activates or blocks)

5. interfere with termination of transmitter action (blocks reuptake or inhibits degradation)

1. what are the NTs?

2. how do I indentify the receptors?

3. where are the receptors located?

4. what is the normal physiologic response?

mediate responses to ACh

cholinergics or cholinergic agonists

muscarinics

parasympathomimetics

cholinomimetic

anticholinergics

cholinergic antagonists/blockers

antimuscarinics

parasympatholytics

atropine-like drugs

muscarinic

nicotinic M

nicotinic N

the study of drugs that alter processes controlled by the nervous system

these drugs produce effects equivalent to those produced by excitation or suppression of neuronal activity

Choline Esters

ACh: used in opth.

carbachol: used in opth.

bethanechol

pilocarpine

Direct-Acting cholinergic/muscarinic Agonist 

used for urinary retention,  IV and PO

also used to stim. GI Tract

duration of action: ~1 hr

SEs: myosis, nausea, diarrhea, bronchoconstriction/spasm, fall in BP, light headedness, sweating, abd pain, salivation

contraindications: asthma, chronic lung disease

does not penetrate the CNS very much

Pilocarpine

MOA: direct-acting cholinergic/muscarinic agonist but also penetrates CNS

Uses: opthalmology (glaucoma) for emergency lowering of IOP : causes aqueous humor to drain out the canal Schlem

secretagogue (for dry mouth) also but not often (for patients who had radiation on the head or neck)

SEs: sweating, salivation, headaches, CNS disturbances, others

used as eye drop, gel or insert

Reversible

physostigmine

neostigmine

pyridostigmine

edrophonium

Irreversible

Organophosphates

malathion

soman

reversible indirect-acting cholinergic agonist 

short acting quarternary ammonium alcohol

ineffective orally, must use IV

Half-life about 10 mins

Indication: primarily in the differential diagnosis of muscle weakness in the patients suspected of having MYASTHENIA GRAVIS

antibodies attack receptors

occurs with infection or a lot of stress

respiratory mm are affected

physostigmine

reversible indirect acting cholinergic agonist 

well absorbed and does penetrate BBB

Indications: glaucoma, treat CNS effects of anticholinergic overdose

irreversible indirect acting cholinergic agonists 

highly lipid soluble and well absorbed

Echothiophate and isoflurophate

malathion

soman

Contraindications: Asthma, really low BP, GI or UI obstructions, peptic ulcer disease

antidote: atropine, pralidoxine

poisoning seen in farmers, pesticides

used to treat chronic glaucoma that doesn't respond to more conservative therapy. Provides 24 hr control. One drop will last for a full day.

irreversible indirect acting cholinergic agonists

used to treat pediculosis capitis (head lice) or scabbies and as a pesticide. Ovide 0.5% lotion

irreversible indirect acting cholinergic agonist

chemical warfare agent

soldiers will carry around physostigmine to counteract this poisoning

irreversible indirect acting cholinergic agonists

antimuscarinics

ganglionic blockers

neuromuscular blockers

cholinergic antagonist 

MOA: block muscarinic receptors and the few exceptional sympathetic neurons that are cholinergic (sweat and salivary glands)

extremely imp. in medicine

cholinergic antagonists 

atropine

scopolamine

hysoscyamine

cholinergic antagonist 

inc HR, but is dose dependent

high affinity for muscarinic receptors

acts both centrally and peripherally

antidote: physostigmine bc it crosses the BBB

duration: ~4 hrs, except when applied to eyes where it can act for days

Actions: antispasmotics

eye dilation, Dec GI secretions and motility, urinary retention, Inc HR, dec secretions

uses: diarrhea, IBS, overactive bladder, bradycardia, opthalamic, antidote for cholinergic agonists, preop as an antisecretory agent

cholinergic antagonist 

produces peripheral effects similar to atropine, buts has greater CNS effects

longer duration of action

Actions: blocks short term memory and produces sedation at low doses, but excitation at high doses

may produce euphoria and is subj to abuse

uses: motion sickness, and to dilate pupils, also used for preop

cholinergic antagonists 

non selective and rarely used, blocks all ganglia

trimethophan used in rare emergency circumstances to lower BP

will see used in neurosurgery so you don't get a bleed into the brain

cholinergic antagonists 

1. Nondepolarizing

2. Depolarizing

MOA: block cholinergic transmission at the neuromuscular endplate

flaccid paralysis

relaxes mm tone

tubocurarine (prototype) - cholinergic antagonist

IV only, bc its a quaternary amine

does not cross BBB

most are eliminated unchanged in urine

Actions: prevents depol. and inhibits mm contracts

Uses: adjunct to anesthesia during surgery and helps with intibation

AE: death

Drug interactions: cholinesterase Inhibitor, Aminoglycosides (synergistic), Calcium channel blockers

cholinergic antagonist 

MOA: 1st stimulates the receptor, then causes flaccid paralysis; patient will have mm fasciculations

Succinylchoine (IV continuously bc of short duration)

metabolized by pseudocholinesterase

cholinergic antagonist - depolarizing NMB 

benefit: much shorter duration, can be used in out patient surgeries

indications: mm relaxation during surgery or when a patient is one a ventilator

 asst with endotracheal intubation

AEs: mucles soreness (esp in neck), apnea if patient is generally deficient in pseudocholinesterase

no bc of its multiplicity of actions and its rapid inactivation by the cholinesterases

Actions: dec in HR and CO

dec in BP

Inc GI secretions and motility

GU detrusor mm tone increase

ciliary mm contraction for near vision

constriction of pupil sphincter mm cause miosis

a study of the bichemical and physiologic effects of drugs and the molecular mechanisms by which those effects are produced

provides basis for the selection and use of drugs in specific diseases

Mechanisms of actions

therapeutic effects

specialized target macromolecules

very specific

enzymes

nucleic acids

membrane receptors

do all drugs exert their effects by interacting with a receptor?

most durgs act by forming weak, reversible, ionic bonds so the drug can dissociate

some drugs form very tight covalent bonds so they can't bounce off (ie poisons)

the relationship btwn the size of an administered dose and they intensity of the response produced

it determines the minimum amt of a drug we can use and the maximum response the drug will ilicit

ex: one aspirin will not do as much as two

as you increase the dose you get an increased response up to a certain point

as dosage is increased, the response increases and the therapeutic effects can be adjusted to fit the need of the patient

we can adjust a dose until we reach phase 3 when further increases in dose will not elicit a greater therapeutic response

the ability of the drug to illicit a response when it interacts with a receptor

dependent on the number of drug-receptor complexes formed

a drug that reacts with its receptor to produce a response that mimics the response to the endogenous ligand

it has intrinsic activity

quantal dose-response relationship

the influence of the magnitude of the dose on the proportion of the population that responds

therapeutic index = TD50/ED50

a measure of the drug's safety

TD = the does that produces toxicity

ED = the does that produces a therapeutic or desired response

measure the frequency of the desired response , to toxic response, at various doses of the drug

determined during drug trials and after market clinical experience

most drugs have a range of effective doses and a range of toxic doses