Pharm final 2

what do neurons influence

influences the behavior of postsynaptic cells (muscle cells, glandular cells)

axonal conduction

- conducts action potential through the axon of a neuron- activates all nerves it comes in contact

most common drug that uses axonal conduction

local anesthetics

synaptic transmission

- most drugs work via this pathway- info is carried across the gap between presynaptic neuron and postsynaptic neuron- involves neurotransmitter and receptor- once they bind = series of events occur

what happens when neurotransmitter and receptor bind

- series of events occur- depends on the neurotransmitter and the type of cell involved - if muscle: either relax or contract

presynaptic neuron

releases the neurotransmitter

postsynaptic neuron

where receptors are found

can neuronal process be altered while leaving other processes unchanged

- yes- there are multiple types of receptors regulating the process

high selectiveness of synaptic transmission

- effects of synaptic transmission can be highly selective
- the more receptors involved in a process = the more selective a drug because the drug can only affect the receptor that it has to

what happens if body process only has one receptor

- drug will be less selective bc there's not a lot of receptors to act on- drug would affect numerous organs and cause lots of ADRs

receptor binding

- directly binds reversibly to receptors on postsynaptic cell- 2 net effects: 1. enhance receptor activation (agonist)2. reduce receptor activation (antagonist)

agonist

- binds to receptors (affinity) then causes receptor activation (intrinsic activity)- agonists mimic the endogenous/natural substances in the body- ex. epinephrine, insulin

antagonist

- binds to receptors (affinity) to block receptor activation by the agonists (either endogenous or exogenous)- no intrinsic activity- cannot activate a receptor- ex. naloxone, antihistamines

termination of transmission

- transmitter becomes detached from receptor and needs to be removed from synaptic gap- 3 processes: reuptake, enzymatic degradation, reuptake/enzyme inhibitors

reuptake

- pumps transport transmitter molecules back into the neuron- either destroyed or packaged in vesicles for reuse

enzymatic degradation

synapse can contain large \# of enzymes to inactivate the transmitter

drugs can also interfere with reuptake or enzymatic degradation

- drugs can interfere with termination process (either reuptake or enzyme degradation)- increases concentration of transmitter in the synaptic gap = increased receptor activation
1. reuptake inhibitors - block transmitter reuptake (SSRI)2. enzyme inhibitors - inhibit transmitter degradation (cholinesterase inhibitors)

what is in CNS

- brain- spinal cord

what is in peripheral NS

1. somatic motor system - controls voluntary movement of muscles2. autonomic nervous system - for involuntary processes (parasympathetic or sympathetic)

3 principle functions of autonomic nervous system

1. regulation of heart2. regulation of secretory glands3. regulation of smooth muscles
- functions are shared between PNS and SNS

parasympathetic nervous system

- rest/digest- does housekeeping chores of body- digestion of food, excretion of waste- poisons act by mimicking or blocking the effects of PNS (insecticides, nerve gas)

7 regulatory functions of the parasympathetic NS

\>>1. increasing gastric secretion\>>2. emptying of bladder\>>3. emptying of bowel\>>4. focusing the eye for near vision (miosis)\>>5. constriction of pupil6. slowing HR7. contraction of bronchial smooth muscle
\>>primary reason why PNS drugs are used

3 regulatory functions of sympathetic NS

1. regulating CV system- increasing CO- vasoconstriction of blood vessels
2. regulating body temp
3. implementing acute stress response- fight/flight

how does SNS regulate cardiovasc system

- maintains brain blood flow- compensation of blood flow during blood loss- redistribution of blood flow during exercise

how does SNS regulate body temp

- it regulates blood flow to the skin: \> dilates vessels to cause heat loss when hot\> constricts vessels to conserve heat
- promotes sweat when body needs to cool- causing piloerection of skin hair for heat conservation

how does SNS promote fight/flight during stressful events

- increase HR and BP- dilate bronchi to increase oxygenation- shunt blood away from skin to the skeletal muscles- dilate pupils to enhance visual acuity- mobilize stored energy (glucose) to brain and muscles

drugs that affect SNS are good for what

- HTN- HF- angina- ashtma

mechanisms of regulating physiological processes

1. patterns of innervation and control2. feedback regulation3. autonomic tone

3 patterns of innervation and control

1. opposition2. complementary3. single innervation

opposition

- when process is innervated by both PNS and SNS- when sympathetic nerves oppose effect of parasympathetic nerves- ex. increase HR vs decrease

complementary

- innervated by both PNS and SNS- when symph nerve complements parasymph nerve effect- erection is parasympathetic; ejaculation is sympathetic

single innervation

- innervated by only one division- blood vessels solely innervated by sympathetic nerves- sweat glands solely innervated by parasympathetic nerves

feedback regulation

- allows system to adjust itself based on incoming data- ex. baroreceptor reflex

baroreceptor reflex

- regulates BP- frequently opposes attempts to modify BP with drugs
1. baroreceptors in carotid sinus and aortic arch monitor BP changes and sends it to brain2. brain sends impulses to heart and vessels to behave in a way that will normalize BP- to increase BP: vasoconstrict and increase CO- to decrease BP: vasodilate and lower CO

autonomic tone

- provides basal level of control - the predominant tone of an organ- most organs: PNS dominates except in the blood vessels bc it's only innervated by SNS

PNS anatomy

1. preganglionic neuron (spinal cord -> ganglion)2. ganglion - mass of nerve cell bodies3. postganglionic neuron (ganglion -> effector organ)

2 sites where drugs can act in PNS pathway

1. synapse between pregang and postgang neurons2. junctions between postgang and effector organ

SNS anatomy

- preganglionic and postganglionic neurons and effector organs- "preganglionic neuron": nerve leading to spinal cord -> adrenal medulla

adrenal medulla

- influences release of epi in blood- mimics effect when postgang neurons are stimulated

3 sites that drugs can act on in SNS

1. synapse between pregang and postgang neurons2. synapse between pregang and adrenal medulla3. junction between postgang and effector organ

somatic motor system anatomy

- only has one neuron- drugs affecting somatic system affects only one site: neuromuscular junction

neurotransmitters of parasympathetic NS

- acetylcholine

what neurons release acetylcholine

- all preganglionic neurons of PNS and SNS- all postganglionic neurons of PNS- postganglionic neurons of SNS that go to sweat glands- all motor neurons to skeletal muscles

what terminates Ach release

- enzymatic degradation by acetylcholinesterase (Ach-E)

neurotransmitters of sympathetic NS

- epinephrine- norepinephrine- dopamine

what releases norepinephrine and how it's terminated

- released by postganglionic neurons of SNS EXCEPT sweat glands- transmission terminated by reuptake of norepi- either reused or inactivated by monoamine oxidase or COMT

epinephrine

- major transmitter released by adrenal medulla- terminated by hepatic metabolism

dopamine

- primarily in CNS

peripheral NS receptor categories

1. cholinergic receptors - mediated by Ach - subtypes: nicotinic N, nicotinic M, muscarinic
2. adrenergic receptors- mediated by epi and norepi- subtypes: alpha 1&2, beta 1&2, dopamine

receptor subtypes

- responds to/mediated by the same transmitter but functions differently - knowing the sites of specific receptor subtypes helps predict what organ the drug will affect

importance of receptor subtypes

- allows dramatic increase in drug selectivity- drugs can be developed to influence certain receptor subtypes without affecting other ones

cholinergic receptor subtypes

- mediated by Ach (PNS, rest/digest)- nicotinic N (neuronal)- nicotinic M (muscle)- muscarinic

nicotinic N receptor

- promotes transmission at all ganglia of the PNS and SNS- also promotes release of epi from adrenal medulla

nicotinic M receptor

- causes skeletal muscle contraction at the neuromuscular junction

muscarinic receptor

- found on target organs of PNS1. increases glandular secretion in pulmonary, gastric, intestinal, sweat glands2. contraction of bronchial smooth muscles and GI3. decrease HR4. contraction of iris sphincter (=miosis)5. contraction of ciliary muscle = allows lens to focus for near vision6. blood vessels dilate7. contraction of detrusor muscle = allows voiding8. erection (increase blood flow to penis)

alpha 1 adrenergic receptor (SNS)

1. mydriasis (dilation of pupil)2. vasoconstriction of blood vessels3. contraction of smooth muscles of the bladder (trigone and sphincter) and prostatic capsule = prevents voiding4. ejaculation

alpha 2 adrenergic receptor (SNS)

- found on nerve terminals, not on organs- AKA presynaptic or prejunctional receptor
- regulates norepi release when too much has accumulated- ex. norepi can bind to alpha 2 and suppress further norepi release

beta 1 adrenergic receptor (SNS)

- found in heart and kidney1. cardiac beta 1- increases HR, force of contraction, and velocity of impulse at AV node
2. renal beta 1- releases renin in blood = promotes angiotensin (potent vasoconstrictor) = increased BP

beta 2 adrenergic receptor (SNS)

- lungs: bronchial dilation- uterus: relaxes uterine muscles to prevent delivery during stressful events- vasodilation of arterioles of heart, lungs, skeletal muscles (opposite of alpha 1)- liver: promotes glycogenolysis to increase glucose = for energy utilization - contraction of skeletal muscle

epinephrine can activate

- all alpha and beta receptors- but NOT dopamine receptors- only epi can activate beta 2, so only during fight/flight does beta 2 become significant

norepinephrine can activate

- alpha 1, alpha 2, beta 1 receptors- but NOT beta 2 or dopamine receptors

dopamine can activate

- alpha 1, beta 1, dopamine receptors

characteristics of cholinergic drugs

- influences activity of cholinergic receptors (nicotinic N, M, muscarinic)
- either:1. acts DIRECTLY at the receptors to MIMIC or BLOCK actions of Ach2. cholinesterase inhibitors act INDIRECTLY by preventing the breakdown of Ach to increase Ach activity

overview of muscarinic agonists

AKA parasympathomimetic agent, cholinergic drug- selectively MIMICS ach at muscarinic receptors- causes DIRECT receptor activation via binding to muscarinic receptors

principle structures affected by muscarinic agonists

- heart- exocrine glands- smooth muscles- eye

heart

decrease HR, vasodilation of vessels

exocrine glands

- increased gland secretion- increased sweat, salivation, bronchial secretion, gastric acid secretion

smooth muscles

- bronchoconstriction- GI constriction- increased GI tone and motility - bladder emptying bc contraction of detrusor and relaxed trigone and internal sphincter

eye

- miosis- ciliary muscle contraction (focuses the lens to allow near vision) (lens take on convex shape)

muscarinic agonist prototype

bethanechol - structurally the same as Ach

MOA for bethanechol

- interacts DIRECTLY with muscarinic receptors; little to no effect on nicotinic receptors - binds reversibly - causes typical PNS stimulation - not destroyed by Ach-E

therapeutic use of bethanechol

- to relieve urinary retention- activates muscarinic receptors in the bladder = contraction of detrusor; relaxation of trigone and sphincter
- for pts with urinary retention post-op and post-partum- NOT for pts with physical obstruction in the bladder bc increased contraction can cause injury/rupture

off label use of bethanechol

- tx for GERD (it increases esophageal motility)- for GI paralysis (it increases GI tone and motility)

bethanechol ADR

1. cv: hypotension (from vasodilation), bradycardia- so contraindicated in pts with low BP and CO
2. GI: excess salivation, increased GI acid secretion, diarrhea - contraindicated to pts with gastric ulcer (PUD)- increased gastric secretion can result to GI erosion, bleeding, perforation
3. rupture of bladder (from detrusor contraction)
4. respiratory: bronchoconstriction, increased bronchial secretion- contraindicated for asthma
5. eyes: blurred vision- constricted pupils can't see far vision

hyperthyroidism and bethanechol

- bethanechol is contraindicated to pts with hyperthermia
- normal person: muscarinic drug will lower BP -> baroreceptor reflex stimulated to fix this -> norepi release- norepi in hyperthyroidism pt can cause cardiac dysrythmia

topical pilocarpine

- eye drops/ophthalmic drug- for open angle glaucoma- reverses mydriasis by causing miosis- lowers intraocular pressure indirectly bc of contraction of iris sphincter and ciliary body = increases outflow of aqueous humor

oral pilocarpine

- Salagen- increases salivation- tx for xerostomia from Sjogren's Syndrome or salivary gland damage d/t radiation therapy of head and neck

acetylcholine

- produces rapid miosis following cataract surgery- limited use bc:1. lacks selectivity (will activate all cholinergic receptors, not just muscarinic)2. rapid enzyme degradation by Ach-E = too short of a half-life for clinical application

sources of toxicology of muscarinic agonists

1. ingestion of certain mushrooms 2. OD of direct-acting muscarinic agonists OR cholinesterase inhibitors

symptoms of muscarinic poisoning

diarrhea, diaphoresisurination (excess)miosisbradycardia (can lead to heart block), bronchospasm, bronchial secretions, hypotensionemesislethargylacrimation, excesssalivation, excess

treatment for muscarinic poisoning

atropine (selective muscarinic antagonist)

overview of muscarinic antagonists

AKA parasympatholytic agent, anticholinergic drug- only muscarinic receptor is affected, not nicotinic- competitively blocks Ach from binding at muscarinic receptors- also blocks some receptors of SNS target organs (blood vessels, sweat glands)- produces receptor blockade- effects opposite of muscarinic agonists

muscarinic antagonist prototype

atropine - no direct effect on its own (no intrinsic activity)- just simply prevents Ach binding (has affinity) and muscarinic activation

where is atropine found

- naturally in a variety of plants- Atropa belladonna (deadly nightshade)

atropine overview

- affects same structures as muscarinic agonists- effects are dose dependent- occupies receptor sites at parasympathetic nerve endings, leaving few free to respond to Ach- adm orally, topically (ophthalmic), parenterally

atropine therapeutic uses

1. preanesthetic medication- anesthesia can cause profound bradycardia = atropine prevents dangerous decease in HR- prevents secretions of glands (saliva, bronchial secretions)
2. tx for bradycardia - increases HR
3. for eye disorders- can cause mydriasis and paralysis of ciliary body = helps in eye exams and eye surg- causes cycloplegia (eye doesn't move)
4. tx for intestinal hypertonicity and hypermotility - decreases BM, abdominal cramps- for diverticulitis, dysentery
5. tx for muscarinic agonist poisoning (with bethanechol)
6. tx for biliary colic- abdominal pain bc of gallstone blockade- relaxes bile tract smooth muscle via vasodilation of vessels

atropine for PUD and asthma

- for PUD: decreases gastric secretion but there's S/E = xerostomia, constipation, urinary retention- secondary drug if H2RA or PPI don't work
- for asthma: decrease bronchial secretion and cause dilation of lungs

atropine ADR (8)

1. xerostomia- decreased salivation = can impede swallowing- oral hygiene, sip fluids, chew sugar-free gum, alc-free mouthwash, saliva substitute
2. blurred vision, photophobia- near vision is blurry d/t mydriasis, ciliary muscle relaxation- lower bright light, sunglasses, avoid hazardous activities
3. elevated IOP bc of mydriasis and ciliary body paralysis- can block aq humor so contraindicated for glaucoma pts
4. urinary retention- relaxed detrusor, contracted internal sphincter- contraindicated for BPH- tx with catheterization or bethanechol - void before taking atropine to prevent retention

atropine ADR cont

5. constipation- bc of decreased GI motility- increase dietary fiber, fluids, physical activity, may need laxative
6. anhidrosis - no sweating = risk for hyperthermia- no overexertion
7. tachycardia
8. asthma exacerbation- drying and thickening of bronchi

atropine in older adults

- don't give for elderly pts bc of the ADRs- weigh benefits vs risks

5 muscarinic receptors

1. M1, M3, M5- activators- when stimulated, opens Ca channels = increases actions of Ach in muscarinic receptors
2. M2, M4- inhibitors- when stimulated, opens K channels = decreases actions of Ach
*M4, M5 not clinically relevant

M1

- found in salivary glands and CNS- increased saliva- enhance memory, cognition

M2

found only in heart- decrease HR

M3

- found in:1. salivary glands (increase) 2. detrusor muscle of bladder (contracts = pee)3. GI smooth muscle (promote peristalsis)4. eye - contraction of iris (miosis)- contraction of ciliary muscle (will allow near vision)- contraction of lacrimal gland (promotes tears)

what happens if muscarinic M2 receptor is activated

- M2 is found in heart = decreases HR

urge incontinence or overactive bladder

disorder with 4 major symptoms:1. urinary urgency2. nocturia3. urinary frequency (8x more/day)4. urge incontinence (involuntary urine leakage)

nonpharmacologic intervention for OAB and incontinence

- bladder training (voiding schedule)- Kegel exercises- time fluid intake - avoid caffeine

anticholinergic therapy for urge and OAB

1. darifenacin2. oxybutynin3. tolterodine4. mirabegron

darifenacin

- highest degree of M3 selectivity- blocks M3 on bladder to prevent contraction of detrusor

oxybutynin

blocks M3 on detrusor muscle