Chapter 2 Peripheral nervous system drugs - cholinergic agonists (cholinomimetics) Flashcards
Direct cholinergic systems
- NT of parasympathetic nervous system, NMJ (neuromuscular junction), and autonomic ganglia — acetylcholine
- in brain as well — memory formation, motor skills
- Muscarinic (M) receptors — postganglionic parasympathetic and CNS functions of acetylcholine
- Nicotinic receptors — ganglia + NMJ
- Choline esters — choline bound to acetyl derivate by an ester bond [this bond is hydrolyzed by enzymes called cholinersterases [acetylcholinesterase])
- Cholinomimetic alkaloids – derived from platns by alkaline extraction; cannot be metaoblized by cholinesterases (d/t being chemically distinct from choline esters)
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Nicotine —
1) stimulates CNS
2) releases epinephrine from adrenal glands
3) stimulates + blocks receptors in ganglia and at NMJ (in these two cases; when nicotine binds to nicotinic receptor L/T depolarization of postsynaptic neuron - in contrast to other agonists, nicotine remains at receptors preventing further stimulation of occupied receptor; the action of nicotine at each target visceral organ depends on the sympathetic or parasympathetic being predominant at the time
acetylcholine
M 1-3, N
**M1 **
1) stomach - increased acid pepsin in secretion stimulation
2) ganglion – increased stimulation (increased autonomic ganglia depolarization)
3) CNS – increased neurotransmission (inc’d memory, attention and emotional response)
M2
1) SA node – slow diastolic depolarization, bradycardia (inc’d k+ conduction or in the case of hyperkalemia – means membrane potential decreases making it more positive (d/t more +K inside cell) thus increasing excitability HOWEVER — the onset value of membrane potential determines how many sodium voltage gated channels open in beginning of action potential)
- therefore, LOWER (or in this case more positive membrane potential) resting membrane value closer to the action potential threshold means less Na+ channels open causing the depolarization to occur more slowly [the resting membrane potential is shifted to a less negative value, that is, from −90 mV to −80 mV, which in turn moves the resting membrane potential closer to the normal threshold potential of −75 mV, resulting in increased myocyte excitability.]
2) Atria – decreased contractility, dec’d conduction velocity, and decreased refractory period ( a period of time during which a cell is incapable of repeating an action potential. In terms of action potentials, it refers to the amount of time it takes for an excitable membrane to be ready to respond to a second stimulus once it returns to a resting state)
3) AV node – slow conduction (Conduction is how electrical impulses travel through your heart, which causes it to beat. Some conduction disorders can cause arrhythmias, or irregular heartbeats), AV block (Atrioventricular block is a heart rhythm disorder that causes the heart to beat more slowly than it should. It’s caused by communication problems within the heart’s electrical conduction system. )
4) Lung — bronchoconstriction (slow breathing rate), increased secretion
5) Stomach — increased motility
6) bladder — contract detrusor, relax sphincter
7) penis – erection
M3
1) glands – increased secretions
2) eye - miosis (When your pupil shrinks (constricts), it’s called miosis.)
nicotinic
1) skeletal muscle — contraction
2) ganglion — stimulation (ganglionic transmission) – refer to diagram in google docs with muscarinic receptors in yellow borders (HAS acetylcholine nicotinic receptors)
3) CNS — neurotransmission (CNS excitation and release of adrenaline [adrenal medulla])
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clinical use — miosis in cataract surgery
contraindications
* peptic ulcer, CAD, hyperthyroidism (atrial fibrillation), asthma, mecahnical bladder obstruction
autonomic ganglia
An autonomic nerve pathway involves two nerve cells. One cell is located in the brain stem or spinal cord. It is connected by nerve fibers to the other cell, which is located in a cluster of nerve cells (called an autonomic ganglion). Nerve fibers from these ganglia connect with internal organs. Most of the ganglia for the sympathetic division are located just outside the spinal cord on both sides of it. The ganglia for the parasympathetic division are located near or in the organs they connect with.
action potential
- Normally, the inside of the cell is more negative than the outside; neuroscientists say that the inside is around -70 mV with respect to the outside, or that the cell’s resting membrane potential is -70 mV.
- This membrane potential isn’t static. It’s constantly going up and down, depending mostly on the inputs coming from the axons of other neurons. Some inputs make the neuron’s membrane potential become more positive (or less negative, e.g. from -70 mV to -65 mV), and others do the opposite.
- These are respectively termed excitatory and inhibitory inputs, as they promote or inhibit the generation of action potentials (the reason some inputs are excitatory and others inhibitory is that different types of neuron release different neurotransmitters; the neurotransmitter used by a neuron determines its effect).
- Action potentials are the fundamental units of communication between neurons and occur when the sum total of all of the excitatory and inhibitory inputs makes the neuron’s membrane potential reach around -50 mV (see diagram), a value called the action potential threshold.
- Neuroscientists often refer to action potentials as ‘spikes’, or say a neuron has ‘fired a spike’ or ‘spiked’. The term is a reference to the shape of an action potential as recorded using sensitive electrical equipment.
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* dendritic receptors (release chemical signal to active channels)
* ca++, na+, and cl- (more outside) can enter the cell with these ligand gated channels (starts in one end of axon) // while inside (k+ and a- or neg charged anions ==> give net negative charge inside the cell of -65 mv relative to the outside environment)
* voltage gated k+ and na+ closed
* enough EPSP (excitatory postsynaptic potentials) around the dendrites (intiial part of axon) then can collectively push membrane potential to about -55 mV (becomes less negative or becomes less polar or depolarized!) /// can be an inhibitory PSP or IPSP
* at axon hilock w/ bunch of voltage gated channels (e.g na+ gated channels) activate when this (-55 mv threshold value) => sodium rush into cells
* setting off chain reaction off entire axon ==> action potential (essentially fired)
* cell becomes positively charged relative to external environment ( +40 mv)
* depolarization ends when Na+ channel stops allowing sodium to flow into cells (inactivation gate [blocks channel compared to closed state], which blocks Na+ influx shortly after depolarization until cell repolarizes and channel enters a closed state again [no more inactivation gate this point])
* **OPENED na+ voltage gated channels stay open for short window **
* Potassium voltage gated channel (slow to respond and don’t open until na+ channels have already opened and become inactivated
* After initial na+ rush, K+ flows out (down its electrochemical gradient) removing some positive charge and blunt the na+ depolarization [K+ has no inactivation gate, so stays open longer causing membrane potential to become more negative or repolarize
* DURING repolarization, the cell also relies on na+-K+ pump (active transporter; removes 3 na+ out of cell for 2 K+ back into cell) => during this phase it’s called the absolute refractory period since na+ channels are inactivated and won’t respond to any amount of stimuli!
* this refractory period keeps APs from happening too closely or moving backward
* this l/t hyperrepolarization (d/t pump and extended potassium channel opening) or overcorrection relative to resting potential (na+ channels go back to intitial closed state and potassium remain open longer) [-75 mv]
* Next is relative refractory period [sodium channels closed, and potassium channels remains open a bit longer meaning the cell can be depolarized again only with a STRONGER stimulus]
* finally as K+ channels close => reach resting membrane potential (As the potassium channels close, the sodium-potassium pump works to reestablish the resting state)
* resting membrane potential
1. more sodium ions outside than inside the neuron
2. more potassium ions inside than outside the neuron
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The cell however maintains a fairly consistent negative concentration gradient (between -40 to -90 millivolts). How?
- The neuron cell membrane is super permeable to potassium ions, and so lots of potassium leaks out of the neuron through potassium leakage channels (holes in the cell wall).
- The neuron cell membrane is partially permeable to sodium ions, so sodium atoms slowly leak into the neuron through sodium leakage channels.
- The cell wants to maintain a negative resting membrane potential, so it has a pump that pumps potassium back into the cell and pumps sodium out of the cell at the same time.
Carbachol (miostat) (isopto carbachol)
choline derivative
M 1-3, N
**M1 **
1) stomach - increased acid pepsin in secretion stimulation
2) ganglion – increased stimulation (increased autonomic ganglia depolarization)
3) CNS – increased neurotransmission (inc’d memory, attention and emotional response)
M2
1) SA node – slow diastolic depolarization, bradycardia (inc’d k+ conduction or in the case of hyperkalemia – means membrane potential decreases making it more positive (d/t more +K inside cell) thus increasing excitability HOWEVER — the onset value of membrane potential determines how many sodium voltage gated channels open in beginning of action potential)
- therefore, LOWER (or in this case more positive membrane potential) resting membrane value closer to the action potential threshold means less Na+ channels open causing the depolarization to occur more slowly [the resting membrane potential is shifted to a less negative value, that is, from −90 mV to −80 mV, which in turn moves the resting membrane potential closer to the normal threshold potential of −75 mV, resulting in increased myocyte excitability.]
2) Atria – decreased contractility, dec’d conduction velocity, and decreased refractory period ( a period of time during which a cell is incapable of repeating an action potential. In terms of action potentials, it refers to the amount of time it takes for an excitable membrane to be ready to respond to a second stimulus once it returns to a resting state)
3) AV node – slow conduction (Conduction is how electrical impulses travel through your heart, which causes it to beat. Some conduction disorders can cause arrhythmias, or irregular heartbeats), AV block (Atrioventricular block is a heart rhythm disorder that causes the heart to beat more slowly than it should. It’s caused by communication problems within the heart’s electrical conduction system. )
4) Lung — bronchoconstriction (slow breathing rate), increased secretion
5) Stomach — increased motility
6) bladder — contract detrusor, relax sphincter
7) penis – erection
M3
1) glands – increased secretions
2) eye - miosis (When your pupil shrinks (constricts), it’s called miosis.)
nicotinic
1) skeletal muscle — contraction
2) ganglion — stimulation (ganglionic transmission) – refer to diagram in google docs with muscarinic receptors in yellow borders (HAS acetylcholine nicotinic receptors)
3) CNS — neurotransmission (CNS excitation and release of adrenaline [adrenal medulla])
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clinical use — glaucoma (topically); Antiglaucoma miotics stimulate the parasympathetic nervous system to make pupils contract (miosis), which increases the outflow of aqueous humor and reduces the pressure inside the eye (intraocular pressure). Aqueous humor is a clear fluid that fills the space between the lens and the cornea in the eyes)
contraindications
* where constriction is undesirable
additional — reisistive to cholinersterase degradation (long half-life)
methacholine (provocholine)
choline derivative
- M1, M2, M3
- weak nicotinic agonist
M1
1) stomach - increased acid pepsin in secretion stimulation
2) ganglion – increased stimulation (increased autonomic ganglia depolarization)
3) CNS – increased neurotransmission (inc’d memory, attention and emotional response)
M2
1) SA node – slow diastolic depolarization, bradycardia (inc’d k+ conduction or in the case of hyperkalemia – means membrane potential decreases making it more positive (d/t more +K inside cell) thus increasing excitability HOWEVER — the onset value of membrane potential determines how many sodium voltage gated channels open in beginning of action potential)
- therefore, LOWER (or in this case more positive membrane potential) resting membrane value closer to the action potential threshold means less Na+ channels open causing the depolarization to occur more slowly [the resting membrane potential is shifted to a less negative value, that is, from −90 mV to −80 mV, which in turn moves the resting membrane potential closer to the normal threshold potential of −75 mV, resulting in increased myocyte excitability.]
2) Atria – decreased contractility, dec’d conduction velocity, and decreased refractory period ( a period of time during which a cell is incapable of repeating an action potential. In terms of action potentials, it refers to the amount of time it takes for an excitable membrane to be ready to respond to a second stimulus once it returns to a resting state)
3) AV node – slow conduction (Conduction is how electrical impulses travel through your heart, which causes it to beat. Some conduction disorders can cause arrhythmias, or irregular heartbeats), AV block (Atrioventricular block is a heart rhythm disorder that causes the heart to beat more slowly than it should. It’s caused by communication problems within the heart’s electrical conduction system. )
4) Lung — bronchoconstriction (slow breathing rate), increased secretion
5) Stomach — increased motility
6) bladder — contract detrusor, relax sphincter
7) penis – erection
M3
1) glands – increased secretions
2) eye - miosis (When your pupil shrinks (constricts), it’s called miosis.)
nicotinic
1) skeletal muscle — contraction
2) ganglion — stimulation (ganglionic transmission) – refer to diagram in google docs with muscarinic receptors in yellow borders (HAS acetylcholine nicotinic receptors)
3) CNS — neurotransmission (CNS excitation and release of adrenaline [adrenal medulla])
clinical use – diagnostic for bronchial airway hyperreactivity (an increase in sensitivity to a wide variety of airway narrowing stimuli. Most patients with asthma and chronic obstructive pulmonary disease (COPD) exhibit such an enhanced sensitivity) w/o clincally apparent asthma
contraindicated for pts receiving beta blockers (Beta blockers work by blocking the effects of the hormone epinephrine, also known as adrenaline. Beta blockers cause the heart to beat more slowly and with less force, which lowers blood pressure. Beta blockers also help widen veins and arteries to improve blood flow.)
note — short duration d/t cholinesterase degradation
bethanechol (urecholine) (duvoid)
choline derivative
M 1-2, and nicotinic agonist
M1
1) stomach - increased acid pepsin in secretion stimulation
2) ganglion – increased stimulation (increased autonomic ganglia depolarization)
3) CNS – increased neurotransmission (inc’d memory, attention and emotional response)
M2
1) SA node – slow diastolic depolarization, bradycardia (inc’d k+ conduction or in the case of hyperkalemia – means membrane potential decreases making it more positive (d/t more +K inside cell) thus increasing excitability HOWEVER — the onset value of membrane potential determines how many sodium voltage gated channels open in beginning of action potential)
- therefore, LOWER (or in this case more positive membrane potential) resting membrane value closer to the action potential threshold means less Na+ channels open causing the depolarization to occur more slowly [the resting membrane potential is shifted to a less negative value, that is, from −90 mV to −80 mV, which in turn moves the resting membrane potential closer to the normal threshold potential of −75 mV, resulting in increased myocyte excitability.]
2) Atria – decreased contractility, dec’d conduction velocity, and decreased refractory period ( a period of time during which a cell is incapable of repeating an action potential. In terms of action potentials, it refers to the amount of time it takes for an excitable membrane to be ready to respond to a second stimulus once it returns to a resting state)
3) AV node – slow conduction (Conduction is how electrical impulses travel through your heart, which causes it to beat. Some conduction disorders can cause arrhythmias, or irregular heartbeats), AV block (Atrioventricular block is a heart rhythm disorder that causes the heart to beat more slowly than it should. It’s caused by communication problems within the heart’s electrical conduction system. )
4) Lung — bronchoconstriction (slow breathing rate), increased secretion
5) Stomach — increased motility
6) bladder — contract detrusor, relax sphincter
7) penis – erection
M3
1) glands – increased secretions
2) eye - miosis (When your pupil shrinks (constricts), it’s called miosis.)
nicotinic
1) skeletal muscle — contraction
2) ganglion — stimulation (ganglionic transmission) – refer to diagram in google docs with muscarinic receptors in yellow borders (HAS acetylcholine nicotinic receptors)
3) CNS — neurotransmission (CNS excitation and release of adrenaline [adrenal medulla])
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clinical use — induce evacuation of non-obstructed bladder; ALSO increase GI motility following surgery
contraindications – peptic ulcer, CAD, hyperthyrodism (atrial fib.), asthma, mechanical bladder obstruction, beta blockers, bradycardia, parkinsonism, epilepsy, hypotension, hypertension, constriction not needed (bladder, GI)
Cevimeline
alkaloids
M 1-3
M1
1) stomach - increased acid pepsin in secretion stimulation
2) ganglion – increased stimulation (increased autonomic ganglia depolarization)
3) CNS – increased neurotransmission (inc’d memory, attention and emotional response)
M2
1) SA node – slow diastolic depolarization, bradycardia (inc’d k+ conduction or in the case of hyperkalemia – means membrane potential decreases making it more positive (d/t more +K inside cell) thus increasing excitability HOWEVER — the onset value of membrane potential determines how many sodium voltage gated channels open in beginning of action potential)
- therefore, LOWER (or in this case more positive membrane potential) resting membrane value closer to the action potential threshold means less Na+ channels open causing the depolarization to occur more slowly [the resting membrane potential is shifted to a less negative value, that is, from −90 mV to −80 mV, which in turn moves the resting membrane potential closer to the normal threshold potential of −75 mV, resulting in increased myocyte excitability.]
2) Atria – decreased contractility, dec’d conduction velocity, and decreased refractory period ( a period of time during which a cell is incapable of repeating an action potential. In terms of action potentials, it refers to the amount of time it takes for an excitable membrane to be ready to respond to a second stimulus once it returns to a resting state)
3) AV node – slow conduction (Conduction is how electrical impulses travel through your heart, which causes it to beat. Some conduction disorders can cause arrhythmias, or irregular heartbeats), AV block (Atrioventricular block is a heart rhythm disorder that causes the heart to beat more slowly than it should. It’s caused by communication problems within the heart’s electrical conduction system. )
4) Lung — bronchoconstriction (slow breathing rate), increased secretion
5) Stomach — increased motility
6) bladder — contract detrusor, relax sphincter
7) penis – erection
M3
1) glands – increased secretions
2) eye - miosis (When your pupil shrinks (constricts), it’s called miosis.)
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clinical use - dry mouth assoicated with sjogren’s syndrome (An autoimmune disease that causes dryness of the mouth, eyes and other places)
contraindications – peptic ulcer, CAD, hyperthyrodism (atrial fib.), asthma, mechanical bladder obstruction, beta blockers, bradycardia, parkinsonism, epilepsy, hypotension, hypertension, constriction not needed (bladder, GI)
note – DERIVED FROM seed known as betel nut!
Pilocarpine (pilocar) (sopto-carpine)
alkaloids
M 1-3 (not nicotinic?)
M1
1) stomach - increased acid pepsin in secretion stimulation
2) ganglion – increased stimulation (increased autonomic ganglia depolarization)
3) CNS – increased neurotransmission (inc’d memory, attention and emotional response)
M2
1) SA node – slow diastolic depolarization, bradycardia (inc’d k+ conduction or in the case of hyperkalemia – means membrane potential decreases making it more positive (d/t more +K inside cell) thus increasing excitability HOWEVER — the onset value of membrane potential determines how many sodium voltage gated channels open in beginning of action potential)
- therefore, LOWER (or in this case more positive membrane potential) resting membrane value closer to the action potential threshold means less Na+ channels open causing the depolarization to occur more slowly [the resting membrane potential is shifted to a less negative value, that is, from −90 mV to −80 mV, which in turn moves the resting membrane potential closer to the normal threshold potential of −75 mV, resulting in increased myocyte excitability.]
2) Atria – decreased contractility, dec’d conduction velocity, and decreased refractory period ( a period of time during which a cell is incapable of repeating an action potential. In terms of action potentials, it refers to the amount of time it takes for an excitable membrane to be ready to respond to a second stimulus once it returns to a resting state)
3) AV node – slow conduction (Conduction is how electrical impulses travel through your heart, which causes it to beat. Some conduction disorders can cause arrhythmias, or irregular heartbeats), AV block (Atrioventricular block is a heart rhythm disorder that causes the heart to beat more slowly than it should. It’s caused by communication problems within the heart’s electrical conduction system. )
4) Lung — bronchoconstriction (slow breathing rate), increased secretion
5) Stomach — increased motility
6) bladder — contract detrusor, relax sphincter
7) penis – erection
M3
1) glands – increased secretions
2) eye - miosis (When your pupil shrinks (constricts), it’s called miosis.)
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clinical use —
* cystic fibrosis sweat test
* glaucoma (miotic)
* xerostomia (sensation of oral dryness, which can result from diminished saliva production)
Cystic fibrosis (CF) is a genetic (inherited) disease that causes sticky, thick mucus to build up in organs, including the lungs and the pancreas. In people who have CF, thick mucus clogs the airways and makes it difficult to breathe. Management includes ways of clearing lungs and eating correctly.
If you do have CF, thick mucus clogs the airways and makes it difficult to breathe.
Mucus also blocks the ducts in the pancreas, causing problems with digesting food. Babies and children who have CF might not be able to absorb enough nutrients from food. CF, which is chronic (long-lasting) and progressive (getting worse over time), also affects your liver, sinus, intestines and sex organs.
contraindications – peptic ulcer, CAD, hyperthyrodism (atrial fib.), asthma, mechanical bladder obstruction, beta blockers, bradycardia, parkinsonism, epilepsy, hypotension, hypertension, constriction not needed (bladder, GI)
nicotine
- nicotinic
nicotinic
1) skeletal muscle — contraction
2) ganglion — stimulation (ganglionic transmission) – refer to diagram in google docs with muscarinic receptors in yellow borders (HAS acetylcholine nicotinic receptors)
3) CNS — neurotransmission (CNS excitation and release of adrenaline [adrenal medulla])
clinical use – smoking cessation aid
- contraindications – peptic ulcer, CAD, hyperthyrodism (atrial fib.), asthma, mechanical bladder obstruction, beta blockers, bradycardia, parkinsonism, epilepsy, hypotension, hypertension, constriction not needed (bladder, GI)
2nd messengers (apply to all drugs here!)
- m1 – G-protein + phosphatidyl inositol
- m2 - inc K+ conduction (SA node), dec cAMP (atria and AV node), inc cGMP (other ograns)
- m3 - phosphatidyl inositol
nicotinic receptor — opens Na+ channel; influx depolarizes cell
