Pharmacology

Front 1

What are the three components of the ANS? What can they be divided into? What are the neurotransmitters? What are the major regulators (if applicable?)

Back 1

1. The sympathetic system ("fight or flight"). The main neurotransmitters are adrenaline and noradrenaline.
2. The parasympathetic system ("rest and digest"). The main neurotransmitter is acetylcholine.
3. The enteric system--a collection of nerve fibers innervating the GI tract, pancreas, and gall bladder--specifically, their smooth muscle, secretory cells, endocrine cells, and blood vessels. The enteric nervous system is regulated by a balance between the sympathetic and parasympathetic systems.
Major regulators of the enteric nervous system are:
a. Substance P
b. VIP
c. 5-hydroxytryptamine

Front 2

In the ANS, how are efferent messages carried down? To where?

Back 2

Efferent messages from the autonomic nervous system get carried down a pre-ganglionic neuron, which extends from the brain, down the spinal cord, and synapses on a ganglion. Then, a post-ganglionic neuron transmits the information from the ganglion to the target organ.

Front 3

How do the ganglia in the parasympathetic and sypathetic systems differ?

Back 3

In the parasympathetic system, the ganglia tend to be close to the target organ.

In the sympathetic system, the ganglia form two chains on either side of the spinal cord, far from their target organs.

Front 4

What is the established structure of regulation of the ANS? (Integrates and transmits afferent information that feeds into the ANS)

Back 4

Cerebral cortex (frontal lobe)

Limbic lobe (emotional input)

Hypothalamus (overall integration of ANS - "the boss")

Reticular formation of brain stem (regulation of pupil size, respiration, heart, BP, swallowing, etc)

Spinal cord (urination, defecation, erection, ejaculation)

Front 5

Which branch of the NS dominates the arteriole?

Back 5

Sympathetic (adrenergic)

Front 6

Which branch of the NS dominates the veins?

Back 6

Symp (adrenergic)

Front 7

Which branch of the NS dominates the heart?

Back 7

Parasymp

Front 8

Which branch of the NS dominates the radial muscle of he iris?

Back 8

Symp (alpha andregenic)

Front 9

Which branch of the NS dominates the sphincter of the iris

Back 9

Parasymp

Front 10

Which branch of the NS dominates the ciliary muscle of the eye?

Back 10

Parasymp

Front 11

Which branch of the NS dominates Muler's muscle

Back 11

Symp (a-andregenic)

Front 12

Which branch of the NS dominates the bronchial smooth muscle?

Back 12

Parasymp

Front 13

Which branch of the NS dominates the GI tract?

Back 13

Parasymp

Front 14

Which branch of the NS dominates the urinary tract?

Back 14

Parasymp

Front 15

Which branch of the NS dominates the salivary glands?

Back 15

Parasymp

Front 16

Which branch of the NS dominates the eccrine sweat glands?

Back 16

Symp (cholinergeic)

Front 17

Which branch of the NS dominates the apocrine sweat glands?

Back 17

Symp (a-andregenic)

Front 18

Which branch of the NS dominates the pilomotor muscles?

Back 18

Symp (a-andregenic)

Front 19

What are the parasympathetic (1) and sympathetic (2) actions for the eye?

Back 19

1. Contraction of pupil for near vision, increased secretion from lacrimal glands

2.Dilation of pupil for ar vsion

Front 20

What are the parasympathetic (1) and sympathetic (2) actions for the trachea and bronchioles?

Back 20

1. Constiction, increased secretion

2. Dilation

Front 21

What are the parasympathetic (1) and sympathetic (2) actions for the adrenal medulla?

Back 21

1. none

2. Secretion of epinephrine and norepinephrine

Front 22

What are the parasympathetic (1) and sympathetic (2) actions for the kidney?

Back 22

1. none

2. Secretion of renin

Front 23

What are the parasympathetic (1) and sympathetic (2) actions for the ureters and blader?

Back 23

1. Contraction of detrusor, relaxation of trigone a sphincter

2. Relaxation of detrusor, contraction of trigone and sphincter

Front 24

What are the parasympathetic (1) and sympathetic (2) actions for the male genitalia?

Back 24

1. Erection

2. Ejaculation

Front 25

What are the parasympathetic (1) and sympathetic (2) actions for the female genitalia?

Back 25

1. None

2. Relaxation of the uterus

Front 26

What are the parasympathetic (1) and sympathetic (2) actions for the lacrimal glands?

Back 26

1. Tears

2. None

Front 27

What are the parasympathetic (1) and sympathetic (2) actions for the salivary glands?

Back 27

1. Thick, viscous secretion

2. Copious, watery secretion

Front 28

What are the parasympathetic (1) and sympathetic (2) actions for the heart?

Back 28

1. Inreased rate and contractility

2. Decreased rate and contractility

Front 29

What are the parasympathetic (1) and sympathetic (2) actions for the GI tract?

Back 29

1. Increased motility and muscle one. Increased secretion.

2. Decreased motility and muscle tone

Front 30

What are the parasympathetic (1) and sympathetic (2) actions for the blood vessels in skeletal muscle?

Back 30

1. Dilation

2. None

Front 31

What are the parasympathetic (1) and sympathetic (2) actions for the blood vessels in skin, mucous membranes, and splanchnic areas?

Back 31

1. None

2. Consticton

Front 32

What are the organs that only have sympathetic innveration?

Back 32

Adrenal medula
Kidneys
Pilomotor muscles
Sweat glands

BP also mainly controlled by symp innervatiion.

Front 33

What are andregenic receptors? What are cholinergenic receptors? Both of these receptors can be involved in the sympathetic NS.

Back 33

1. Receptors on which epinephrine and norepinephrine act

2. Receptors on which ACh acts

Front 34

The parasympathetic NS only utlizes what type of receptors?

Back 34

Cholinergenic

Front 35

What are the steps in cholinergenic neurotransmission?

Back 35

1. Ach synth
2. Storage of Ach
3. Release of Ach
4. Receptor binding
5. Degreadation of Ach
6. Choline reuptake

Front 36

Describe ACh synthesis. What drug can block this step?

Back 36

1. i. A Na/choline co-transporter brings choline (a charged molecule, derived from a phospholipid called lecithin) from the ECF into the cell. Choline cannot diffuse through the membrane on its own because it has a positively charged N group. This is a slow process, and the rate limiting step in choline synthesis.

Can be blocked by hemichollinium.

Choline reacts with acetyl CoA to form ACh. This reaction is catalyzed by acetyltransferase.

Front 37

Describe storage of ACh. What drug can block this step?

Back 37

a proton-driven active transport system moves choline in vesicles for storage, along with ATP and proteoglycan.

Vesamicol blocks the uptake of ACH into the vesicles

Front 38

Describe release of Ach. What drug can block this step?

Back 38

an action potential triggers the opening of voltage-gated Ca channels in the pre-synaptic membrane. Ca floods the cell and triggers the ACH vesicles to fuse with the cell membrane and release ACH into the synaptic cleft.

i. The botulinum toxin blocks ACH release
ii. Black widow spider venom causes uncontrolled ACH release

Front 39

Describe receptor binding. What drug can block this step?

Back 39

ACH diffuses across the synaptic cleft and binds to a receptor on the post-synaptic cell. There are two different classes of receptors that ACH can bind to:
i. Muscarinic
ii. Nicotinic

Front 40

Describe degradation of ACh. What drug can block this step?

Back 40

acetylcholine esterase cleaves ACH into choline and acetate.
Butyrylcholine esterase, found in the plasma, does not play a significant role in signal termination.

Front 41

Describe choline reuptake?

Back 41

a Na-coupled transporter moves choline back into the pre-synaptic cell, for use in forming new ACH. ACH can also be recycled directly, via ACH autoreceptor proteins on the membrane of the presynaptic cell.

Front 42

What is the process of neurotransmitter release? What triggers?

Back 42

1. Docking

2. Priming

3. Fusion with plasma membrane

Fusion of the vesicle with the plasma membrane is triggered by calcium.

Front 43

What are the major proteins involved in the docking and fusion process?

Back 43

1. Synaptobrevin and synaptotagmin

2. SNAP-25 and syntaxin

Front 44

Describe the docking and fusion process.

Back 44

1. Synaptobrevin tangles with SNAP-25 and syntaxin

2. Fusion occurs when Ca binds to synaptotamin, on the vesicular membrane, signaling it to fuse with the plasma membrane.

Front 45

How does botulinum work? What is it? What are the subgroups?

Back 45

Botulinum is a proteaste that inhibits ACh release by degrading these proteins.

A and E degrade SNAP-25
C1 degrades syntaxin
B, D, F, and G degrade synaptobrevin

Front 46

How is ACh is degraded?

Back 46

by ACh esterase into choline and acetate.

Front 47

What is the structure of ACh esterase? Where does cleavage occur? How does it work out?

Back 47

1. Anionic binding site

2. Eseratic binding site

Cleavage happens first at the anionic site, then at the esteratic site, releasing choline and acetate.
Blocking ACH esterase will initially increase ACH concentration in the synaptic cleft. However, eventually, ACH concentration will go back down, since a feedback loop will signal the presynaptic neuron to stop synthesizing ACH.

Front 48

What is BChE, and where is it found?

Back 48

similar to ACH esterase, but is present in higher concentrations in the circulation, and in lower concentrations in neurons and the NMJ.

Front 49

What are the two types of cholinergenic receptors?

Back 49

1. Nicotinic (ligand-gated)

2. Muscarinic (GPCRs)

Front 50

Where are nicotinic receptors? What is their structure? How do they function? What are they inhibited by?

Back 50

ligand-gated ion channels, composed of 5 subunits, that open when ACH binds to the α subunit and allow Na into the cell and K out of the cell, resulting in depolarization.

Nicotinic receptors are present in the CNS, autonomic ganglia, adrenal medulla, and NMJ.
Nicotinic receptors in neurons are called Nn receptors. They are inhibited by hexamethonium.

Nicotinic receptors in the NMJ are called Nm receptors. They are inhibited by tubocurarine.

Front 51

What are the effects of nicotine?

Back 51

1. Blood pressure increase (mediated by the sympathetic system)

2. Increase in peristalsis (mediated by the parasympathetic system)

3. NA and adrenalin release (sympathetic system, due to effects of nicotine on adrenal gland)

Front 52

What characterizes the odd-numbered M receptors?

Back 52

excitatory. ACH binding triggers increased concentrations of IP3 and DAG as second messengers.

Front 53

Where are the locations of the M1 receptors?

Back 53

CNS and autonomic ganglia

Front 54

Where are the locations of the M3 receptors?

Back 54

smooth muscle of the colon, bladder, and bronchi (triggers contraction)

Front 55

Where are the locations of the M5 receptors?

Back 55

nerves in the CNS (participate in positive, presynaptic feedback in the CNS)

Front 56

wher are the locations of the M4 receptors?

Back 56

Nerves in the CNS

Front 57

What is the general action of the M3 receptor?

Back 57

Trigger contraction of smooth muscle.

GPCR that activates PLC to cleave PIP2 in the cell membrane into IP3 and DAG.

IP3 triggers the release of Ca from the SR. Calcium then activates myosin light chain kinase which phosphorylates myosin and triggers muscle contraction.

Front 58

Go through the process of muscle contraction.

Front 59

Go through the process of muscle contraction.

Back 59

Front 60

What effect do M3 channels have on endothelial cells? Why? How?

Back 60

smooth muscle relaxation, rather than smooth muscle contraction. This is due to the presence of nitric oxide.
1. In endothelial cells, two mechanisms provide for an increase in intracellular Ca:
A. Shear (mechanical) stress on the cells
B. Binding of ACH to the M3 channels, as previously described (ad nauseum)
2. Then, Ca activates an enzyme called nitric oxide synthase, that catalyzes the degradation of L-arg into NO and citrulline
3. NO diffuses into the smooth muscle cells, where it activates guanylate cyclase
4. Guanylate cyclase converts GTP to cGMP, stimulating smooth muscle relaxation

Front 61

Describe the process of smooth muscle relaxation

Back 61

Front 62

What are NANCs? What is their purpose?

Back 62

Another source of NO to stimulate blood vessel dilatation are NANCs (non-adrenergic non-cholinergic neurons), which secrete NO directly into the smooth muscle cells.

Front 63

What are the two mechanisms in which NO concentration is increased in the penis?

Back 63

1. M3 activation, leading to activation of NO synthase, and NO production from L-arg
2. NANCs

Front 64

In terms of NO release in the penis, what does increased NO concentration result in? How is it inhibited?

Back 64

Increased NO concentration results in increased levels of cGMP, which causes smooth muscle relaxation.
This process can be stopped by an enzyme called phosphodiesterase 5, which degrades cGMP into GMP.
Viagra works by inhibiting phosphodiesterase 5. This prevents the degradation of cGMP and increases arteriolar relaxation, causing prolonged erection

Front 65

What two types of nicotinic receptors exists? What is the difference?

Back 65

1. Nn
2. Nm
Both are ligand gated Na/K channels, letting Na out and K into the cell. They are composed of five subunits, the first four of which are the same. However, the Nn channels have a γ subunit, while the Nm channels have an ε subunit.

Front 66

Describe Nm receptors and their role in muscle contraction.

Back 66

The entry of Na into the muscle cell causes the membrane to depolarize.
Entry of Na into the cell triggers the release of Ca from the SR, activating contraction. Then, a voltage-gated receptor called the DHPR receptor, and binds to a Ca channel on the SR called the ryanodine receptor. The ryanodine receptor then opens, flooding the cell with Ca, which triggers muscle contraction.

Front 67

What are the co-transmitters of cholinergenic sypases?

Back 67

1. ATP--activates a purinergic receptor called the P2Y receptor at the edge of the cholinergic nerve, and inhibits more ACH release from the presynaptic nerve
2. VIP--also released with ACH, VIP causes relaxation of smooth muscle
i. In the salivary glands, VIP relaxes the blood vessels while ACH increases the secretion of saliva

Front 68

What are the general efects of cholinergenic muscarinic agonists?

Back 68

1. On internal organs--the same effects sympathetic innervation would have, i.e. increased muscle contractility and secretion from glands

2. Blood vessels--relaxation and vasodilatation, due to activation of NO synthase via the M3 channels

3. Sweat glands--increased secretion

Front 69

What are the effects of specific muscarinic agonists on M1 of the ELC (in stomach)?

Back 69

Increased histamine secretion, causes increased acid secretion.

Front 70

What are the effects of specific muscarinic agonists on M3 in the eye?

Back 70

Contracts the pupil for near vision, increases secretion from the lacrimal glands

Front 71

What are the effects of specific muscarinic agonists on M3 in the salivary glands?

Back 71

Increased secretion

Front 72

What are the effects of specific muscarinic agonists on M3 in the bronchiolar SM?

Back 72

Contraction

Front 73

What are the effects of specific muscarinic agonists on M3 in the staomch?

Back 73

Contraction of SM, increased gastrin and acid secretion (Which are also increased indrectly, by histamine secreted from ECL cels, which bin to H2 receptors on parietal cells)

Front 74

What are the effects of specific muscarinic agonists on M3 in the colon?

Back 74

Increased peristalsis

Front 75

What are the effects of specific muscarinic agonists on M3 in bladder?

Back 75

Contraction of detrusor to release uine.

Simultaneously, NO relaxes the urethra.

Front 76

What are the effects of M3 agonists on the eye?

Back 76

1. Iris--contracts, to shrink pupil (miosis)
2. Ciliary muscle--contracts to relax lens and enable near vision
3. Lacrimal glands--increased secretion

Front 77

What are M3 agonsts used for in the eye?

Back 77

To enhance near vision and treat glaucoma.

Front 78

What are direct M3 muscarinic agonists? What are they used for?

Back 78

Muscarinic agonists mimic the effects of ACH on muscarinic receptors. They are used to treat GI tract and genitourinary system disorders. They are also used for post-operative atony and neurogenic bladders.

Front 79

What are examples of M3 agonist drugs? What are they used for?

Back 79

1. Bethanechol -- promote Gi and urinary tract motility

2. Pilocarpine -- mitotic agent and sialogogue in treatment of xerostomia

3. Methacholine -- diagnosis of asthma

Front 80

What is Bethanechol?

Back 80

a derivative of acetylcholine, in which the acetate is replaced by carbamate, and the choline is methylated. This methylation protects bethanecol from degradation by ACH esterase.

Front 81

What s pilocarpine?

Back 81

has a similar structure to muscarine.

Because pilocarpine is lipophilic, it can cross the BB. It's primary use is in treating eye disorders, such as glaucoma. It produces rapid miosis and contraction of the ciliary muscle. Because it stimulates secretion from the lacrimal gland, it is very useful in lowering intraocular pressure. Because it is not specific to a particular type of muscarinic receptor, it is given topically, in small doses.

Front 82

What is methacholine?

Back 82

has the same structure as ACH, but with an additional methyl group, to prevent degradation by ACH esterase.

Front 83

What are the systemic side effects of muscarinic antagonists?

Back 83

1. Dry mouth, swallowing difficulties
2. Blurred vision
3. Urinary retention
4. Constipation
5. Dry, reddish skin (dry, due to decreased secretions, red, due to unexplained vasodilation of blood vessels in the skin)
6. Increased heart rate
7. Reduced gastric acid secretion
8. "Atropine fever," increased body temperature, due to increased metabolic rate, especially in children
9. Hallucination and confusion

Front 84

What are the clinical uses for muscarinic antagonists?

Back 84

1. Diagnostic purposes in eye exams (Atropine/Atrospan)
2. GI disorders such as IBS and colon spasms (Atropine/Spasmalgin)
3. Asthma, to relax bronchiolar smooth muscle (Ipratropium bromide/Aerovent)
4. Bradycardia, especially during surgery (Atropine)
5. Incontinence (tolterodine/Dertozitol)
6. Nerve gas toxicity (Atropine, with TMB-4, or Toxogonine, Atropine, and Benactizine; "TAB")

Front 85

What are examples of direct muscarinic antagonists?

Back 85

1. Atropine
2. Scopolamine

Front 86

How do atropine and scopolamine work> What so they do?

Back 86

In the eye, atropine relaxes the sphincter muscle of the iris to causes mydriasis (dilated pupil). The ciliary muscles contract, flattening the lens and enhancing far vision. Atropine should NOT be given to patients with glaucoma.
In the GI tract, atropine reduces motility and is used as an antispasmodic. It also can treat hypermotility of the bladder and excess secretions, especially in the salivary glands.
In the heart, atropine causes:
-bradycardia at low doses
-increased heart rate at higher doses
Another direct muscarinic antagonist, scopolamine, produces similar effects to atropine, but has a longer duration, and a greater impact on the CNS. It is used to treat motion sickness.

Front 87

What are examples of indirect cholinergic agonists? What do they do?

Back 87

Inhibitors of ACHE and BCHE
ACH esterase (and BCH esterase) prevent degradation of ACH in the synaptic cleft, thereby increasing its concentration.

Endrophonium
Physostigmine
Pyridostigine

ACHE inhibitors bind to ACH esterase and inactivate it. Their action is reversible. The half life of the drug depends on its affinity for ACHE.

Front 88

What do indirect cholinergic agonist affect?

Back 88

1. Sympathetic and parasympathetic ganglia
2. Target organs innervated by parasympathetic fibers or sympathetic cholinergic fibers
3. The NMJ
4. The CNS (if the agent crosses the BB)

Front 89

What are the parasympathetic effects of indirect cholinergenic agonists?

Back 89

Decreased heart rate
Bronchiolar contraction
Increased colon motility and secretion
Increased activity and secretion in the bladder

Front 90

What are the sympathetic effects of indrect cholinergenic agoniss?

Back 90

sweating

Front 91

What are the NMJ efects of indirect cholinergenic agonists?

Back 91

Muscle contraction

Front 92

How does diagnosis and treatment of myasthenia gravis utilize indirect cholinergeic agonists?

Back 92

Endrophonium, a short-acting indirect cholinergic agonist, is used for diagnosis

Pyridostigmine, a long-acting indirect cholinergic agonist, is used for treatment

Front 93

What are organophosphate toxins?

Back 93

irreversible ACHE inhibitors of ACHE, due to their extremely high affinity for ACHE. Organophosphate toxins are present in nerve gases such as Soman, Sarin, Tabun, and Vx. Nerve gas binds to the esteratic and anionic sites of ACHE, incapacitating its activity.

Front 94

What are the effects of nerve gas? Sympathetic, Sympthatic, Skeletal Muscle, CNS effects.

Back 94

1. Parasympathetic effects--
i. Decreased heart rate
ii. Contraction of bronchiolar SM
iii. Increase in saliva secretion
iv. Diarrhea
v. Increased urination
2. Sympathetic effects
i. Sweating
ii. Hypotension
3. Skeletal muscle effects
i. Paralysis, due to desensitization of nicotinic receptors in the NMJ
4. CNS effects (because it can cross the BB)
i. Spasms
ii. Loss of concentration
iii. Inhibition of the respiratory system

Front 95

How can defense of nerve gas be made?

Back 95

Organophosphate toxins are present in nerve gases such as Soman, Sarin, Tabun, and Vx. Nerve gas binds to the esteratic and anionic sites of ACHE, incapacitating its activity.
These compounds will fall off the ACHE if another compound is injected that binds to the nerve gas with a higher affinity than ACHE (ex: oxime). Such compounds are given to soldiers in injections, combined with atropine, to combat the cholinergic effects, as a defense against nerve gas. The combined injection is called TMB-4. Quick IV administration is need in order to be effective. High doses are needed, but an overdose will inhibit ACHE, due to the atropine included in the injection.

Front 96

What are examples of nicotinic receptor agonists?

Back 96

1. Nicotine (present in tobacco)
2. Lobeline (present in tobacco)
3. DMPP (does not cross the BB)

Front 97

What are the effects of nicotinic agonists?

Back 97

1. Parasympathetic
i. Contracts colon, bladder, and bronchioles
2. Sympathetic
i. Contracts blood vessels
ii. Tachycardia
3. Skeletal muscle
i. Increased contraction
4. CNS
i. Increased alertness
ii. Stimulation of the respiratory system

Front 98

What does nicotinic toxicity result in?

Back 98

1. Hypertension
2. Arrhythmias
3. Convulsions
4. Respiratory interruptions

Nicotinic receptor drugs work on both the sympathetic and parasympathetic systems, and have widespread effects.

Front 99

What are specific nicotinic agonists?

Back 99

Specific nicotinic antagonists (that are not in clinical use) include:
1. Hexamethonium
2. Trimethaphan
Their effects are exactly opposite to the effects of nicotinic agonists.

Front 100

What are NMJ blockers? Examples?

Back 100

NMJ blockers block ACH from acting on nicotinic receptors in the NMJ. They are structural analogues of ACH, and can be either antagonists or agonists.

1. Tuocurarine
2. Sucinylcholine

Front 101

What is tubocurarine?

Back 101

NMJ blocker that competitively inhibits the binding of ACH to nicotinic receptors on the muscle cell. It also triggers the release of histamine from mast cells (which in turn can cause bronchiolar constriction). Tubocurarine may be used in surgery to relax skeletal muscle.

Front 102

What is succinylcholine?

Back 102

depolarizing blocker, which will bind to the nicotinic receptors and cause a transient muscle twitch, but then not fall off, prevent further action potentials from being transmitted to the muscle.
Eventually, in the presence of a depolarizing blocker, the receptors will become desensitized and the cell will gradually repolarize, producing flaccid paralysis.

Front 103

What are clinical uses of NMJ blockers?

Back 103

1. Easing intubations
2. Relaxing skeletal muscles during surgery
3. Easing invasive tests
4. During electroshock therapy to depressive tests, to ease convulsions

Front 104

What are examples of AChE(irreversible)?

Back 104

ISOFLURATE
Echothiophate
Parathion

Chronic treatment of open-angle glaucoma
Nerve gas
Atropine used to treat organophosphate poisoning

Front 105

What are examples of AChE reactivation drugs? What do they do?

Back 105

Pralidoxime

reactivate inhibited acetylcholinesterase before aging occurs

Front 106

What are examples of ganglionic blockers? What are they used for?

Back 106

NICOTINE
HEXAMETHONIUM
Mecamylamine
Trimethaphan

Trimethaphan- emergency lowering of BP

Front 107

What are examples of antimuscarinic drugs? For what are they used?

Back 107

ATROPINE
Ipratropium
Scopolamine
Propantheline
Benztropine

- Atropine- mydriatic + cycloplegic effects
- antidote for organophosphate overdose
- Scopalamine- prevention of motion sickness
- Ipratropium- second-line therapy in Asthma, COPD
- Benztropine- treatment of Parkinson’s disease
-Toxic effects- “Dry as a bone, Hot as a hare, Red as a beet, Blind as a bat, Mad as a hatter”- Dry mouth, Inhibition of sweating, Tachycardia and cutaneous vasodilation, Blurring of vision, Hallucinations and delirium

Front 108

What are NMJ blockers (nondepolarizing) used for?

Back 108

adjuvant drugs for anesthesia
actions can be reversed by edrophonium or neostigmine

Drugs that end in "curonium"

Front 109

What are NMJ blockers (depolarizing)? What are they used for?

Back 109

Succinylcholine
Decamethonium

rapid hydrolosis by plasma cholinersterase
Phase I blockade- continuous depolarization; Phase II blockade- neuromuscular blockade (muscle resistant to further depolarization
Dantrolene- treats malignant hyperthermia caused by administration of halothane/succinylcholine
- blocks release of Ca++ from sarcoplasmic reticulum

Front 110

What are the neurotransmitters that act in the sympathetic NS?

Back 110

adrenaline (technically, a hormone)and noradrenaline (a neurotransmitter). ACH still plays a role in the sympathetic system because it is the neurotransmitter that acts on the sympathetic ganglia. It also stimulates secretion of adrenaline from the adrenal medulla. Dopamine is the neurotransmitter that acts on renal vascular smooth muscle.

Front 111

How is noradrenaline converted to adrenaline?

Back 111

Noradrenaline is converted to adrenaline mainly in the adrenal medulla, by the addition of a methyl group to the amine, catalyzed by N-methyl transferase.

Front 112

What is the process of the adrenergic synapse?

Back 112

1. Dopamine synthesis
2. NA synth and storage
3. NA secreted from vescles
4. NA can bind to receptors, dffuse into blood, or undergo reuptake then enter the post-ganglionic cell where it is degraded.

Front 113

Describe dopamine synthesis in the adrenergic synapse? What is the rate limiting step?

Back 113

i. Tyrosine (from which all catecholamines are derived) enters the cell via a Na co-transporter
ii. Tyrosine hydroxylase converts tyrosine to DOPA in the cytoplasm (rate limiting step)
iii. DOPA is decarboxylated to form dopamine (DA)

Front 114

Describe NA synth and storage in the adreneric synaspse.What is it inhibited by?

Back 114

i. DA is transported into the vesicles by an amine transporter system (inhibited by reserpine)
ii. In the vesicles, DA is converted into NA by dopamine hydroxylase

Front 115

Describe secretion of NA from vesicles in the adrenergic synapse/ What is it inhibited by?

Back 115

3. NA is secreted from vesicles, in response to a calcium influx (inhibited by guanethidine and bretylium)

Front 116

What happens when NA is finally inside the adrenergic synaptic cleft Is there any inhibition? Degradation? How?

Back 116

i. Bind to receptors and continue the signal transduction
ii. Diffuse into the blood
iii. Undergo reuptake by adrenal receptors on the pre-synaptic cell (inhibited by cocaine and imipramine)
1. Once back inside the cell, it can either be degraded by monoamine oxidase (MAO), an enzyme present on the outer membrane of the mitochondria, or transported back into the vesicles.
Inside the cell, NA has no effect. Its only activity comes from binding to adrenoreceptors.
4. Enter the post-ganglionic cell, where it is degraded by a cytoplasmic enzyme called COMT.

Front 117

Describe the synthesis of NA. What happens in the brain? In storage vesicles?

Back 117

Tyrosine (or phenylalanine) is converted to DOPA by the addition of a hydroxyl group to the benzene ring, via tyrosine hydroxylase.
DOPA is converted to DA by removal of the carboxyl group, via DOPA decarboxylase.
In the brain, the pathway ends with the step, leaving DA as the end product.
In the storage vesicles, DA is converted to NA by the addition of a hydroxyl group, via DA β-hydroxylase

Front 118

Describe the synthesis of NA. What happens in the adrenal glands? In dopaminergic neurons?

Back 118

In the adrenal glands, phenylethanolamine reacts with NA to form adrenaline, via the addition of a methyl group. This reaction is catalyzed by phenylethanolamine N-methyl transferase.

In dopaminergic neurons, tyrosine is converted to DA, and does not continue on to become NA.

Front 119

What regulates adrenaline storage? How is it transported? How is it formed?

Back 119

regulated by alterations in pH. The pH in the cytoplasm is 7.1. the vesicles are more acidic, with a pH of 5.5, which is maintained by an ATP-driven proton pump. To get into the vesicles, DA (or NA) is transported by a non-specific catecholamine/proton exchanger. Therefore, the entry of DA into the vesicles is accompanied by a loss of protons, hence, a rise in pH.
At a concentration of .3-1 M, NA combines with 4 ATPs and chromogranin A to form a complex. However, as the pH in the vesicle rises, driven by an influx of NA, this complex dissociates, freeing the NA to be active, upon release.

Front 120

What are MAO and COMT? VMA?

Back 120

In the pre or post-synaptic cell, NA is degraded either by MAO or COMT
MAO is an enzyme found on the outer mitochondrial membrane in adrenergic nerves and epithelial cells of the liver and colon
COMT is found in the cytoplasm of post-synaptic cells and in epithelial cells of the liver and colon
NA should not be given per os, because it will be degraded in the liver by COMT before it reaches its target cells.
The final product of NA metabolism is VMA (vanilyl mandelic acid). Because VMA is excreted by the kidneys, it can be detected in the urine, and is used for diagnostic purposes.

Front 121

What are agents that decrease NA concentration in the adregenic synaptic cleft? For what are they use? How do they work?

Back 121

1. α-methyltyrosine--inhibits tyrosine hydroxylase, which ultimately inhibits DA and NA formation. Not in clinical use.
2. Reserpine--inhibits the storage of NA in vesicles by inhibiting the NA transporter. This results in the accumulation of NA in the cytoplasm, where it is metabolized by MAO. Reserpine was previously used to treat hypertension, but was discontinued because it causes depression.

Front 122

What are agents that increase NA concentration in the andergenic synaptic cleft? For what are they used? How do they work?

Back 122

1. Cocaine--inhibits the reuptake of NA. It also acts as a local anesthetic, by blocking Na channels. Cocaine has a short half life, and is degraded by BuCHE.
2. Indirect sympatomimetic agents--increase the release of catecholamines from vesicles and competitively inhibit their reuptake.

Front 123

What are examples of indirect synaptomimetic agents?

Back 123

i. Amphetamine, methamphetamine
ii. MDMA (street name, ecstasy)
iii. Ephedrine-
iv. Tyramine-
v. Ritalin (methylphenidate)

Front 124

What are amphetamines used for?

Back 124

used to treat ADHD, narcolepsy, and obesity. Chronic abuse causes paranoia, hallucination, and other psychiatric symptom.

Front 125

How does MDMA work?

Back 125

uses the Na-coupled tyr transporter to get into the cell, and from there, enters the vesicles. In the vesicles, MDMA binds to protons, thereby raising the pH. This allows NA to dissociate from the ATP/chromogranin complex, leave the vesicles via the H+ coupled NA transporter, and exit the cell through non-voltage-gated NA channels. Thus, in the presence of MDMA, NA can exit the cell without being triggered by an action potential.

Front 126

How does ephedrine work? What is it used for?

Back 126

a partial adrenergic agonist that has a long half life, because it is a poor substrate for MAO and COMT. Can cross the BBB. Stimulates the CNS and raises heart rate and blood pressure. Sometimes used for asthma and runny noses (because it causes blood vessels to constrict).

Front 127

What is tyramine?

Back 127

a normal byproduct of tyrosine metabolism, normally oxidized by MAO. Not widely used clinically, and found in fermented foods.

Front 128

What is ritalin? How does it ork?

Back 128

)--similar to amphetamines, Ritalin increases the concentration of DA and NA. It is given to hyperactive children to increase focus and concentration, and is sometimes abused as a stimulating drug.
(Amphetamine, ephedrine, tyramine, and Ritalin all cross the BBB.)

Front 129

What are the effects of agents that increase catecholamines? Talk about the effects on the CNS, in the perphery, and in the cases of OD.

Back 129

1. In the CNS
i. Wakefulness, concentration, loss of appetite, mental and motor stimulation
2. In the periphery
i. Tachycardia
ii. Increase in blood pressure
3. In cases of an OD
i. Cardiac arrhythmias
ii. Critical hypertension
iii. CNS convulsions

Front 130

What are the metabolites of catecholamines?

Back 130

COMT degrades compounds that have two hydroxyl groups.
MAO degrades compounds that have a methyl group on the alpha position
Tyramine, amphetamine, and ephedrine are all degraded by MAO, but not by COMT

Front 131

Why should patients on MAO inhibitors avoid tyramine in their diets?

Back 131

Foods rich in tyramine, such as aged cheese and red wine should be avoided by patients on MAO inhibitors because tyramine is degraded only by MAO, and not COMT. Therefore, tyramine will build up, and lead to hypertension and tachycardia.

Front 132

Where are the a1 adrenergic receptors work? What are their mechanisms?

Back 132

Smooth muscle in blood vessels

Increases IP3 and DAG, which raises Ca concentrations and contractility

Front 133

Where are the a2 adrenergic receptors work? What are their mechanisms?

Back 133

Adrenergic nerves, vasomotor center

Decreases cAMP, which opens K channels, hyperpolarizing the cell

Front 134

Where are the b1 adrenergic receptors work? What are their mechanisms?

Back 134

Cardiac muscle

Increases cAMP, leading to an increase in Ca and contractility

Front 135

Where are the b2 adrenergic receptors work? What are their mechanisms?

Back 135

Smooth muscle on internal organs

Increases cAMP

Front 136

Where are the b3 adrenergic receptors work? What are their mechanisms?

Back 136

Fat cells

Increases cAMP

Front 137

What happens when NA binds to an a1 receptor in smooth muscle?

Back 137

When NA binds to α1 receptors in smooth muscle cells in blood vessels, it increases intracellular calcium, resulting in contraction.

ATP acts as a co-transporter for the α1 receptor.

Front 138

What are the effects of a1 receptors?

Back 138

1. Raise blood pressure, due to contraction of smooth muscle on most blood vessels
2. Contract the bladder sphincter to retain urine
3. Dilate pupils (mydriasis) by contracting radial muscle of iris
4. Contract pilomotor muscles on hair follicles

Front 139

What are the effects of a2 receptors? Example of an agonist? Side effects?

Back 139

1. Inhibit noradrenaline release from presynaptic cells
2. Decrease sympathetic activity
3. Cause contraction of some blood vessels
And example of an α2 agonists is Clonidine (α-methyldopa), which is used to treat hypertension and drug withdrawal (for addicts). Side effects include platelet aggregation, inhibition of fat decomposition, inhibition of insulin release, and sweating.

Front 140

What are the effects of b1 receptors?

Back 140

1. Increase heart rate and contractility
2. Increase renin release in the kidneys

Front 141

What are the effects of b2 receptors?

Back 141

1. Stimulate relaxation of the smooth muscle in the blood vessels, bladder, bronchi, and uterus
2. Increase glycogenolysis and K+ uptake in smooth muscle
i. Overactivity may result in a tremor
3. Stimulate glycogenolysis and gluconeogenesis in the liver
4. Stimulate insulin secretion

Front 142

What are the effects of b3 rceptors?

Back 142

Stimulate fat decomposition in adipose cells

Front 143

How is ATP used as a co-transmitter with NA?

Back 143

1. Activates ligand-gated Na channels called P2x channels in blood vessel smooth muscle. This activation produces the depolarization that triggers the influx of Ca.
2. Activates channels called P2y channels in adrenergic nerves that inhibit the release of noradrenaline

Front 144

How is Nueropeptide Y used as a c-transmitter with NA?

Back 144

1. Acts as an additional neurotransmitter in sympathetic neurons innervating blood vessels
2. Activates receptors in adrenergic neurons to inhibit the release of noradrenaline
3. Activates postsynaptic receptors on blood vessels that cause prolonged contraction

Front 145

What are the different responses of ATP, NA, and NPY in blood vessel contraction?

Back 145

ATP has a short-term effect
Noradrenaline has a medium range effect
NPY has a long-term effect

Front 146

Wat are the effects of NA on the b1 receptor in the heart? SA node vs pacemaker.

Back 146

In the SA node, noradrenaline has the opposite effects to ACH; it binds to a β1 receptor which leads to increased cAMP-->PKA function, and increased heart rate.


In pacemaker cells, NA also binds to β1 channels, which increase cAMP concentrations (via adenylate cyclase). This opens Na channels, allowing the cells to depolarize and fire, increasing contractility and heart rate. NA also stimulates the entry of Ca through L-type channels by increasing cAMP and PKA concentrations. PKA then phosphorylates the L-type channels, increasing their activity, and further depolarizing the cells.

Front 147

What, again, are the effects of ACh during vagal stimulation of muscarinic channel?

Back 147

cAMP and PKA concentrations are lowered, thereby downregulating the activity of the If and L-type Ca channels.

Front 148

What are the effects of NA on the b1 receptors in heart? Cardiac muscle cells.

Back 148

, NA binds to β1 receptors, increasing cAMP and PKA levels, as usual. Then, PKA opens Ca channels in the cell membrane and the SR, allowing Ca to enter the cell and promote contraction.

Front 149

What are the Effects of NA on The β2 Receptor in Smooth Muscle?

Back 149

When NA binds to β2 receptors on smooth muscle cells, it increases cAMP--> PKA concentrations. PKA inactivates the MLCK (myosin light chain kinase) by phosphorylating it, thereby preventing muscle contraction.

Front 150

What are the effects of NA on the bladder?

Back 150

NA has different effects on different parts of the bladder:
The detrusor muscle contains β2 receptors. When stimulated by NA, it relaxes.
The sphincter contains α1 receptors. When stimulated by NA, it contracts.
The net effect is urine retention (Mnemonic: type A is tense, type B is relaxed)

Front 151

Describe fluctuating blood pressure in relation to the NSs and NA.

Back 151

When baroreceptors in the carotid sinus sense increased blood pressure, the vasomotor center in the brain responds by increasing parasympathetic activity and decreasing sympathetic activity.
A neuron in the vasomotor center uses NA to signal inhibitory α2 receptors. This downregulates adrenergic neurons going to the blood vessels and heart. At the same time, parasympathetic innervation of the heart increases. Peripheral vascular resistance and heart rate decrease.

Front 152

What are the general names for drugs that affect the sympathetic NS?

Back 152

Sympathomimetics--direct or indirect sympathetic agonists
Sympatholytics/sympathoplegics--sympathetic antagonists

Front 153

What are examples of drugs that affect the sympathetic system? What receptors do they affect? What are their clinical uses?

Back 153

Front 154

What are Adrenergic Agonists' Effects on Blood Pressure?

Back 154

α1 Vasoconstriction TPR and BP go up
β1 Heart rate and stroke volume increase Cardiac output and BP go up
β2 vasodilatation TPR and BP go down

Front 155

What are examples of adrenergic agonists and their effects on blood pressure?

Back 155

1. Noradrenaline--acts on α1 and β1 receptors, causing blood pressure to rise.
2. Adrenaline--acts on α1, β1, and β2 receptors, causing BP to go up slightly
3. Isoprenaline--acts on β1, and β2 receptors, causing TPR to fall and BP to remain basically the same

Front 156

In the nervous system, the transfer of information in the brain involved what? What is the main factor in information transfer?

Back 156

Presynaptic spikes
Transmitter release
Postsynaptic response
Postsynaptic spikes

It is unclear whether the main factor in information transfer is the number of voltage spikes, or their temporal patter (i.e. their frequency).

Front 157

What are the different types of information loops in which neurons can participate?

Back 157

1. Feeback
2. Feed-forward
3. Lateral inhibition

Front 158

How can excitatory synapses be distinguished from inhibitory ones?

Back 158

Excitatory synapses can be distinguished from inhibitory synapses, because they have small structures called spines on the dendrites of the post-synaptic neurons that have high receptor concentrations.

Front 159

A single dendrite will receive what kind of signals?

Back 159

A single dendrite will receive both excitatory and inhibitory signals. The ratio of excitatory:inhibitory synapses across a neuron is roughly 3:1.
Excitatory neurons depolarize.
Inhibitory neurons hyperpolarize.

Front 160

What are potential drug drug targets during neurotransmitter synthesis, storage, and release?

Back 160

1. Uptake of precursors
2. Synthesis of the neurotransmitter (can happen either in neurons or in glial cells)
3. Storage of neurotransmitters in synaptic vesicles (ex: amphetamine inhibits vesicular transporters)
4. Degradation of the neurotransmitter in the vesicles or neurons (ex: MAO inhibitors)
5. Depolarization, via the action potential (ex: Phenytoin)
6. Influx of Ca2-
7. Exocytosis of neurotransmitter vesicles
8. Diffusion of the neurotransmitter in the synaptic cleft
9. Interaction of the neurotransmitter with postsynaptic receptors (ex: Diazepam, Memantine)
10. Interaction of the neurotransmitter with presynaptic receptors
11. Inactivation of the neurotransmitter (ex: Tacrine)
12. Reuptake of the neurotransmitter (Prozac, cocaine)

Front 161

What determines the number of neurotransmitters? Where is concentration the highest?

Back 161

1. NT concentration
2. Vesicular size
3. Vesicular transport

The concentration of NT is high in the synaptic cleft, since a single action potential can trigger the release of multiple vesicles.

Front 162

What factors have effect on receptors? What is horizontal alignment?

Back 162

The kinetics of vesicle release also affect the concentration of NT in the synaptic cleft (e.g. full fusion v. kiss and run mechanism). The geometry of the cleft (note the curves near the regions of NT release) is another factor that helps concentrate NT in regions where there is a high concentration of postsynaptic receptors. Between curves, there is spillover of neurotransmitter between neighboring synapses. Because the geometry of the synapse is so important, misalignment of the synaptic cleft can greatly reduce the efficacy of neurotransmitter release. Horizontal alignment is important for keeping concentration effective.

Front 163

What are the factors that affect receptor activation?

Back 163

1. Amount of NT released
2. Kinetics of vesicle release
3. Concentration of NT near the surface of postsynaptic receptors

Front 164

What are the major types of neurotransmitters?

Back 164

1. Amino Acids
2. Catecholamines
3. ACh
4. Neuropeptides
5. Other

Front 165

What are the amino acid NT?

Back 165

Excitatory:
Aspartate
Glutamate
(NDMA, AMPA, Kainate, AP-4)

Inhibitory:
GABA
Glycine
(Muscimol, Baclofen)

Front 166

What are the catecholamine NT?

Back 166

1. Noradrenaline
2. Dopamine
3. Serotonin (5-HT)

Front 167

What are the "other" NT?

Back 167

1. NO
2. Histamine
3. Purines

Front 168

What are the three mechanisms of NT action? What are the major difference b/w these three pathways?

Back 168

1. Direct activation -- the NT causes an ion channel to open or close

2. Indirect membrane activation of a channel -- through GPCR/Gβγ signaling --all the participants are membrane proteins.

3. Indirect activation of a channel through diffusion of a second messenger -- classical GPCR pathway

The major difference b/w these pathways is the time frame.

Front 169

What is glutamate's role in the brain? What are its pathways for its synthesis?

Back 169

Glutamate is the major excitatory NT in the brain. There are two possible pathways for its synthesis:
1. Transamination of alpha-ketoglutarate (a substrate of the Kreb cycle) in neurons.
2. Production from glutamine in glial cells, which is then transported to the presynaptic terminal and converted to glutamate by the enzyme glutaminase.

Front 170

What are the categories of glutamate receptors? What are some examples?

Back 170

1. Ionotropic -- form ion channel pores
- AMPA
- NMDA
- Kainate

2. Metabotropic -- do not form ion channel pores and are usually located on the periphery of the synapse (extrasynaptic receptors)
- mGluR (of which there are 8 known subtypes)

Front 171

What are AMPA receptors? Where are they located ? What are the different subunits? What is the significance? How are they activated? What is the process of desensitization?

Back 171

AMPA receptors are widespread in the CNS. They have 4 subunits, and are cation-selective channels, permeable to both Na+ and K+. Receptors that contain the Glu-R2 subunit are impermeable to Ca. Receptors that don't contain the Glu-R2 subunit are permeable to Ca, and act as inward rectifiers.
Activation of AMPA receptors is determined by phosphorylation. One glutamate can bind to each subunit of the receptor. These receptors are easily desensitized, and mediate fast, excitatory currents.
AMPA receptors play a role in learning and memory.

Front 172

Where do AMPA receptors play the biggest role? How are AMPA receptors related to age?

Back 172

AMPA receptors are the major receptors in nerve terminals, because they are responsible for transmitting the depolarization. A synapse with no AMPA receptors is called "silenced."
Young animals have many silenced synapses, that lack AMPA receptors. As they learn, they develop more AMPA receptors, indicating that the insertion of AMPA receptors in synapses is a possible mechanism for learning and memory. This has been demonstrated in animal models, but not yet in people.

Front 173

How are kainate receptors structured?

Back 173

Kainate receptors are similar to AMPA receptors, also composed of 4 subunits (GluR5-7 and Ka1-2). They are permeable to Na+ and K+, and some subunits to Ca+.
(NB: kainate is a synthetic glutamate analogue.)

Front 174

What are NDMDA receptors? What are they involved in? What is the significance of the various subunits? What are the most crucial subunits?

Back 174

NMDA receptors are also composed of 4 subunits (two NR1 and two NR2 subunits), and involved in learning and memory. The type of subunits determine decay kinetics of the current, and are developmentally regulated--the more NR2b subunits the receptors have, the greater capacity for learning and memory they will confer. The NR2 subunits are the most crucial, and the receptor is not functional without them. The major function of NMDA receptors is to allow for Ca influx.

Front 175

What are the requirements for NMDA receptor activation?

Back 175

1. Glutamate binding
2. Glycine or D-serine binding as a co-agonist (glycine is released by astrocytes)
3. Removal of a Mg2+ block by depolarization (caused by the opening of AMPA receptors)

Front 176

How do NMDA receptors change over time? Where are they located? What are their affinities? What does this mean?

Back 176

During early development, most NMDA receptor subunits are NR2b. Later in life, the NR2a subunits become prominent. The NR2b subunits are "extrasynaptic," further from the active zone of the synapse, and have half the glutamate affinity as the NR2a subunits, as well as a much lower affinity for glycine. This lowered affinity slows the current that runs the NMDA channels with the NR2b subunits. Because the current is slower, it lasts longer.

Front 177

How is glycine needed?

Back 177

Glycine is an obligatory agonist for the NMDA receptors. It is not obligatory for the kainate receptors.

Front 178

What are the different types of metabotropic glutamate receptors? Where are they found? What type of feedback to they engage in? How do they differ?

Back 178

Metabotropic autoreceptors participate in a negative feedback mechanism. When glutamate is released, it binds to presynaptic metabotrobic receptors, and inhibits further glutamate release (i.e. they inhibit their own neurotransmitter).

Metabotropic heteroreceptors are present on GABA-releasing neurons. They bind glutamate spillover from other synapses, and inhibit future GABA release (i.e. they inhibit another neurotransmitter). Heteroreceptors have a much higher glutamate affinity than autoreceptors, so are able to sense spillover glutamate, even at very low concentrations.

Front 179

How can pre-synaptic inhibition be achieved? What does inhibition depend on?

Back 179

1. Tonic--inhibition from ambient neurotransmitters that is always active

2. Evoked--inhibition comes in response to action potentials. Evoked inhibition is dependent on the frequency of the spikes--it is high when the action potentials are at a low frequency, and low when the action potentials are at a high frequency. Thus, such inhibition works selectively for low frequency stimulation only (this mechanism is called a "high pass filter"). For unknown reasons, the high pass filter effect works only when the metabotropic receptor is on the postsynaptic cell. It does not work when the metabotropic receptor is on the presynaptic cell.

Front 180

What are the three subtypes of metabotropic receptors? Where are they found? What are their functions?

Back 180

Group I--found on postsynaptic cells. Their function is to increase Ca release.
Groups II and III--their major function is presynaptic inhibition. They act to decreases Ca concentration.

Anti-epileptic drugs that are group I antagonists and group II agonists are currently in development.

Front 181

What is special about cyclothiazine?

Back 181

removes desensitization of AMPA receptors, acts as an AMPA agonist.

Front 182

What are the functional aspects of rugs that act on glutamatergic receptors? What are examples?

Back 182

1. Long term synaptic plasticity--learning and memory
2. Anesthetics (NMDA antagonists, such as ketamine)
3. Neurodegenerative diseases
Ex: memantine, a drug used to slow the onset of Alzheimer's, is a voltage-dependent NMDA antagonist

Front 183

What is Alzheimer's? What is memantine?

Back 183

Alzheimer's is the most common late-life dementia. It is characterized by the accumulation of amyloid-β plaques in the brain, due to increased concentrations of amyloid-β. It is thought that loss of synapses plays a role in the cognitive impairment of Alzheimer's, since a major change in Alzheimer's patients' brains is a loss of functional synapses, including a decrease in the transmission, plasticity, and number of synapses. Amyloid-β, in some unknown way, ends up triggering endocytosis of NMDA receptors, leading to spine loss.
Memantine acts by binding to NMDA receptors and inhibiting their endocytosis. It slows the onset of Alzheimer's, but does not stop or reverse it.

Front 184

What is the basic mechanism for generation of long term memory?

Back 184

long term potentiation of synaptic strength--i.e. a persistent increase in synaptic strength, following some stimulus from the external environment.

Front 185

What are the two phases to long-term potentiation?

Back 185

1. Induction
2. Expression

Front 186

What is induction?

Back 186

results in an increase or decrease in synaptic strength. The mechanism of induction is an influx of Ca through NMDA receptors.

Front 187

NMDA receptors open in response to what stimuli?

Back 187

1. Glutamate binding
2. The presence of glycine as a co-transmitter, released from surrounding glial cells
3. Removal of the Mg block by depolarization, produced by AMPA receptors
Depolarization of one receptor is not enough to open NMDA receptors; rather, many receptors need to open simultaneously.

Front 188

What is expression?

Back 188

an increase in synaptic strength, due to
i. An increase in the number of active AMPA receptors on the post-synaptic cell
ii. An increase in the possibility of NT release (i.e. more glutamate)
iii. An increase in the number of functional synapses

Front 189

What governs short-term memory? What are its phases?

Back 189

short-term alteration in synapse strength (lasting seconds to milliseconds), and is composed of the same two phases as LTP:
1. Induction
2. Expression --in most cases of short term potentiation, expression involves a change in the probability of NT release and a depletion in the number of vesicles in the presynaptic cell.

Front 190

What is synaptic facilitaion? depression?

Back 190

each pulse needed to get an AP requires less depolarization

each pulse needed to get an AP gets higher. The depression is less pronounced in the presence of ACH.

Front 191

What is a major inhibitory NT in the brain?

Back 191

GABA

Front 192

Describe the synthesis and metabolism of GABA?

Back 192

1. The synthesis of GABA from glutamate is catalyzed by an enzyme called GAD.
Vitamin B6 is required as a co-factor for GAD.
2. After synthesis, GABA transporters package the GABA into the vesicles.
3. Upon signaling, GABA is released into the synaptic cleft.
4. Transporters on glial cells are responsible for GABA reuptake, clearing it from the synaptic cleft.
- A mitochondrial enzyme called GABA transaminase catalyzes the conversion of GABA into succinic semialdehyde, which eventually enters the Kreb cycle
GABA transaminase can also regenerate glutamate (to be converted into GABA) from α-ketoglutarate
Drugs that inhibit GABA transaminase (ex: Vigabatrin) block the breakdown of GABA, therefore increasing GABA concentration.

Front 193

What are the two types of GABA receptors?

Back 193

1. Ionotropic--GABA(A) receptors
2. Metabotropic--GABA(B) receptors

Front 194

Wha are the GABA(A) receptors? What is their structure?

Back 194

Major receptors in inhibitory synapses. Pentameric transmembrane proteins with four membrane-spanning domains. Expression of different subunits leads to different GABA(A) receptor subtypes. They bind to two active sites on GABA, with their α and β subunits.

Activation triggers opening of an ionic pore. The GABAA receptor also has a regulatory site called the benzodiazepine site (BZD site), to which benzodiazepines (which are allosteric modulators of GABA receptors) can bind.

Front 195

What are the drugs that act on GABA receptors?

Back 195

1. Benzos
2. Barbiturates
3. Neurosteroids

Front 196

What are benzos? What do they do? What do they treat?

Back 196

1. Increase the affinity of the receptor for GABA
2. Increase the probability of the GABAA channel opening
Benzos alone do not have any effect on the receptor--their effects are only relevant in the presence of GABA.

treat anxiety disorders (short term), insomnia, status epilepticus, acute mania, and physical dependence. They are also used as a short term anesthetics and muscle relaxants.

Front 197

What are the adverse effects of benzos? What can be used to treat overdoses?

Back 197

drowsiness, sedation, ataxia, rebound insomnia, amnesia in the elderly, depression of respiration, and CNS depression when taken in combination with alcohol.

Flumazenil--a competitive antagonist for benzos that is used to treat overdoses, and to aid in recovery from benzos used as anesthetics.

Front 198

How effects do barbituates have?

Back 198

1. At low doses, they prolong GABA-induced opening of Cl channels
2. At high doses, they act like GABA and open chloride channels even in the absence of GABA
Barbiturates are rarely used, due to side effects.

Front 199

What are GABA(B) receptors? What are the differnt subtypes? Where are they expressed? What are the implications?

Back 199

Metabotropic GPCRs, slower than GABAA.

The specific GPCR of GABAB receptors is GPCRc, which is an obligatory dimer, composed of two subunits GB1 and GB2.

Alternative splicing of the GB1: GB1a--expressed at excitatory presynaptic terminals. lack = severe problems with learning and memory

2. GB1b--expressed in spines on postsynaptic cells. lack has not been shown to have learning and memory problems
Lack of either subunit renders the receptors non-functional.

Front 200

What effects do GABA(B) have on presynaptic and postsynaptic cells?

Back 200

On presynaptic cells, induce reduction of cAMP (via a Gio protein) and inhibit pre-synaptic Ca channels, thereby inhibiting pre-synaptic NT release.

On postsynaptic cells, activate GIRK channels (GPCRs that are inward rectifying K channels) to produce hyperpolarization , resulting in a decreased firing rate.

Front 201

What effect does a high firing frequency have on GABA?

Back 201

At high firing frequency, GABA will have a less pronounced inhibitory effect than at low firing frequency, due to short-term plasticity (this is almost always the case with regards to GPCRs on the pre-synaptic cell--the effects of an agonist or an antagonist to a NT will be more pronounced at low firing frequency).

Front 202

What effects do glycine receptors

Back 202

produce post-synaptic inhibition, just like the GABAB receptors

Front 203

What are drugs that act on GABA receptors?

Back 203

1. Sedatives
2. Anesthetics
3. Anti-epileptics

Front 204

What are anti-epileptic drugs? What are examples and their mechanisms?

Back 204

Anti-epileptic drugs are often designed to increase GABAergic transmission in a variety of ways, thus increasing the inhibitory signals in the brain (since GABA is an inhibitory NT)
They include:
1. Vigabatrin--inhibits GABA-T
2. Tiagabine--inhibits GABA reuptake
3. Benzos, barbiturates, Felbamate, topiramate, zonisamide--positive regulates of GABA receptors

Front 205

Where is ACh synthesied? That are the three major pathways?

Back 205

interpeduncular nucleus, and can also be synthesized in the striatal interneurons. There are three major ACH pathways in the brain:
1. Nucleus basalis
2. Septohippocampal pathway
3. Pontomesencephalon pathway

Front 206

What are the two types of ACh receptors? What are the subtypes in the brain?

Back 206

1. Ionotropic (nicotinic)
2. Metabotropic (muscarinic)--most CNS receptors. The major M subtypes in the brain are--
i. M2--mostly at presynaptic terminals.
ii. M1--mostly at postsynaptic terminals.
The major function of muscarinic receptors is inhibition

Front 207

How is ACh synthesized?

Back 207

ACH is synthesized from choline by choline acetyltransferase, and transported into storage vesicles by the vesicular ACH transporter (VAChT). In the synaptic cleft, ACH is degraded by ACH esterase.

Front 208

What is ACh functionally involved in?

Back 208

1. Arousal
2. Learning and memory
3. Neurodegenerative diseases (Parkinson's, treated with some anti-cholinergic drugs, and Alzheimer's, treated with some ACHE inhibitors and positive allosteric modulators)

Front 209

What are the two catecholamines? How are they synthesized?

Back 209

1. Noradrenalin/norepinephrine
2. Dopamine

synthesized from tyrosine, which is obtained from the diet and converted into DOPA by tyrosine hydroxylase. DOPA is then converted into DA. In the dopaminergic neuros, the pathway ends with the synthesis of DA. In adrenergic neurons, DA is converted into NA.

Front 210

With what must NA be released with in order to work properly?

Back 210

NA needs to be released with ATP as a co-factor, in order to work properly. In the extracellular space, NA can bind to either presynaptic or postsynaptic receptors.

Front 211

What is the negative feedback mechanism that inhibits NT release?

Back 211

Activation of α2 adrenergic receptors inhibits adenylate cyclase, thereby reducing cAMP levels and Ca influx. This comprises a negative feedback mechanism that inhibits further NT release.

Front 212

Where is NA synthesized? What are the pathways it is involved in?

Back 212

In the CNS, NA is synthesized in the locus ceruleus, which is connected by several pathways to the:
1. Limbic system (emotion, mood)
2. Frontal cortex (two pathways)
3. Cerebellum

Front 213

What is the result of an NE deficiency in the CNS?

Back 213

1. Impaired attention span
2. Impaired concentration
3. Impaired working memory
4. Slowed information processing
5. Depression
6. Psychomotor retardation
7. Fatigue

Front 214

How is DA metabolized?

Back 214

1. MAO--found on the mitochondrial membrane
2. COMT--found in the cytoplasm

Front 215

What are the DA pathways in the brain?

Back 215

1. Mesocortical
2. Nigrostriatal
3. Mesolimbic
4. Tubero-hypophyseal

Front 216

What are the two major types of DA receptors? Where are they expressed?

Back 216

1. D1--mainly postsynaptic (inhibitory) and function to increase cAMP
2. D2--presynaptic or postsynaptic (inhibitory or stimulatory) and function to either decrease cAMP or increase IP3.

DA has a higher potency for the D2 receptors than for the D1 receptors.
In general, drugs for Parkinson's target the D2 receptors.

Front 217

How is DA used?

Back 217

1. Antipsychotics--antagonists of D2 receptors
2. Antiparkinson's--drugs that increase DA activity
- Levodopa--can cross the BBB, and is then metabolized to DOPA
- Amantadin--increases DA release
- MAOB inhibitors--the MAOB subtype only acts on DA, not on other neurotransmitters
- COMT inhibitors
3. Anti-nausea
4. Neuroendocrine functions (e.g. used to treat hyperprolactinemia)

Front 218

How are DA neurons involved in Parkinson's?

Back 218

neurons going from the substantia nigra to the striatum inhibit GABAergic output from the striatum. This results in less GABA-mediated inhibitory signals, which results in the characteristic symptoms of Parkinson's. Dopamine agonists are being explored as treatment options.

Front 219

How is serotonin (5-HT) synthesized and metabolism?

Back 219

Serotonin is synthesized from tryptophan by tryptophan hydroxylase and then by DOPA decarboxylase.
After release, serotonin is degraded by MAO and aldehyde dehydrogenase, into 5-HIAA.

Front 220

Where is serotonin made? What are its various pathways?

Back 220

Raphe nucleus and sent over various pathways to the:
1. Frontal cortex
2. Basal ganglia
3. Limbic system
4. Brainstem
5. Hypothalamus

Front 221

A serotonin deficiency results in what?

Back 221

1. Depression
2. Anxiety
3. Panic, phobia
4. OCD
5. Food cravings, bulimia

Front 222

What are the three major hypothesis about depression?

Back 222

1. The major cause of depression is a reduction in serotonin release (could be caused by impaired metabolism, storage, release, etc.)
2. The major cause of depression is impaired upregulation of serotonin receptors in response to low serotonin concentrations
3. The gene expression hypothesis claims that 5-HT triggers activation of GPCRs that ultimately triggers expression of a gene called BDNF (brain derived neurotropic factor) that's involved in brain development and neuronal plasticity.

Front 223

What are the target sites for antidepressants?

Back 223

1. 5-HT reuptake inhibitors
2. Monoamine pump reuptake inhibitors
3. Blockage of presynaptic α2 receptors
4. MAO inhibition

Front 224

What are the three major categories of antidepressants?

Back 224

1. Tricyclics
2. Selective serotonin reuptake inhibitors (SSRIs)
3. MAO inhibitors

Front 225

What are tricyclics?

Back 225

5-HT and NE reuptake, are also negative allosteric modulators of NT reuptake. They also all block α1, adrenergic, histaminergic, M1 cholinergic receptors, and Na channels leading to lots and lots of nasty side effects (ex: cardiac arrhythmias from the impaired Na channels).

Front 226

What are SSRIs?

Back 226

don't bind to all the other receptors that tricyclics bind to, so they have fewer side effects. Their exact mechanism is unknown. Prozac is an SSRI.

Front 227

What are MAO inhibitors?

Back 227

there are two types of MAO inhibitors--
i. MAOA--selective for 5-HT and NE
ii. MAOB--protect neurons by metabolizing certain amines. Also degrade dopamine, and are therefore used for Parkinson's.

Front 228

What are the challenges of drug delivery?

Back 228

1. Protecting the drug from degradation by proteases in the plasma
2. Getting the drug across biological membranes
3. Getting the drug across cell membranes

Front 229

What contributes to tumor formation?

Back 229

Tumor cells
Angiogenesis
Growth factors

Front 230

What is sequence of events in tumor angiogenesis?

Back 230

1. Tumor cells secrete angiogenic factors
2. Blood vessels become hyperpermeable, due to VEGF. Plasma proteins extravasate and form a temporary fibrin scaffold.
3. Proteolytic destruction of the ECM by a protein called MMP
4. Endothelial cells migrate to the location of the sprouting capillary, and begin to proliferate
5. The new tumor vasculature is stabilized by pericytes and SMCs. Anastamosis is formed between the old vessel and the new vasculature.

Front 231

Compare normal cells and cancerous cells.

Back 231

Normal cells are relatively homogenous with little mitosis, regulated division, lack angiogenesis, and have contact inhibition.
Cancerous cells are heterogenous with lots of mitosis, secrete a lot of GF, express oncogenes but not tumor suppressor genes, have angiogenesis, and lack contact inhibition.

Front 232

For tumors to grow, what genetic changes need to accumulate? Examples?

Back 232

1. Primary genetic change--leads to an increase in cell proliferation and apoptotic cell death
Ex: loss of pRb function, overexpression of c-myc
2. Secondary genetic change--leads to a decrease in apoptosis
Ex: dysfunction of p53, overexpression of bcl-2
3. Subsequent genetic changes--lead to further phenotypic alterations
Ex: invasiveness, metastasis

Front 233

Describe tumor cell growth.

Back 233

Tumor cells grow at a logarithmic rate, which is important in deciding therapy doses. The doubling time is unique to each tumor type. Aggressive tumors have faster doubling times.
30 doublings will produce about a billion cells, enough for a lump to appear.
40 doublings will produce about a trillion cells, enough for a significant mass to manifest.

Typical doubling times:
Time For some…
24 hours Lymphomas
2 weeks Leukemias
3 months Breast cancer

Front 234

Describe tumor growth kinetics.

Back 234

It takes about 10 generations of dividing for a tumor to divide from a 1 gram mass to a 1 kilogram mass.

Since tumors grow with first order kinetics, a given dose will kill a constant percent of the cancer cells, not a constant number (i.e. the same dose will reduce the number of cells from 106 to 103 as from 103 to 100).

Chemotherapy, unlike most drugs, has a very narrow therapeutic index--the toxic does is very close to the therapeutic dose.

Front 235

How does chemotherapy work?

Back 235

Cancerous cells decline with each dose and recover between doses. Recover less with each dose, while the normal body cells recover equally between each dose. Therefore, the overall number of cancer cells should decline, while the number of normal cells should fluctuate within set limits.

If the tumor mass is too large or too aggressive to be treated with surgery and/or drugs, it will decline between drug doses, but not enough, as the mass continues to grow. In such cases, palliative care becomes the primary concern.

Front 236

What are the types of chemotherapies? When are they given?

Back 236

Curative chemotherapy--given in order to cure the disease

Adjuvant chemotherapy--given to patients in remission with no evidence of residual disease for a certain time period after signs of the disease have disappeared, to protect against recurrence.

Neoadjuvant chemotherapy--given prior to surgery or irradiation, in order to increase chances of success. Neoadjuvant therapy is given mainly in cases where the tumor is hard to access, or has the potential to damage crucial organs (e.g. lung tumors that are very near the heart). Surgery can then be performed after the tumor has shrunk from the chemo.

Palliative chemotherapy--given to improve symptoms.
70% of chemotherapies are given with palliative intent.

Front 237

What are the effects of anti-cancer drugs?

Back 237

1. Tumorigenic stress
2. Cell-cycle arrest
- reversible
- irreversible
3. Cell death

Front 238

How does the Rb protein involved in the cell cycle?

Back 238

Activated CDKs in these complexes drive the cell cycle by phosphorylating proteins that are critical for cell cycle transitions. One such protein is the retinoblastoma susceptibility (RB) protein, which normally prevents cells from replicating by forming a tight, inactive complex with the transcription factor E2F. Phosphorylation of RB causes its release, which activates E2F and allows it to stimulate transcription of genes whose products drive cells through the cycle.

Front 239

What are CDK inhibitors?

Back 239

Embedded in the cell cycle are surveillance mechanisms that are geared primarily at sensing damage to DNA and chromosomes. These quality control checks are called checkpoints; they ensure that cells with damaged DNA or chromosomes do not complete replication.[53] The G1/S checkpoint monitors the integrity of DNA before replication, whereas the G2/M checkpoint checks DNA after replication and monitors whether the cell can safely enter mitosis. When cells sense DNA damage, checkpoint activation delays the cell cycle and triggers DNA repair mechanisms. If DNA damage is too severe to be repaired, the cells are eliminated by apoptosis, or enter a nonreplicative state called senescence, primarily through p53-dependent mechanisms. Checkpoint defects that allow cells with DNA strand breaks and chromosome abnormalities to divide produce mutations in daughter cells that may lead to neoplasia

Front 240

What are growth factors? How do they work?

Back 240

The proliferation of many cell types is driven by polypeptides known as growth factors. These factors, which can have restricted or multiple cell targets, may also promote cell survival, locomotion, contractility, differentiation, and angiogenesis, activities that may be as important as their growth-promoting effects. All growth factors function as ligands that bind to specific receptors, which deliver signals to the target cells. These signals stimulate the transcription of genes that may be silent in resting cells, including genes that control cell cycle entry and progression.

Front 241

What advantage does the frog egg have for studying cell cycle?

Back 241

They divide quickly and the stages are easy to follow

Front 242

In a malignant tumor, what 2 stages of the cell cycle have a larger percentage of cells?

Back 242

G2 and S

Front 243

Discuss the second two phases of the Interphase period of the cell cycle.

Back 243

The S phase (synthetic phase) lasts 8-12 hours in most cells. DNA is replicated and proteins are synthesized, resulting in duplication of hte chromosomes. Centrosomes are also duplicated.

The G2 phase (gap two phase) lasts 2-4 hours. This phase follows the S phase and extends to mitosis. The cell prepares to divide. The centrioles grow to maturity. Energy required for the completion of mitosis is stored and RNA and proteins necessary for mitosis are synthesized, including tubulin for the spindle apparatus.

Front 244

Please discuss control factors that have been identified which initiate and/or induce progression through the cell cycle.

Back 244

Several control factors, including a category of proteins known as cyclins as well as cyclin-dependent kinases (CDKs) have been identified.

During G1 phase, cyclins D and E bind to their respective CDKs. These complexes enable the cell to enter and advance through the S phase.

Cyclin A binds to its CDKs, thus enabling the cell to leave the S phase and enter the G2 phase, and also to manufacture cyclin B.

Cyclin B binds to its CDK, inducing the cell to leave the G2 phase and enter the M phase.

Front 245

Which cell cycles are targeted in certain chemotherapies?

Back 245

The main phase targeted is the S phase. Others ()(ex:tubulin inhibitors) interfere with the M phase.
Drugs that bind covalently to the DNA may kill cells in the S phase or may hang out in the DNA until the cell reaches the S phase and then kill it. These drugs are considered non-phase specific (ex: alkylating agents).

Front 246

Name S phase-specific drugs?

Back 246

cytosine arabinoside
hydroxyurea

Front 247

Name S phase-specific, self-limiting drugs.

Back 247

6 mercaptopurine
methotrexate

Front 248

Name M phase-specific drugs.

Back 248

vincristine
vinblastine
paclitaxel

Front 249

Name phase-nonspecific drugs.

Back 249

alkylating drugs
nitrosoureas
antitumor antibiotics
procarbazine
cisplatin
dacarbazine

Front 250

What regulates apoptosis?

Back 250

Apoptosis is regulated by bcl-2, and induced by proteins called caspaces.

p53, and important mediator of the cellular response to DNA damage, is mutated in a lot of cancers but is hard to use as a target, because it is not stable. Proteins involved in the p53 pathway make more practical targets.

Front 251

What types of cancer exist?

Back 251

1. Hematological malignancies
i. Leukemia--proliferation of immature WBC precursors. Non-localized and disseminated
ii. Lymphomas--a disease of the lymph nodes. Localized and disseminated
A. Hodgkin's
B. Non-Hodgkins
2. Solid tumors--localized
i. Carcinomas--originate in epithelial cells
ii. Sarcomas--originate in mesenchymal cells (embryonic connective tissue) and grow in soft tissue

Front 252

What is the difference between malignant and benign cancers?

Back 252

Malignant cancers are invasive, non-encapsulated, and metastatic.
Benign cancers are encapsulated and non-metastatic.
Pic: an encapsulated tumor (bottom) compared to a non-encapsulated tumor. In the non-encapsulated tumor, muscle cells and tumor cells can be seen mixed together.

Front 253

What are cancer etiologies?

Back 253

1. Environmental factors
2. Radiation
3. Oncogenic viruses
4. Iatrogenic--e.g. chemotherapies that work by damaging the DNA, hormone replacement therapy, immunosuppressive drugs
5. Contributing factors--age, sex, race, genetics, geography, lifestyle, exposure levels

Front 254

What are ways of evaluating response to therapy?

Back 254

1. Physical exam
2. Imaging
3. Tumor markers (a big area of investigation today, for both diagnosis and evaluation of treatment)
i. CEA, CA-125, β-HCG, α-fetoprotein, PSA
4. Repeated biopsy

Front 255

What are the classes of anti-cancer drugs?

Back 255

1. Alkylating agents--DNA damaging, mutagenic agents
2. Anti-metabolites--imitate endogenous compounds in the body
3. Antibiotics--DNA damaging, mutagenic
4. Antimitotics
5. Hormones and antagonists
6. Molecularly-targeted therapy
7. Anti-angiogenics

Front 256

What are examples of anti-metabolites?

Back 256

i. Purine analogs (6-MP, 6-TG)
ii. Pyrimidine analogs (5-FU, Ara-CTP)
iii. Antifolates (MTX)

Front 257

What are examples of antimitotics? Examples?

Back 257

i. Microtubule inhibitors
1. Vinca alakloids
2. Paclitaxel (Taxol), Docetaxel
ii. Chromatin function inhibitors
1. Podophyllotoxins (etoposide, teniposide)
2. Camptothecin

Front 258

What is an isobologram?

Back 258

An isobologram is a graph designed to evaluate drug interactions. Down the middle of the graph will be a line called the line of additivity. Anything to the left of the line is synergistic. Anything to the right of the line is antagonistic. Anything on the line is additive.

Front 259

What is the mechanism of action for akylating agents? What do they target?

Back 259

Alkylating agents are strong electrophiles that act by covalently binding to nucleophilic groups on the DNA, usually the N7 of guanine. They can be either--
1. Monofunctional--bind to one DNA strand at a time
2. Bifunctional--bind to two DNA strands at a time, and are more effective
They are non-cell cycle specific, very toxic, mutagenic, and carcinogenic (so they can actually induce the reappearance of a new cancer years after treatment).

Their targets include amino acids, carboxyl, sulfhydryl and imidazole groups, and nucleic acids.
When alkylating agents bind to the DNA, they form cross-links, leading to the impairment of replication and RNA transcription

Front 260

Describe the chemistry of alkylating agents.

Back 260

alkylating agents have highly electrophilic chloroethylamine groups (boxed in red). Some have one chlorodiethylamine groups (monofunctional), and others have two (bifunctional). The R group will differ, depending on the drug. The alkylating agent will work by electrophilic attack on N, O, and S on the DNA (preferably, the N7 of guanine).

Bifunctional agents can cause either intrastrand linking, or cross-linking between the two strands.

Front 261

What does DNA alkylation lead to?

Back 261

DNA alkylation will result in cross-linking, mutations, disruption of base pairing, depurination, and strand breaks. A variety of biochemical events in nucleic acid and protein synthesis will be disrupted.
Alkylating agents are highly cytotoxic, and specific to all rapidly dividing cells.

Front 262

What are the mechanisms of tumor resistance? How?

Back 262

1. Decreased drug uptake or increased drug removal
Cells can eliminate drugs via the P-glycoprotein pump ("P" for permeable) which uses ATP to remove harmful substances. Upregulation of this pump can help confer resistance to many drugs.
2. Increased repair of the defect caused by the drug
One mechanism of resistance to alkylating agents is high expression of DNA excision agents, enzymes which cut out the cross-linked DNA.
Because these enzymes will make the cells even more prone to mutation, alkylating drugs can, in the long run, make cancer cells even more dangerous. Years after treatment, patients can develop secondary malignancies that are the product of the treatment of the first cancer.
3. Cross-resistance to drugs of the same family

The faster the doubling time of the tumor, the more effective alkylating agents will be, since they act on rapidly dividing cells. Dormant cells in G0 can repair the damage they cause.

Front 263

What are examples of nitrogen mustards?

Back 263

1. Mechlorethamine
2. Chlorambucil
3. Melphalan
4. Cyclophosphamide

Front 264

What are examples of nitroureas?

Back 264

1. Streptozocin
2. Carmustine (BCNU)
3. Lomustine (CCNU)
4. Semustine (methyl-CCNU)

Front 265

What are examples of methylating agents?

Back 265

1. Procarbazine
2. Dacarbazine
3. Temodal

Front 266

Mechlorethamine

Back 266

the first anti-cancer drug in clinical use. Side effects include nausea, vomiting, CNS stimulation (because it can cross the BBB), and bone marrow suppression (BMS). Latent viral infections may appear, due to immunosuppression.

Chlorambucil, melphalan also have BMS

Front 267

Cyclophosphamide

Back 267

most commonly used nitrogen mustard, with wide application. Cyclophosphamide is given as a pro-drug which is metabolized by the P450 system in the liver into its active form (a bifunctional alkylating agent that is very toxic). Because cyclophosphmide is not activated until it gets to the liver, it can be administered per os.

Front 268

How is cyclophophamide activated? How is it metabolized?

Back 268

Cyclophosphamide depends on liver enzymes for its activation. Therefore, it may not be effective in patients with liver disease.
Metabolism of cyclophosphamide in the liver yields two products:
i. The active metabolite, phosphoramide mustard
ii. Acrolein, a substance which is highly toxic to normal cells, but can be neutralized by another drug, called Mesna. Therefore, cyclophosphamide is given in conjunction with Mesna.

Front 269

How do nitrosoureas work? What is special about them? What are their side effects? What are they used for?

Back 269

produce interstrand DNA cross-links and protein carbamoylation. They are lipophilic, and can cross the BBB which makes them a popular drug for brain cancer. They are non-cross reactive, meaning that if a cancer develops resistance to one nitrosourea, it will not develop resistance to other alkylating agents.
This is because nitrosoureas are more vulnerable to the P-glycoprotein pump than other alkylating agents.
Side effects include nausea, vomiting, and BMS
Clinically, they are used for primary and metastatic CNS tumors. They are also effective in lung cancer.

Front 270

Streptozocin

Back 270

a nitrosourea that is toxic to the β cells of the pancreas, used to treat insulinomas. It has a low bone marrow toxicity.

Front 271

Dacarbazine

Back 271

a purine intermediate analog. Needs to be transformed to an active metabolite called methylhydrazine. Nausea, vomiting, etc.

Front 272

Temodal

Back 272

mostly used for brain tumors

Front 273

Busalfan

Back 273

an oral agent used against chronic granulocytic leukemia. Myelosuppressive

Front 274

Ethyleneimines (Aziridines)

Back 274

have three member ethyleneimmonium rings, and are more effective at low pH. Used to treat bladder cancer.

Front 275

Cisplatin

Back 275

cisplatin is an alkylating agent with its electrophilic groups attached to platinum. Its major side effect is renal toxicity, which can be countered by giving lots of fluids, to help clear the kidneys. Other side effects include vomiting and neuropathies.

Front 276

How can cisplatin toxicity be limited?

Back 276

i. Secluding the drug within a liposome
ii. Conjugating the drug to a macromolecule. Because tumor blood vessels tend to be new and leaky, the enlarged version of Cisplatin will still be able to exit the blood vessels into the tumor and affect the cancer cells. However, it will not be able to pass through normal blood

Front 277

What are antimetabolite? How are they used? In what cell cycle are they most effective?

Back 277

Antimetabolites are analogs of normal compounds within the cell that generally interfere with purine or pyrimidine availability by:
i. Competitively inhibiting them
Ex: agonists of purines and pyrimidines
ii. Inhibiting their synthesis
Ex: inhibitors of thymidylate synthase and DNA polymerase
Antimetabolites are cell cycle specific, and are cytotoxic during the S phase. They are most effective against rapidly proliferating cells.

Front 278

What is most effective method of using antimetabolites?

Back 278

The dose response curve of an antimetabolite is non-linear (i.e. increasing the dose only increases the effect up to a certain threshold), since once all the enzyme the drug is blocking is blocked, increasing the dose won't help. Increasing the length of treatment time is more effective than increasing the dose.

Front 279

What are the four major antimetabolites? How are they used?

Back 279

1. Methotrexate--a folic acid analog that inhibits dihydrofolate reductase
2. 5-FU--a uracil analog that inhibits thymidylate synthase and interferes with RNA synthesis and action
3. Gemcitabine--a sugar similar to deoxyribose, that inhibits DNA polymerase
4. Ara-C--similar to Gemcitabine

Front 280

Why is folic acid important?

Back 280

Folic acid is a vitamin that is essential to cell replication. If deficient, it will prevent DNA and RNA synthesis and the cell's entry into the S phase. It is structurally similar to folic acid.
Inhibition of folic acid is particularly lethal to cancer cells, since they are rapidly dividing.

Front 281

How is folic acid metabolized?

Back 281

Folic acid is obtained from the diet or produced by intestinal flora, and reduced to the tetrahydrofolate form by dihydrofolate reductase (DHFR). Then, tetrahydrofolic acid receives a methylene group from vitamin B12 in order to be activated. Then, the activated form (5,10 methylenetetrahydrofolate) reacts with uracil in a reaction catalyzed by thymidylate synthase, to produce thymidine.

Front 282

What are MTX and 5-FU?

Back 282

1. Methotrexate--a folic acid analog that inhibits dihydrofolate reductase
2. 5-FU--a uracil analog that inhibits thymidylate synthase and interferes with RNA synthesis and action

5-FU has a similar action to MTX. It is a uracil analog that gets incorporated into the RNA, and blocks thymidine synthase.

MTX blocks tetrahydrofolate production by inhibiting DHFR.
5-FU blocks thymidine production by inhibiting thymidylate synthase.

Front 283

What is administered in the case of MTX toxicity? How does it work?

Back 283

A drug called Leucovorin is administered in cases of MTX toxicity. Leucovorin is an exogenous version of 5,10 methylenetetrahydrofolate. Therefore, cells can produce thymidine directly from it, using thymidine synthase, and do not need folic acid and DHFR.

Front 284

How do cancer cells develop resistance to MTX?

Back 284

1. Decreasing polyglutamation, which makes MTX less active
2. Increasing DHFR expression
3. Altering DHFR, with a lower affinity for MTX
4. Altering the folate carrier or receptor binding protein

Front 285

How do cancer cels develop resistance of 5-U?

Back 285

1. Alterations in thymidylate synthase
2. Decreased intracellular activation
3. Loss of p53 (for unknown reasons)

Front 286

Capecitabine (Xeloda)

Back 286

an oral pro-drug of 5-FU, which can sometimes be toxic to the heart. It may also cause redness, itching, and swelling in the wrists and feet ("hand and foot syndrome").

Front 287

What is Ara-C (Cytosine Arabinoside)?

Back 287

Ara-C is an analog of cytosine, with an extra hydroxyl group that inhibits DNA polymerase. It acts as a pyrimidine antagonist, and is specific to the S phase.

Front 288

What is Gemcitabine?

Back 288

Gemcitabine is another nucleoside analog that gets incorporated into the DNA and blocks synthesis. It is the only available drug that can prolong survival time for pancreatic cancer. Aside from the typical side effects, it causes transient elevations of serum transaminases, proteinuria, and hematuria.

Front 289

What are antitumor antibiotics?

Back 289

bacterial or funal derivatives, interfere with cellular processes such as DNA or protein synthesis

Front 290

Doxorubicin

Back 290

fungal anthracycline that intercalates within the DNA, causes single and double strand breaks, and inhibits topoisomerase II

Front 291

Mitomycin C

Back 291

binds to DNA and form cross-links and DNA adducts

Front 292

Bleomycin

Back 292

a small peptide that binds to DNA, which results in single-stranded and double-stranded breaks

Front 293

What is the mechanism for doxorubicin cytotoxicity?

Back 293

1. Topo II inhibition (the most important mechanism)
2. DNA intercalation between base pairs
3. Free radicals formation (relevant mainly for cardiac toxicity)

Front 294

Which drugs target topoisomerase II? How?

Back 294

Anthracyclines & Epipodopylotoxins
Topo II is a molecular target for epipodophyllotoxins and anthracyclines. These drugs form a covalent topo II-DNA complexes that prevent the enzyme from completing the religation portion of the process (and induce protein-linked breaks in the DNA)

(Topo II inhibition with stabilization of the DNA-Topo II complex and production of DNA double-strand breaks).

Front 295

How do anthracyclines work in terms of OH radicals?

Back 295

Anthracyclines undergo chemical reduction through enzymatically catalyzed or iron catalyzed pathways to yield reactive free radical intermediates (hydrogen peroxide and hydroxyl radical) that can cause oxidative damage to cell membrane proteins and DNA.
(in addition, iron-drug complexes are formed, that bind to DNA).

Front 296

What are signs of doxorubin toxicity?

Back 296

Myelosuppression (mainly neutropenia)
Cardiomyopathy
Alopecia
Nausea and vomiting
A vesicant
Diarrhea
Etc.

Front 297

What happens with pegylated liposomal doxorubicin? (Doxil)

Back 297

Same mechanism of action as doxorubicin
Doxorubicin is encapsulated in Pegylated liposomes (resulting in different P/K profile and different spectrum of toxicity & activity).

Front 298

What are some doxorubicin analogues? Their effects?

Back 298

Epirubicin
Mitoxanthrone

Similar activity
Less cardiotoxicity

Front 299

How does dactinomycin work?

Back 299

Binds to DNA by DNA intercalation: blocks the ability to serve as a template for RNA (and DNA) synthesis.

Front 300

What is the mechanism of action for antimitotics? Examples?

Back 300

natural products that interfere with microtubule synthesis and degradation, leading to inhibition of cell division.

Paclitaxel (Taxol): stabilizes microtubules, inhibit the cell cycle during mitosis.
Vinblastine: plant alkaloid that causes depolymerization of microtubules.

Front 301

How do vinca alkaloids work?

Back 301

Inhibiting microtubules assembly
M-phase

Front 302

How do taxanes work?

Back 302

Promote microtubules assembly , resistance to de-polymerization
M-phase

Front 303

What is the mechanism of action for vinca alkaloids?

Back 303

binding to specific site on tubulin with prevention of polymerization, inhibition of microtubule assembly and mitotic spindle formation (leading to metaphase arrest)

Front 304

How does resistance come about?

Back 304

MDR-1 = multi drug resistance gene- Encodes p-Gp (p-glycoprotein) efflux pump
Resistance=over expression of MDR-1
Cross resistance among natural products
Drugs that effectively and safely inhibit the pump are still looked for. (Verapamil…)
mutations in alpha and beta tubulin

Front 305

What is the mechanism of action for taxanes?

Back 305

Binding is reversible and stabilize the microtubules against depolymerization (induce tubular polymerization), thereby disrupting normal microtubule dynamics (halts mitosis)(and lead to arrest at G2/M phase).

Front 306

What are the mechanisms of resistance to taxanes?

Back 306

P-gp overexpression ;MDR (mediated by the 170-kD p gp pump efflux, encoded by the mdr1 gene)

Mutations of tubulin

p53 mutations (taxanes induce apoptosis, induced by p53)

overexpression of Bcl-2

Front 307

What are the topo-I inhibitors?

Back 307

Irinotecan
Topotecan

Failure to repair DNA breakage and interference with transcription and replication

Front 308

How do topoisomerase I interactive agents work?

Back 308

Topo I “inhibition”, with production of single-strand DNA breaks:
Topo I breaks DNA to allow strand to uncoil.
the drug stops topo I from repairing the strand in one spot.
Completion of DNA replication is prevented.


Note: the term “Topo I inhibition”, although commonly used, is inaccurate (since the DNA breakage by the enzyme is enhanced). “Topoisomerase I interactive agents” or “poisoning topo I” are more accurate terms.

Front 309

Irinotecan

Back 309

Colorectal cancer (in combination with 5FU and leucovorin) and lung cancer
Metabolise in the liver
Clears in the kidney
Toxicity:
Diarrhea
Netropenia
Nausea and vomiting
Abdominal cramps
etc

Front 310

Topotecan

Back 310

Ovarian cancer
Metabolise in the liver
30% clears in the kidney
Toxicity:
Myelosuppression
Nausea and vomiting
Diarrhea
Abdominal cramps
Alopecia
fatigue
etc

Front 311

What are the mechanisms for irinotecan resistance?

Back 311

Low carboxylesterase (=the enzyme that catalyzes the conversion of irinotecan to SN-38) expression.

Overexpression of UGT (Uridine diphosphate glucuronosyltransferase=the enzyme that inactivates SN-38, a toxic active metabolite).

Front 312

Filgrastim (Neupogen):

Back 312

non-glycosylated methionyl G-CSF; produced in culture by bacteria; has an additional amino acid and is not glycosylated (addition of a saccharide residue following the assembly of amino acids).

Front 313

Lenograstim (Granocyte):

Back 313

glycosylated G-CSF; produced in culture by mammalian cells; identical to the natural molecule.

Front 314

Summary of alkylating agents.

Back 314

CCNS drugs. Form reactive molecular species that alkylate
nucleophilic groups on DNA bases (e.g N7 guanine)- leads to cross linking of bases,
Abnormal base pairing and DNA strand breakage.
Resistance: Increased DNA repair, decreased drug permeability, production of trapping
agents (Thiols).
Examples:
Cyclophasphamide (nitrogen mustard), Cisplatin/carboplatin
Mechanism, Pharmacokinetics (e.g. Hepathic Cytocrome P450- acrolein), clinical use,
toxicity, resistance, rescue (e.g. hydration, mesna).

Front 315

Summary of antimetabolites.

Back 315

CCS drugs (S phase- DNA synthesis pathway-see figure).
Structurally similar to endogenous compounds and are antagonists of folic acid,
purines, or pyrimidines. Interfers with nucleic acid and protein metabolism.
Formation of polyglutamate derivatives, DHFR, TS.
Examples:
Methotrexate, Ara-C, Gemcitabine, 5-FU/Xeloda.
Mechanism, PK, clinical use, toxicity, resistance (decreased drug accumulation,
changes in drug sensitivity or DHFR activity, decreased polyglutamation),
rescue (e.g. leucovorin).

Front 316

Summary of vinca alkaloids.

Back 316

CCS drugs. (M phase).
Block formation of mitotic spindle by preventing the assembly or disassembly
of tubulin dimers into microtubules.
Examples:
Vinblastine, Vincristine, paclitaxel, docetaxel.
Mechanism, PK, clinical use, toxicity, resistance (increased efflux via membrane drug
transporter), rescue.

Front 317

Summary of antibiotics.

Back 317

CCNS drugs.
Intercalation between base pairs, inhibition of topoisomerase II, generation of free
radicals. Block synthesis of RNA and DNA and cause DNA strand scission and
membrane disruption.
Examples:
Anthracyclins: Doxorubicin/Doxil, Mitomycin.
Mechanism, PK, clinical use, toxicity (BM, GI, alopecia, cardiotoxicity), resistance,
rescue (e.g. dexrazoxane-inhibitor of iron-mediated free radical).

Front 318

How to manage side effects of chemotherapy?

Back 318

CCNS drugs.
Intercalation between base pairs, inhibition of topoisomerase II, generation of free
radicals. Block synthesis of RNA and DNA and cause DNA strand scission and
membrane disruption.
Examples:
Anthracyclins: Doxorubicin/Doxil, Mitomycin.
Mechanism, PK, clinical use, toxicity (BM, GI, alopecia, cardiotoxicity), resistance,
rescue (e.g. dexrazoxane-inhibitor of iron-mediated free radical).

Front 319

What are the rules for effective chemotherapy combinations?

Back 319

Each drug produces at least some response
Different mechanism of action
Different dose limiting toxicity

Front 320

Trastuzumab (Herceptin)

Back 320

Herceptin is humanized anti-HER2 MAB (95% human and 5% murine). It binds with the extracellular domain of the HER2 cell-surface receptor, thereby inhibiting the growth of breast tumor cells that over express HER2.
Tumors strongly overexpressing HER2 (IHC 3+) and/or with proven HER2 gene amplification (FISH positive) are most responsive to herceptin.

Front 321

What are the steps required for angiogenesis?

Back 321

1. Secretion of angiogenic factors
2. Degradation of ECM
3. EC proliferation and migration
4. Stabilization of new vessels

Front 322

What is the relationship b/w ErbB receptors and cancer?

Back 322

Overexpression of ErbB-1 and/or ErbB-2 is associated with poor prognosis and advanced-stage cancers

Overexpressed ErbB proteins still respond to regulation, making them attractive targets for anticancer therapies

Front 323

What is ErbB-1?

Back 323

Also known as epidermal growth factor receptor (EGFR)

First family member identified

Involved in normal cell growthand differentiation

Disturbances in ErbB-1 signaling can lead to cell transformation

Ligands specific for ErbB-1 include EGF, transforming growth factor (TGF)-α, and amphiregulin

Front 324

What is ErbB-2?

Back 324

Also known as HER2/neu

No known ligands

Activation thought to occur through heterodimerization with other ErbB family members

ErbB-2 is the preferred heterodimerization partner with other family members

Most resistant to intracellular degradation, slower to inactivate compared to other family members

ErbB-2 overexpression in tumors correlates with poor prognosis and decreased survival times

Front 325

What is ErbB-?

Back 325

Lacks intrinsic tyrosine kinase activity

Often found in heterodimerswith ErbB-2

Cytoplasmic domain contains 6 sites where the p85 subunit of PI3 kinase can bind

Heterodimers containing ErbB-3 (especially ErbB-2/ErbB-3) are thought to be particularly strong activators of the PI3K/Akt pathway that is associated with cell survival and resistance to cancer therapy

Front 326

What is ErbB-4?

Back 326

Important in cardiac and brain development

Expression might correlate with presence of hormone receptors in breast tumors, more favorable prognosis

Multiple splice variants, some of which contain binding sites for PI3K

Slow internalization

Ligands include neuregulins, betacellulin, epiregulin, and heparin-binding (HB) EGF

Front 327

What are the common mechanisms for ErbB activation in tumors?

Back 327

Protein mutation(ie, EGFRvIII—constitutively active deletion mutant lacking most of the ECD)

Genetic changes resultingin overexpression of either normal or constitutivelyactive receptors

Production of EGF or TGF-α by tumor cells: sets up an autocrine loop leading to constitutive ErbB-1 activation

Front 328

How are hormones and antagonists used is chemotherapy?

Back 328

Mechanism of action:
inhibits synthesis or effects of the steroid hormones that are necessary for growth of certain tumors, such as breast and prostate tumors.

Examples:
Tamoxifen: binds to estrogen receptors (ER) as an antagonist inhibitor of estrogen.
Anastrozole: inhibits aromatase, the enzyme that catalyzes the final step in estrogen production.

Front 329

Fulvestrant

Back 329

Classified as a “pure antiestrogen”: functions by destroying the estrogen receptors (unlike tamoxifen, does not have an agonist effect).

Front 330

What is a major effect of aspirin? What can it be used to treat and prevent?

Back 330

Reduces platelet aggregation

1. Angina
2. Stroke
3. Peripheral vascular disease

Blocking prostanoid synthesis has an anti-inflammatory effect.
Aspirin blocks prostaglandin synthesis by inhibiting COX.

Front 331

Progestins

Back 331

Indirect action on the hypothalamus-pituitary axis consisting of inhibition of gonadotropin-releasing hormone release.
Direct action resulting in the inhibition of cellular proliferation.
Examples:
-Medroxyprogesterone acetate (Provera)
-Megestrol acetate (Megace)

Front 332

What are autocoids? What are examples?

Back 332

a diverse group of signaling molecules that have local effects and often act on smooth muscle. They include:
1. Eicosanoids (the biggies)
2. Serotonin
3. Endothelin
4. Histamine
5. Bradykinin
6. Angiotensin

Front 333

What are eicosanoids? How are they synthesized? Where do they exist? What is the most common form? From where are they derived?

Back 333

Eicosanoids are lipid-derived autacoids synthesized by the oxidation of polyunsaturated long-chain fatty acids, with 20 carbons and more than one double bonds. They exist all over the body, and have diverse functions.
The most common eicosanoid is arachidonic acid (C20:4).

Eicosanoids are derived from the diet as omega-3 and omega-6 fatty acids (found in fish oil).

Front 334

Aminogluthetimide

Back 334

Aminogluthetimide is a non selective aromatase inhibitor. Although it inhibits aromatization of androgens to estrogens, its main action is inhibition of adrenal steroidogenesis at early steps (inhibition of the synthesis of aldosterone, cortisol ,and androgenes).

Front 335

What is the eicosanoid cascade?

Back 335

1. AA is released from the cell membrane, usually by phospholipase A2 (found in snake venom)
2. Synthesis of eicosanoids
3. Excretion from the cell
4. Binding to membrane receptors on nearby cells
5. Signal transduction, via a GPCR
6. Effect

Front 336

Ketoconazole

Back 336

High doses inhibit gonadal and adrenal steroidogenesis by inhibiting the P-450-dependent enzyme system.

Front 337

What are the two potential pathways for archidonic acid?

Back 337

1. The lipoxygenase pathway, which produces leukotrienes
2. The cyclooxegenase pathway, which produces prostaglandins, prostacyclins,and thromboxanes

Front 338

What is the process of prostaglandin synthesis?

Back 338

In the COX pathway, the addition of an oxygen to AA creates a closed ring structure, which converts AA into prostaglandin G2. Then, PGG2 is peroxidized to produce PGH2.

PGH2 can give rise to many different prostaglandins, prostacyclins, and thromboxanes.

Front 339

Where do prostacylcins affect?

Back 339

endothelium
kidney
platelets
brain

Front 340

Where does thromboxane A2 affect?

Back 340

platelets
vascular SM cells
macrophages
kidney

Front 341

Where does prostaglandin D2 affect?

Back 341

mast cells
brain
airways

Front 342

Where does prostaglandin E2 affect?

Back 342

brain
kidney
vascular SM cells
platelets

Front 343

Where does prostaglandin F2a affect?

Back 343

uterus
airways
vascular SM cells
eye

Front 344

Which prostanoids dilate arterial tonus? constrict?

Back 344

Dilate:
PGE2
PGD2
PGI2

Constrict:
PGF2a
TXA2

Front 345

C4b2a fxns in:

Possible answers:
a. C3 convertase Alternative Pathway
b. C3 convertase Classic Pathway
c. C5 convertase Alternative Pathway
d. C5 convertase Classic Pathway
e. MAC

Back 345

is the C3 convertase of the Classical Pathway

(Anything C4 is classical pathway!)

Front 346

Which prostanoid relaxes the bronchial tree?

Back 346

PGE2 (EP2)
PGI2

Front 347

Which prostanoids contract GI peristalsis? Relax?

Back 347

Contract:
PGE2 (EP1+3)
PGF2a

Relax:
PGE2 (EP2)
PGD2

Front 348

Which prostanoid decreases stomach acid secretion? Increases muscoal protection?

Back 348

PGE2 (EP3)

Front 349

Which prostranoids contract the uterus? relax?

Back 349

Contract:
PGE2
PGF2a

RelaxL
PGD2

Front 350

Which prostaglandins mediate swelling?

Back 350

Increased capillary permeability

PGE2
PGI2

Front 351

Which prostaglandins mediate redness and heat?

Back 351

Vasodilation

PGE2
PGI2
PGD2

Front 352

Which prostaglandins mediate pain? fever?

Back 352

PGE2

Front 353

What is COX? How is it shaped? What is its catalytic site? How does aspirin work on it?

Back 353

COX is a tunnel-shaped enzyme, with a catalytic site inside its tunnel. The catalytic site has a serine residue at position 529.
Aspirin acts by irreversibly binding to the serine in the active site of COX and acetylating it. This acetylation blocks AA from entering the tunnel and reaching the active site.

Front 354

Is the acetylation of serine reversible? What happens?

Back 354

Because acetylation of the serine is irreversible, a COX molecule bound to aspirin will never regain functionality, and new COX molecules will need to be synthesized for more prostaglandins to be made.

Front 355

What is the technique for evaluating platelet function? What happens with the addition of aspirin?

Back 355

Platelet aggregation can be evaluated using a sample of platelet-rich plasma, shining a light through the sample, and measuring the absorbency. Then, factors that should induce clotting are added to the sample. If the platelets are functioning properly, they will clot, making the sample clearer and allowing more light to pass through it upon a second measurement.


If aspirin (ASA in the graph below) is added to a sample of plasma and then clotting factors are added, light absorption will not go down as much as it would without the aspirin, because clotting is inhibited.

Front 356

What are the three major actions of NSAIDs?

Back 356

1. Anti-inflammatory
2. Analgesic
3. Antipyretic
All NSAIDs inhibit COX (usually by reversible, competitive inhibition).

Front 357

What are the clinical indications for aspirin use?

Back 357

1. Fever
2. Acute pain, especially if caused by inflammation
i. Menstrual pain, since prostaglandins cause uterine contraction
3. Chronic pain
i. Rheumatological disease
ii. Degenerative bone diseases
4. Anti-platelet effects (only Aspirin is used, not the other NSAIDs)

Front 358

What are adverse effects of NSAIDS? (6) GI, kidneys, platelets, uterus, etc

Back 358

1. Erosions of the GI tract, leading to ulcers, perforations, and bleeding, especially in the gastric and duodenal area. May also cause nausea and abdominal discomfort.
2. Water and Na retention in the kidneys, especially in patients with CHF and cirrhosis
3. Decreased renal function and nephrititis
i. Long term NSAID use can cause renal failure, called analgesic neuropathy
4. Decreased platelet function, which may cause bleeding
5. Relaxation of the uterus (can prolong labor, so NSAIDs are not used during childbirth)
6. Hypersensitivity reactions, possibly due to diversion of the arachidonic acid metabolism into the leukotriene pathway, since leukotrienes mediate asthma-like responses.

Front 359

How can NSAIDS have adverse effects on the kidneys? Particularily on which patient population? Why?

Back 359

NSAIDs have particularly adverse effects on the kidneys in people with CHF or cirrhosis. This is because both of those conditions will activate the release of renin/angiotensin, which constrict the arterioles of the glomerulus. Normally, prostaglandins have vasodilatory effects on the afferent arteriole. However, if a patient is on NSAIDs, this effect will be eliminated, allowing the vasoconstrictive effects of angiotensin on the afferent arteriole to be unopposed. The afferent arteriole will clamp down, messing up the pressure gradient in the glomerulus.

Front 360

What is the explanation of adverse of NSAIDS on the GI tract?

Back 360

NSAIDs inhibit prostaglandins in the gastric mucosa, where prostaglandins normally reduce acid secretion, increase bicarb secretion, and stimulate proliferation of epithelial cells (which helps heal erosions). This results in an increased tendency towards ulcers.
Even very low doses of aspirin can cause damage to the GI tract.

Front 361

What are the two COX isoforms? What do they express? What are they involved in?

Back 361

1. COX-1--expressed constitutively, fulfills housekeeping functions (e.g. gastroprotection, clotting)
2. COX-2--is inducible in response to particular signals (ex: stress, cytokines) and mediates pain and inflammation

Front 362

What happens when COX is selectively inhibited? What are examples of COX-2 inhibitors?

Back 362

Inhibiting both COX enzymes will eliminate the normal, housekeeping functions of COX-1, resulting in the aforementioned adverse effects of NSAID use. Inhibiting COX-2 only eliminates pain and inflammation, without disturbing other prostaglandin effects.
Glucocorticoids and IL-4 are selective COX-2 inhibitors.

Front 363

What is the structure of COXs? What is the difference b/w COX 1 & 2? What are examples of drugs/what are the mechanics?

Back 363

COXs have two catalytic sites, one for cyclooxygenation, and one for peroxygenation.
The difference between COX-1 and COX-2 is in the cyclooxygenation site--COX-1 has a bulky isoleucine reside in the active site and COX-2 has valine in the same position, allowing a larger entrance to the active site of COX-2:

COX-2 selective drugs are designed to fit into the pocket in the cyclooxygenation active site that is only present in COX-2.

Selective COX-2 inhibitors have "coxib" in their names.

Front 364

What is IC50?

Back 364

: IC50--the concentration of a drug need to achieve 50% of the effect.

Front 365

Compare the different COX inhibitors. , COX-2 selective inhibitors are to the right of the line. Drugs that block both COXs equally are on the line. Drugs that block COX-1 better are to the left of the line.

Back 365

Front 366

What are the tendencies of COX-2 inhibitors in comparison to COX1 inhib? What is an example that was taken off the market for adverse cardio events?

Back 366

Selective COX-2 inhibitors do not tend to block platelet function. They also have much lower GI toxicity.
Rofecoxib (Vioxx) is a selective COX-2 inhibitor. It was taken off the market for causing adverse cardiovascular events

Front 367

How does the body use thromboxanes and prostacyclins? Describe the effects of COX inhibitors here.

Back 367

vascular endothelium of atherosclerotic arteries experiences an inflammatory reaction. Therefore, such arteries use COX-2 to produce prostcyclin.
Platelets use COX-1 to produce thromboxane.


Selective COX-2 inhibitors block prostacyclin synthesis, but do not affect thromboxane. This results in the unopposed effects of thromboxane, which increase the possibility of clotting, resulting in adverse cardiovascular events.

Front 368

What is the problem with coxibs?

Back 368

Coxibs are now sold with a warning. They have approximately a two-fold risk of causing heart attacks. Therefore, they are unlikely to be problematic in people with a low risk for heart attack.
Celecoxib is still on the market in the US but is contraindicated in patients at high risk for adverse cardiovascular event.

Front 369

What are potential problems with medication overdoses? What are examples?

Back 369

1. Exaggeration of the desired therapeutic effect
Ex: beta blocker overdoses cause bradycardia
2. Exaggeration of an adverse effect that may be minor at the therapeutic dose
Ex: decreased renal function in NSAID overdose
3. Toxic effects that are not seen at the therapeutic dose
Ex: acetaminophen overdoses cause liver toxicity

Front 370

What are dose response curves? What is their shape? What do tey express.

Back 370

Dose response curves chart the effect of a drug as a function of its concentration. They are typically sigmoidal, linear in the middle with plateaus at the edges. In the graph below, the blue line indicates the therapeutic dose and the red line indicates the toxic dose. The concentration difference between the therapeutic dose and the toxic dose is called the margin of safety

Front 371

What is the median lethal dose? Why does this variable exist?

Back 371

Because of the variability in response, the median lethal dose of a drug is defined as the LD50--the dose that kills 50% of a population

Front 372

What does it mean for a medication to have linear pharmacokinetics? How does this relate to toxic doses?

Back 372

Most medications have linear (first order) pharmacokinetics--meaning that doubling the dose of a drug will not affect its half life. This is not true with regard to toxic doses, which are usually beyond the linear region in the sigmoidal dose response curve.
Therefore, the half lives and effects of toxic doses may be very different--toxicokinetics studies the kinetics of drugs at toxic doses.

Front 373

What is pill clumping? What is the problem?

Back 373

Another unique effect of toxic doses is called pill clumping, in which a high dose of tablets will form a clump in the stomach, from which medicine will be dispensed into the body at an unpredictable rate. It may take a while for the effects of the drug to manifest, as long as the drug is locked up in the clump, but once the clump starts to dissolve, the effects will be much more pronounced than usual, due to the high dose.

Front 374

What steps are needed for treatment of poisoning?

Back 374

Airway
Breathing
Circulation
Decontamination
Enhanced elimination
Focused therapy
Get toxicological help

Front 375

What are the patterns of toxic syndrome?

Back 375

1. Sedative/hypnotic and opoid
2. Cholinergic
3. Anticholinergic
4. Sympathomimetic
5. Serotonergic

Front 376

What is the clinical presentation of Sedative/Hypnotic and Opoid Toxidrome?

Back 376

Altered mental state
Slow, shallow breathing (apnea in the sedative toxidrome can be fatal)
Hypotension, and sometimes bradycardia and hypothermia
Decreased bowel activity ("hypoperistalsis")

Front 377

What are potential culprits of Sedative/Hypnotic and Opoid Toxidrome?

Back 377

Benzos
Opiates
Antiepileptics
Antipsychotics
Barbiturates
Ethanol

Front 378

What is clinical presentation of cholinergenic toxidrome? How frequently is this seen?

Back 378

Salivation
Lacrimation and meiosis
Urination
Diarrhea
GI cramps
Emesis
Sweating, wheezing, respiratory secretions (which may cause suffocation)

The cholinergic toxic syndrome is rare. It will most commonly occur in cases of chemical warfare or pesticide poisoning.
To simplify, the clinical presentation involves lots and lots of fluid loss.

Front 379

What are potential culprits of cholinergenic toxidrome?

Back 379

Carbamate
Organophosphate Toxins (ACH esterase inhibitors)

Front 380

What is the clinical presentation of anticholinergenic toxidrome? How frequently is this seen?

Back 380

Dry skin, fever, flushing
Psychosis, coma, seizures
Tachycardia, hypertension
Hypoperistalsis
Mydriasis
arrhythmias

(all unopposed, sympathetic activity)

Anticholinergic toxic syndrome is relatively common, since lots of drugs of abuse have anticholinergic side effects.

Front 381

What are potential culprits of anticholinergentic toxidrome?

Back 381

Antihistamines
Tricyclic antidepressants
Antipsychotics (especially phenothiazine)
Atropine
Datura (a weed that contains a high concentration of atropine-like chemicals)

Front 382

What is the clinical presentation of sympathomimetic toxidrome?

Back 382

Hypertension, tachycardia
Sweating
Mydriasis
Tremor
Seizures
Arrhythmias

Front 383

What are the potential culprites of cympathomimetic toxidrome? How to differentiate b/w it and anticholinergenic toxidrome?

Back 383

β-agonists (used to treat hypotension and asthma, found in epipens)
Theophylline
Caffeine (whee!)
Cocaine
Amphetamines
Pseudoephedrine

The sympathomimetic and anticholinergic toxidromes are very similar; however, redness, fever, bladder atony, and hypoperistalsis are more suggestive of an anticholinergic toxin.

Front 384

What is the clincial presentation of serotonergic toxidrome?

Back 384

Irritability, nervousness, tremor
Fever
Hypereflexia, clonus (involuntary muscle contraction), myoclonus
Flushing, sweating
Diarrhea

Front 385

What are the potential culprits of serotonergic toxidrome?

Back 385

SSRIs (ex: Prozac)
Clomipramine

Front 386

How to treat a coma due to an unknown cause? What are each of the parts?

Back 386

1. IV dextrose (to correct for hypoglycemia)
2. Oxygen
3. IV Naloxone (an antidote to opiates)
4. Thiamine (in patients that are suspected of vitamin B1 deficiency, mainly alcoholics)
5. IV flumazenil (used to be used to treat benzo toxicity, but is not widely used today, because if a patient takes psychotropic drugs in conjunction with a benzo sedative, the two drugs will neutralize each other--but if the benzo is neutralized, the psychotropic, pro-epileptic drug will be unopposed, and the patient will go into status epilepticus.)
(pneumonic is DONT)

Front 387

What is a gastric lavage?

Back 387

a large orogastric tube is inserted through the mouth, into the stomach. Then, water is pushed through the tube, the tube is attached to a pump, and the contents of the stomach are pumped back out the tube. Then, the whole procedure is repeated. This is rarely used today, because there are more efficient, less unpleasant ways to prevent absorption.

Front 388

How is activated charcoal used?

Back 388

charcoal is able to bind to a lot of toxins, and prevent them from being absorbed in the body. One gram of charcoal has a lot of pores, giving it a surface area of 500 m2, which increases is binding capacity.
Because charcoal cannot be absorbed by the body, the toxins it binds to get excreted with it.
The recommended dose is 1 gm charcoal/Kg body weight.

Front 389

What are drugs that are not absorbed by activated charcoal?

Back 389

i. Pesticides, potassium
ii. Hydrocarbons
iii. Alcohols
iv. Iron, insectisides
v. Lithium
vi. Solvents

Front 390

When must activated charcoal be given? How does this change for drugs that enter enterohepatic circulation? What are examples of these drugs?

Back 390

Activated charcoal needs to be given within about 1 hour of ingestion of the toxin in order to be effective.
For drugs that enter the enterohepatic circulation, repeated doses of activated charcoal are given. Such drugs include:
i. Antimalarials (quinine, theophylline)
ii. Barbiturates
iii. Carbamazepine
iv. Dapsone

Front 391

What is whole bowel irrigation?

Back 391

similar to gastric lavage. A nasogastric tube is inserted, and then polyethylene glycol is administered through the tube and flushed through the body.

Front 392

How can elimination of a toxin be enhanced?

Back 392

i. Changing the pH of the urine to decrease reabsorption

ii. Hemodialysis (works on small, water soluble compounds such as alcohol, salicylates, lithium, and heavy metal chelates)

iii. Perfusion of the blood with activated charcoal (works on large, protein-bound or lipophilic toxins, such as theopylline, phenytoin, phenobarbital, and carbamazepine)

Front 393

Name the antidote.

Paracetamol

Back 393

N-acetylcysteine

Front 394

Name the antidote.

Opiates

Back 394

naloxone

Front 395

Name the antidote.

Benzodiazepines

Back 395

Flumazenil

Front 396

Name the antidote.

Methanol, ethylene glycol

Back 396

Ethanol/fomepizole

Front 397

Name the antidote.

iron

Back 397

deferoxamine

Front 398

Name the antidote.

organophosphates

Back 398

Atropine+oximes

Front 399

Name the antidote.

Digoxin

Back 399

Fab fragments (Digifab)

Front 400

Name the antidote.

Beta-blocker, CCB

Back 400

Glucagon

Front 401

Name the antidote.

Tricyclic antidepressants

Back 401

Sodium bicarbonate

Front 402

What is the difference between pharmacogenetics and pharmacogenomics?

Back 402

Pharmacogenetics--studies drug responses to variations in the DNA sequence only
Pharmacogenomics --studies drug responses to variations in DNA and RNA, so relates to both genes and gene expression.

Front 403

What are the leading drugs that cause adverse reactions in the US?

Back 403

Warfarin, acetaminophen (liver toxicity), Aspirin, Ibuprofen, Clopidogrel, and Phenytoin.

Front 404

What are causes of adverse drug reactions?

Back 404

1. Poor metabolism of the drug
2. Poor efficacy, possibly caused by
i. Speedy metabolism
ii. Altered drug target

Front 405

What are prodrugs? What are examples?

Back 405

Prodrugs, that are given in an inactive form and metabolized in the body to an active form, have poor efficacy when the metabolism is slowed, but will also be less likely to cause an adverse event in such a case.
Examples of prodrugs include codeine, Tamoxifen, and Clopidogrel

Front 406

How are lipophilic drugs metabolized?

Back 406

In two steps:
Phase I -- liver converts drug into a more hydrophilic form

Phase II -- conjugation og the drug to another compound that makes it even more hydrophilic

Front 407

Explain the purpose of the P450 enzymes. What are they responsible for? Where are they expressed?

Back 407

Most drugs are metabolized in the liver by the P450 enzymes (aka CYPs). There are 57 CYPs in the genome that are responsible for phase I oxidative metabolism of most hydrophobic and aromatic molecules, including:
1. Steroid hormones
2. Xenobiotics
3. Carcinogens

CYPs are mostly expressed in the liver, but can also be expressed in the brain, muscle, intestines, lungs, and placenta.

Front 408

What drugs are metabolized by CYP3A4/5? What inhibits? How?

Back 408

Most drugs are metabolized by CYP3A4/5. Smoking, alcohol, and certain drugs (phenytoin, carbamazepine, certain herbal substances) inhibit CYP3A4/5--this will inhibit metabolism of other drugs, preventing either activation of a prodrug, or clearance of a drug from the body.

Front 409

What drugs are metabolized by CYP2D6? When is it dysfunctional? Deficiencies tend to affect which patient population?

Back 409

CYP2D6 metabolizes about a quarter of drugs. It is dysfunctional in patients who are poor metabolizers and overactive in patients with gene duplications.
Deficiencies in CYP2D6 are more common in Africans and Caucasians than in Japanese and Chinese.

Front 410

Tramadol
Codeine

Administration, metabolization. Sensitivity.

Back 410

1. Tramadol and Codeine--analgesics that are administered as prodrugs and metabolized to active compounds by CYP2D6. Their effects are limited in CYP2D6-deficient patients, so other analgesics (e.g. morphine) need to be given to such patients. People with extra gene copies of CYP2D6 (also pretty common) respond extremely sensitively to these drugs, and need to be treated with lower doses, to avoid the danger of an overdose.

Front 411

Tamoxifen

Administration, metabolization. Sensitivity.

Back 411

an estrogen-blocker, used to treat breast cancer in patients with a normal estrogen receptor, and used preventatively in patients at high risk for breast cancer. Tamoxifen is administered as a prodrug and also metabolized to its active form by CYP2D6. Therefore, patients that are deficient in CYP2D6 do not respond to Tamoxifen.

Front 412

CYP2C19 deficiency affects which patient population? What are some drugs that are metabolized? What do they do?

Back 412

A CYP2C19 deficiency is rare in Caucasians, and more common in Japan.

CYP2C19-metabolized drugs to remember are:
1. Plavix (Clopidogrel)--inhibits platelet aggregation, given to stroke patients
2. Omeprazole--a proton pump inhibitor, given in combination with Amoxicillin, to treat H. pylori infections. Omeprazole is not given as a prodrug but as an active metabolite, so drug concentrations are much higher in poor metabolizers, and too low in ultra-metabolizers.
Poor Omeprazole metabolizers have a higher cure rate, indicating that perhaps the drug should be administered in higher doses.

Front 413

How is acetaminophen metabolized? What happens in patients deficient in these enzymes?

Back 413

Acetaminophen is metabolized both by CYP enzymes and by phase II enzymes, which perform sulfation. Patients deficient in these enzymes will divert acetaminophen metabolism into a toxic pathway, catalyzed by CYP2E1.

Front 414

What is 5-FU? How is it metabolized? When is it not effective?

Back 414

5-FU is a non-competitive inhibitor of thymidylate synthase, used to treat breast and colorectal cancer. It is administered as a prodrug and both
1. Converted into an active metabolite inside cells
2. Metabolized into an inactive compound by dihydropyrimidine dehydrogenase (DHD).
5-FU is not effective in tumors that overexpress thymidylate synthase, and can be toxic in DHD-deficient patients, who need to be treated with doses much lower than the recommended dose.

Front 415

What is deficient in diabetes insipidus? How can it be treated? From where is it released?

Back 415

Vasopressin (ADH)--released in response to rising plasma tonicity or falling blood pressure. Causes vasoconstriction and water retention in the kidneys. Is deficient in diabetes insipidus, which can be treated with a vasopressin analog called Desmopressin.

Front 416

Describe prolactin? What is it similar to? What does it do? What inhibits it? What stimulates its release? What can cause high prolactin?

Back 416

Prolactin similar to GH, that promotes growth and function of the mammary glands. It also may have effects on the immune system and coagulation. Its secretion is inhibited by DA (it is the only AP hormone that is not controlled by a negative feedback mechanism). Its release is stimulated by TRH, oxytocin (secreted during childbirth), and estrogen. Sleep, exercise, sleep.

Hypothyroidism can cause high prolactin, since in primary hypothyroidism, TRH levels will be elevated. Also,
Chronic renal failure
Renal Disease
Drugs (Reserpine, Morphine..)

Front 417

What are clinical manifestations of hyperprolactinema? How does it differ between women and men?

Back 417

1. Women
"galactorrhea amenorrea syndrome"
Typically caused by microadenomas
2. Men
Impotence, erectile dysfunction, infertility
Typically caused by macroadenomas

Front 418

How should hyperprolactinemia be treated? What are some side effects?

Back 418

1. Bromocriptine
2. Carbegoline--the drug of choice, because it has a longer half life and can therefore be given less frequently, and involves fewer side effects
Most prolactin-secreting adenomas will respond to Bromocriptine and Carbegoline, although microadenomas are easier to treat than microadenomas.

Side effects of DA agonist drugs include:
1. Nausea
2. GI side effects
3. Hypertension

Front 419

Describe the release of GH, IGF-I?

Back 419

GH is secreted in a pulsatile function, mostly at night, which should be taken into account clinically, when measuring a patient's GH levels.
IGF-I levels are steady over the course of a day, although they change with age, increasing until about 20, and then decreasing with age.

Front 420

In terms of measuring GH excess, how can is be measured? Wheat the the clinical steps?

Back 420

IGF1 levels can be measured to evaluate GH excess. They are elevated if GH is, and decreased if it is decreased.
If a patient has high IGF-I levels, the next clinical step is to perform an OGTT--a patient with elevated GH will not be able to suppress GH in response to an oral glucose load.
If the OGTT is positive, the next step is to take an MRI, to test for a pituitary tumor.

Front 421

What are the best treatments for acromegaly?

Back 421

is surgical removal of the pituitary. Other treatment options include:
1. Somatostatin analogs--given to most patients in conjunction with surgery. Somatostatins inhibit secretion of ALL the pituitary hormones, as well as suppress the release of insulin in the GI tract.
Synthetic somatostatin analogs with long half lives, that do not inhibit insulin release are on the market.
2. Pegvisomant--a GH receptor antagonist that is effective in decreasing GH and IGF-I levels, although it may be involved in some carcinogenesis.
3. DA agonists
4. Radiation

Front 422

What are the goals of acromegaly treatment?

Back 422

1. Remove the initial tumor
2. Restore GH levels to normal
3. Restore IGF levels to normal
4. Control symptoms, to reduce comortalities

Front 423

What are examples of somatostatin analogs that treat acromegaly? What are some side effects? What can somatostatin analogs also be used to treat?

Back 423

1. Octreotide
2. Lanreotide

Side effects:
1. Adverse GI effects (diarrhea, nausea, abdominal discomfort)
2. Gallstones (since they decrease gall bladder motility)
3. Impaired glucose regulation

Aside from acromegaly, somatostatin analogs are also used to treat TSH-secreting tumors and carcinoid tumors.

Front 424

How can GH deficiency be diagnosed? How can it be treated?

Back 424

Low IGF-I levels are an indication of a GH deficiency. A GH deficiency diagnosis can be confirmed using two tests that, in a normal person, should stimulate GH secretion:
1. Glucagon test
2. GHRH and arginine

Low GH can be treated by subcutaneous administration of GHRH; side effects include headaches, edema, arthralgia, and possibly carcinogenesis.

Front 425

What are gonadotropins? What stimulates their release? How is it secreted?

Back 425

gonadotropins (FSH and LH) are glycoproteins that regulate the steroid sex hormones. Their release is stimulated by GNRH.

Front 426

What are synthetic GNRH analogs that inhibit GNRH release? What can they be used to treat?

Back 426

1. Leuprolide
2. Goserelin
3. Nafarelin
4. Histrelin
They can be used to treat prostate cancer, endometriosis, and precocious puberty. Side effects include hypersensitivity, dermatitis, headache, diminished libido, and in women, sweating, depression, and ovarian cysts, and in men, bone pain and gynecomastia.
GNRH analogs are contraindicated in pregnant and breastfeeding patients.

Front 427

How can infertility be treated? What are some FSH analogs?

Back 427

Gonadotropins are used to treat infertility. FSH analogs, followed by hCG (an LH agonist) injection, are used to stimulate ovulation in women.
FSH analogs include:
1. Menotropins
2. Urofollitropin
3. Follitropin beta

Front 428

How does progestin work?

Back 428

inhibits ovulation by inhibiting LH secretion. Also causes thickening of the cervical mucus, and prevents implantation.

Front 429

How is the thyroid regulated?

Back 429

1. The hypothalamus releases TRH (thyrotropin release hormone)
2. TRH stimulates the anterior pituitary to release TSH (thyroid stimulating hormone)
i. The release of TSH is inhibited by T4 and T3.
3. TSH stimulates the release of thyroid hormone from the thyroid gland. There are two major forms of thyroid hormone:
i. T3--the active hormone, that comprises about 20% of thyroid secretions.
ii. T4--an inactive form, that comprises about 80% of thyroid secretions and is converted into T3 in the liver.
Patients with thyroid deficiency are given T4 supplements.

Front 430

Go through the process or thyroid hormone synthesis?

Back 430

Binding of TSH to TSH receptors on the thyroid stimulates the uptake of iodide (I-) into the epithelial cells of the thyroid.
1. Iodide enters the cells on the basolateral side via the Na/iodide (NIS) transporter, and is oxidized to iodine (I2) by thryoide peroxidase.
2. Iodine is pumped out of the cells on the apical side, into the follicular lumen.
3. In the lumen, iodine binds to tyrosine residues attached to thyroglobulins, to form either DIT (diiodotyrosine) or MIT (monoiodotyrosine). This step is also catalyzed by thyroid peroxidase.
4. Iodination of thyroglobulin can be inhibited by propylthiouracil methimazole or elevated iodide.
i. DIT can combine with another DIT to form T4
ii. DIT can combine with MIT to form T3
1. Condensation of DIT and MIT to form T4 or T3 can also be inhibited by propylthiouracil methimazole
5. TSH stimulation triggers the thyroglobulin complex to be endocytosed back into the follicular cells, where T3 and T4 are released from the thyroglobulin and sent into the bloodstream.
i. Thyroid hormone release is inhibited by elevated iodide.

Front 431

How does thyroid hormone circulate in the blood?

Back 431

Thyroid hormone circulates in the blood bound to thyroid binding protein. T4 is converted into the more active T3 when it enters the cells or in the liver.
Inside the cells, T3 binds to regions on the DNA called thyroid hormone responsive elements, and ultimately activates target genes.
More T4 is present in the bound form than T3.
The T4 half life is 7 days. The T3 half life is one day.
If a patient on T4 replacement therapy forgets to take a pill one day, it's not a big deal, because of the long half life of T4.

Thyroid hormone has two rings; an inner ring and an outer ring. Deiodination of the outer ring converts T4 into the active T3. Deiodination of the inner ring can produce a biologically inert form of T3, call reverse T3 (rT3).

Front 432

What is the Wolff Chaikoff Effect?

Back 432

The Wolff-Chaikoff effect refers to a decrease in thyroid hormone synthesis that will occur as the result of excessive iodine intake (ex: use of iodine as contract material in a CT).
High levels of iodine lead to high intracellular iodide, which inhibits thyroglobulin iodination and thyroid hormone release.
In a normal gland, the Wolff-Chaikoff effect will reverse itself if the iodine overload is removed.

Front 433

What are the effects of thyroid hormone?

Back 433

1. Increased metabolic rate
2. Increased oxygen consumption
3. Increased glucose uptake
4. CNS development and function

Hypothyroidism is more common than hyperthyroidism.

Front 434

What is Hashimoto's Thyroiditis?

Back 434

Hashimoto's is an autoimmune disease that predominates in women between 30-50. In it, antibodies attack thyroid peroxidase and thyroglobulin, leading to decreased production of T3 and T4. It is also associated with increased incidence of other autoimmune disease.
Symptoms of Hashimoto's represent the lowered metabolic rate, including:
1. Fatigue, lethargy, cold intolerance
2. Mental slowness
3. Lessened appetite but increased weight
4. Dry skin and hair
5. Periorbital puffiness
6. Enlarged heart
7. Anemia
8. Hoarseness in severe cases, due to edema of vocal cords

Front 435

What are the lab values for Hashimoto's?

Back 435

Test Value
TSH High
T4 Low (no point in testing T3, which will usually be normal)
CPK (derived from muscle) Elevated (for unknown reasons)
Cholesterol High

Front 436

How can Hashimoto's be treated?

Back 436

Hashimoto's is treated with T4 (thyroxine) replacement therapy.
T4 can lead to complications in patients with heart problems. Such patients should be started on very low doses, and gradually be titrated up.

Front 437

What is the difference between clinical and subclinical hyperthyroidism?

Back 437

In clinical hyperthyroidism, T3 and T4 are elevated.
In subclinical hyperthyroidism, TSH is high, but T4 levels are within a normal range. There is no indication to treat subclinical hyperthyroidism.

Front 438

What is Grave's Disease?

Back 438

Grave's disease is an autoimmune condition in which antibodies that stimulate TSH receptors are produced. It is the most common cause of hyperthyroidism.
About 80% of people with Grave's also test positive for the antibodies to thyroid peroxidase, which are also present in Hashimoto's.

Front 439

What are the symptoms of Grave's?

Back 439

1. Goiter
2. Ophthalmopathy, caused by the stimulation of fibroblasts by the thyroid stimulating Ig
3. Localized dermopathy
4. Association with a higher risk of another autoimmune disease

Front 440

What are the lab test values for Grave's? How is it treated?

Back 440

Test Value
TSH Low
T3 and T4 High (although, sometimes only T3 will be elevated)
Ca and alkaline phosphatase High (due to bone turnover)
Glucose High (due to insulin resistance)
Thyroid antibodies and thyroid stimulating Ig will be detectible in the blood.
Grave's is treated with steroid therapy, and sometimes by surgical removal of the thyroid.

Front 441

How can hyperthyroidism be treated?

Back 441

1. Antithyroid drugs
i. Methimazole
ii. Propylthiouracil (PTU)--not a first-choice drug, because it is associated with rash, urticaria, arthralgia, hepatitis, and agranulocytosis, in rare cases. However, because methimazole cannot be given during pregnancy (it has been correlated with birth defects), PTU becomes the drug of choice during pregnancy, since it binds to large proteins that cannot cross the placenta.
iii. Amiodarone--a new drug that induces thyroid dysfunction
2. Radioactive iodide (I131)--contraindicated in pregnant or nursing women, and only works in patients with normal iodine uptake. Restoration of euthyroidism takes about 8 weeks. Initial treatment coincides with an immediate, transitory worsening of the hyperthyroidism, as destroyed thyroid cells release reserves of hormone into the body.
3. Thyroidectomy--used to treat large goiters, pregnant patients, or patients with severe adverse reactions to anti-thyroid drugs.

Front 442

What can be used to treat the underlying causes of hyperthyroidism?

Back 442

1. β blockers, to decrease the heart rate until the drugs start to work
Anti-thyroid drugs take a while to kick in, which the reserve of hormone in the body is used up
2. Glucocorticoids in patients with thyroid storm (severe thyrotoxicosis)
3. Inorganic iodid for patients who will have their thyroid removed soon, or in patients with thyroid storm, one hour after administration of antithyroid drugs, to block the transformation of iodide into thyroid hormone.
4. Cholestyramine--blocks absorption of T4 in the GI tract
5. Potassium percholate--inhibits the discharge of thyroid hormones from the gland. However, potassium percholate is not a drug of choice, because it causes neutropenia and nephrotic syndrome.

Front 443

How to differentiated b/w thyroiditis and Graves?

Back 443

Initially, thyroid hormone levels will go up, as the destroyed cells release pre-formed hormone into the bloodstream. Then, this hyperthyroidism will be followed by long-term hypothyroidism, as the thyroid cannot synthesize new hormone.
Clinical indications of early thyroiditis are low TSH and high thyroid hormones. It can be differentiated from Grave's, because unlike a patient with Grave's, a scan of a thyroiditis patient will show low uptake of contrast material in the thyroid gland.

Later stages of thyroiditis involve low thyroid hormone levels, after the released hormone gets used up, and TSH will go up, due to the low thyroid hormone levels.
As TSH levels go up, iodide uptake levels will also go up.

Front 444

What are risk factors for osteroporosis?

Back 444

1. Caucasian ethnicity
2. Smoking
3. Low body weight
4. Estrogen deficiency
5. Low Ca intake
6. Alcoholism

Front 445

What are SERMS? What are examples?

Back 445

Selective estrogen receptor modulators (SERMs)--SERMs are estrogen analogues that can bind to the estrogen receptor and act as agonists in some organs, but antagonists in others. Two SERMs in common use are tamoxifen and raloxifene:
Tamoxifen is given for breast cancer
Raloxifene is given for osteoporosis, although it has been shown to also decrease the risk of braest cancer

Front 446

What are drugs for osteoporosis?

Back 446

1. Biphosphanates
2. Teriparatide
3. Denosumab

Front 447

What are biphosphanates? How to they work? Examples?

Back 447

1. Biphosphanates--prevent bone resorption by getting incorporated into the bone and triggering apoptosis of osteoclasts. Biphosphanate action is permanent, and they do not dissociated once they incorporate into the bone. They are used to treat osteoporosis, hypercalcemia, and many malignancies (especially multiple myeloma). They need to be taken orally on an empty stomach. Available biphosphanates are:
i. Alendronate
ii. Risendronate
iii. Ibandronate
iv. Zolendronate (given as a once-yearly injection)

Front 448

What is teriparatide? How is it used?

Back 448

a PTH analog, given as a daily injection to treat osteoporosis. Side effects include transient hypercalcemia, headaches, and hypercalciuria. Teriparatide should only used up to 24 months, since its effects do not persist over time (and 'cause it causes sarcoma in rats).

Front 449

What is denosumab? How does it work?

Back 449

a new drug (approved this year) that acts as a monoclonal antibody to the RANK ligand. The RANK ligand binds to RANK receptors, and activates osteoclasts. Therefore, Denosumab suppresses osteoclast activity. It is given as an injection every six months, and unlike the biphosphanates, its effects are reversible, and disappear once therapy is stopped.

Front 450

What are the symptoms of hypercalcemia?

Back 450

1. GI symptoms (constipation, anorexia, nausea, vomiting, dyspepsia, and rarely, pancreatitis)
2. Renal symptoms (polyuria, polydypsia, nephrolithiasis--in longstanding cases--, nephrocalcinosis
3. Neuromuscular depression, confusion, stupor, coma
4. Bradycardia, AV block, hypertension

Front 451

How to treat hypercalcemia?

Back 451

The first step in treating hypercalcemia is hydration (IV saline).
Other steps include:
1. Inhibit bone resorption with high dose biphosphanates and/or calcitonin
2. Inhibit Ca reabsorption in the kidneys with loop diuretics like Furosemide
3. Glucocorticoids, if the hypercalcemia is related to vitamin D intoxication (counteract the effect of vitamin D) or a malignancy affected by glucocorticoids
4. Dialysis, in cases of renal failure

Cinecalcet--a calcium sensing receptor agonist. Used to treat patients with secondary hyperparathyroidism, due to renal failure.

Front 452

What are the causes and treatments for hypocalcemia?

Back 452

1. Primary hypoparathyroidism--patients are treated with 1,25 hydroxyvitamin D (Calcitriol)
2. Hereditary--pseudohypoparathyroidism, vitamin D resistant Rickets
3. Iatrogenic--e.g. thyroidectomy, which can damage the parathyroid glands

Hypocalcemia is treated with Ca and calcitriol.

Front 453

What are the rapid-acting insulins?

Back 453

Lispro (due to lysine, proline switch(
Aspart
Glulisine

Front 454

What are the long-acting insulins?

Back 454

Glargine (lower isoelectric point)
Detemir

Front 455

What is a synthetic amylin analog? What does it do? What is it for?

Back 455

Pramlintide

Adjunct to mealtime therapy,
Delays gastric emptying,
Decreases postprandial glucagon secretion

Front 456

What sulfonylureas?

Back 456

Tolbutamide
Glyburide (safe for pregnancy)

Promote insulin release from beta cells of pancreas
Blocking K+ channels, leading to Ca influx, reducing hepatic glucose
Risk of hypoglycemia

Front 457

What are meglintides?

Back 457

Rapid onset, short action.
Overlapping action w/sulfonylueras
Post-prandial effect.

Rare risk of hyoglycemia either at night or with a missed meal.

Front 458

What are biguanides?

Back 458

Metformin

Decreases insulin resistance
Inhibits hepatic gluconeogenesis
Reduces LDL

Preferred for Type II.
Monitor renal function.

Front 459

What are glitazones?

Back 459

Insulin sensitizer; insulin required
Targets peroxisome proliferator (PPARy), which regulates adipocyte prodcution, secretion of fatty acids

Pio-- no LDL effect
Resi -- increased LDL

Front 460

What are a-glucosidase inhibitors?

Back 460

Type II, preprandial, delays carb digestion

Arabose (also inhibs pancreatic a-amylase)
Miglitol

Front 461

What are DPP-IV inhibitors?

Back 461

Sitagliptin

Increases glucose-dependent insulin release, descreases secretion of glucagon

Front 462

Where are mineralocorticoids produced? How is secretion regulated?

Back 462

Produced by the adrenal in th zona glomerulosa.

Secretion mainly influenced by renin-angiotensin.

Aldosterone promotes reabsorption of sodium from the distal and collecting renal tubules.

Front 463

What is spironolactone?

Back 463

Mineralocorticoid antagonist:
Spironolactone: onset of action is slow with effect lasting for 2-3 days.
Androgen antagonist therefore is used as a treatment of hirsutism in women
Diuretic
CHF
Side effect: hyperkalemia, gynecomastia, menstrual abnormalities, sedation, headaches , skin rashes.

Front 464

What is glucocorticoid therapy? What for?

Back 464

Glucocorticoids may be administered as replacement therapy in patients with primary or secondary adrenal insufficiency

adrenal suppression therapy in congenital adrenal hyperplasia

as anti-inflammatory or immunosuppressant therapy in a broad range of mostly nonendocrine disorders affecting many different systems

Front 465

What is Addison's Disease? How to treat?

Back 465

Adrenal Insufficency

Hypotension
Hyperpigmentation
Hypoglycemia
Hyponatremia and hyperkalemia

Acute -- IV hydrocortisone
Chonric -- low doses of cortisones

Front 466

What is CAH?

Back 466

Group of disorders characterized by specific defects in the synthesis of cortisol.
Decreased cortisol synthesis leads to a compensatory ACTH release . The gland becomes hyperplastic and produces abnormal amounts of precursors.

Front 467

What is ketoconazole? What does it do? Side effect?

Back 467

Ketoconazole is an imidazole derivative which was originally developed as an oral anti-fungal agent.

An inhibitor of cortisol secretion by 11ß-hydroxylase inhibition (less inhibition of aldosterone and sex steroid through inhibition of other enzymes)

Principal side effect of ketoconazole is hepatotoxicity.

Front 468

What is mitotane? What does it do? Side effect?

Back 468

Mitotane (OPDDD), an isomer of the insecticide DDD (belonging to the same family of chemicals as the insecticide DDT).

Inhibits cholesterol side-chain cleavage and 11-ß-hydroxylase in the adrenal gland.

In treatement for adrenal carcinoma it appears to cause tumor regression and improve survival.

Toxic: adrenal insufficiency, gastrointestinal side effects, nerological disturbance, hepatotoxicity, hypercholesterolemia, rash.

Front 469

What is aminogletethimide? What does it do? Side effect?

Back 469

Inhibits: the side-chain cleavage of choleterol to pregnenolone.

It thus inhibits not only cholesterol but also estrogen and aldosterone production.

Inhibits 11b-hydroxylase and 18-hydroxylase

A strong aromatase inhibitor

Front 470

What is metyrapone? What does it do? Side effect?

Back 470

Metyrapone acts primarily to inhibit the enzyme 11ß-hydroxylase, thus blocking the production of cortisol from 11-deoxycortisol.

Side effect: increase in androgens

Front 471

What is etomidate? What does it do? Side effect?

Back 471

Etomidate is an imidazole derived anesthetic agent.
More potent than ketoconazole (work on similar enzymes)
At higher concentratios it also appears to have an effect on choleterol side-chain cleavage.
Has to ge given parenterally

Front 472

What are the effects of cortisol?

Back 472

1. Promotion of normal, intermediary metabolism--upregulate gluconeogenesis, increase amino acid uptake in the liver and kidney, and stimulate protein and lipid catabolism.
2. Raise plasma glucose levels to deal with stress
3. Enhance vasoconstrictive effects of adrenergic stimuli on small blood vessels
4. Decrease the concentration of WBCs (except for PMNs) in the blood by causing them to relocate to lymphatic tissue, increase concentration of hemoglobin, RBCs, platelets, and PMNs
i. This effect has made corticosteroids a treatment option for leukemia
5. Anti-inflammatory effects
i. Indirect inhibition of phospholipase A2, thereby inhibiting prostaglandin synthesis
6. Stimulate TSH secretion

Front 473

What is the difference between fudrocortisone and spinolacterone?

Back 473

Fudrocortisone is a mineralocorticoid agonist, with a very high affinity for the aldosterone receptor.
Spironolactone is a mineralocorticoid antagonist, used to treat hyperaldosteronism. Side effects include hyperkalemia and hypertension.

Front 474

How can Addison's be diagnosed? How is it fatal?

Back 474

Addison's can be potentially fatal, because patients can become dangerously hypotensive, and go into shock.
Addison's is diagnosed by administering a synthetic ACTH, called cosyntropin. If cortisol levels go up, the patient does not have Addison's. If cortisol levels do not go up, the patient probably does have Addison's.

Front 475

What are drugs that inhibit steroidogenesis?

Back 475

1. Mitotane--a derivative of an insecticide called DDD that inhibits cortisol secretion by inhibting 11 β-hydroxylase. Mitotane will destroy the adrenal cells, if given for a long time period, so is usually used for cancers of the adrenal glands.
2. Ketoconazole--also given for fungal infections, but at a lower dose. Ketoconazole also inhibits cortisol secretion by inhibiting 11 β-hydroxylase. The major side effect is hepatotoxicity. Ketoconazole also impairs the cytochrome P450 system, so can interact with other drugs. Unlike mitotane, ketoconazole does not destroy the adrenal cells.
3. Aminglutethymide--used to treat adrenal carcinomas
4. Metyrapone
5. Etomidate

Front 476

What are drugs that inhibit ACTH secretion?

Back 476

1. Bromocriptine
2. Cypropheptadine
3. Valproic acid
4. Mifepristone--competitive inhibitor of cortisol

Front 477

Biguanides are contraindicated in which patients?

Back 477

-renal dysfunction, indicated by high serum creatinine levels
-CHF (since such patients are more prone to lactic acidosis)
-patients who were given iodinated materal for radiological studies
-patients with acute or chronic metabolic acidosis
-allergic patients

Front 478

When do meglintides stimulate insulin secretion?

Back 478

Meglitinides stimulate insulin secretion ONLY in the presence of glucose (which makes them less likely than sulfonylureas to cause hypoglycemic episodes), but their effects are short-lived.

Front 479

Dopamine

Back 479

a1 agonist at high doses, b- & D1 receptor agonist at low doses
= vasocontriction, increased HR, contractility

promotes renal perfusion

treatment of severe hypotension and shock

Front 480

Pilocarpine

Back 480

muscarinic agonist (like bethanecol and charbacol)

can enter brain, causing CNS disturbances

Front 481

Neostigmine

Back 481

more polar than physostigmine, does not enter CNS

used for myasthenia gravis

Front 482

Nicotine

Back 482

ganglionic blocker

Front 483

Reserpine

Back 483

blocks DA transport into vesicle

Front 484

Cocaine
Imipramine

Back 484

Prevents NA reuptake.

Front 485

bladder (a,b)

Back 485

detrusor -- b2

sphincter -- a1

Front 486

phenoxybenzamine

Back 486

treat pheocytochroma and diffuiculties in urination

reflex tachycardia
orthostatic hypertension

Front 487

doxazosin

Back 487

hypertension and those who have difficulty urinating

decreases blood pressure

Front 488

bleomycin

Back 488

scisson of DNA by oxidaive process

cell-cyle specific, causes cells to acculuate in G2

PULMONARY TOXICITY

Front 489

Side effects of nitrosureas

Back 489

BMD, renal toxicity, pulmonary fibrosis

Front 490

How can the neutropenia due to taxols be reversed?

Back 490

treatment with G-CSF Filgrastim

Front 491

What chemotherapeutric drugs do not cause BMS?

Back 491

bleomycin
vincristine
hormones
most molecularly-target agents

Front 492

What does drug permeation depend on?

Back 492

solubility
concentration gradient
surface area, vascularity

Front 493

volume of distribution

Back 493

V - Dose/C (t=0)

Vd is low when a high % of drug is bound to plasma protein

Front 494

What is zero order elimination?

Back 494

A constant amount of drug is eliminted per unity time; independependent of plasma concentration

no fixed half life

Front 495

What is first-order elimination

Back 495

half life is constant
elimination variable
clearance constant

rate of elimination = GFR + active secretion - reabsorption

Front 496

Maintanence dose

Back 496

MD = C(ss) Cl t
-------------------------
f

Front 497

single dose half life

Back 497

.7 x Vd/Cl

Front 498

Multiple Dose

Infusion rate

Back 498

Cl x C(ss)

Front 499

loading dose

Back 499

(Vd x Cp)/f

Front 500

What is rate of infusion?

Back 500

It determines plasma level at SS (all takes the same amount of time)

Front 501

What is the leading dose?

Back 501

Needed to rapidly acheive effective blood levels

Front 502

What is affinity?

Back 502

Ability of drug to bind to receptor, shown by proximity to y axis *if curve are parallel)

Front 503

Which is a cancer therapy given post-op to destroy microscopic cancer forms?

Back 503

adjuvant therapy

Front 504

A breast cancer patient was given Paclitaxel as an adjuvant therapy--what toxicity is associated?

Back 504

Peripheral neuropathy

Front 505

Not prescribed for epilepsy?

Back 505

GABA A agonists

Front 506

What is D-serine?

Back 506

An allosteric modulator of metabotropic gluatamate receptrors