Exam 1 Flashcards
1
Q
What are the differences in organization/neuron types in the ANS? (ex. cholinergic v. adrenergic, preganglionic v. postganglionic)
A
Cholinergic - Parasympathetic mechanisms
Adrenergic - Sympathetic mechanisms (named because of the adrenal medulla)
Preganglionic - Nicotinic receptor. Neurotransmitter is always ACh.
Postganglionic - For PSNS, neurotransmitter is ACh and receptor is usually muscarinic. For SNS, receptor is adreneric.
2
Q
What are the major neurotransmitters found in the autonomic nervous system?
A
ACh - the pre-ganglionic neurotransmitter for everything; Also post-ganglioic neurotransmitter
NE - post-ganglionic for sympathetic pathway
E - post-ganglionic for adrenal sympathetic pathway
3
Q
What are the major physiological responses under parasympathetic and sympathetic control?
A
Parasympathetic - Cardiac and smooth muscle, gland cells, nerve terminals
Sympathetic - Sweat glands, cardiac and smooth muscle, gland cells, nerve terminals, renal vascular smooth muscle.
4
Q
How can you differentiate the sympathetic control of the sweat glands, kidney, and adrenal glands from other areas of the sympathetic nervous system?
A
Sweat glands - When it’s stress related, the post-ganglionic neurons release NE, but when it’s thermoregulation, post-ganglionic neurons release ACh.
Kidney - Not innervated, so they are not controlled by neurotransmitters that are released by CNS, but neurotransmitters that are released by something else (ex. Dopamine that is produced locally)
Adrenal glands - Preganglionic neurons don’t synapse on paravertebral sympathetic ganglion, but on the adrenal gland itself. Also, adrenal glands release E, not NE.
5
Q
What are the different describing terms for drugs that effect the autonomic nervous system?
A
Drugs either mimic or block ACh and NE/E
Receptor agonist - mimic NTs to activate receptors
Receptor antagonist - block NTs and deactivate.
Parasympathomimetic - mimics ACh, muscarinic agonist, cholinergic
Parasympatholytic - blocks ACh, anticholinergic, muscarinic antagonist
Sympathomimetic - mimics NE, adrenergic, adrenergic agonist
Sympatholytic - blocks NE, antiadrenergic, adrenergic antagonist.
6
Q
What are the major types of neurotransmitter receptors found in the autonomic nervous system organized by structure, signal transduction pathways, tissue distribution, and associated physiological effects?
A
Muscarinic - M1-5 subtypes. M1-3 are main functional ones. They are GPCRs
Nicotinic - Ligand Gated Ion Channel.
Adrenergic - A1-2, b-,2,3
7
Q
How can you predict the effects on an organ system or 2nd messenger formation given a specific drug (agonist or antagonist)? Heart, vasculature, lung, genitourinary, penis/vas deferens, GI, liver, kidney
A
An agonist activates the receptors, antagonist inhibits receptors.
Heart: SNS - Increase rate and force of contraction (mainly b1); PSNS - Decrease rate and force of contraction (m2)
Vasculature: SNS - constriction (a1, a2, b2)
Lung: SNS - dilate (b2) and PSNS (m2,3) constrict
Genitourinary: SNS - halts urination; PSNS - stimulates urination
Penis/vas deferens: Only one where they work together!
GI: SNS inhibits secretion; PSNS increases secretion
Liver: SNS - Glucose production/degradation through a1 and b2
Kidney: SNS - increases renin secreation by b1
8
Q
What are the signal transduction pathways that are associated with each of the major receptor types in the ANS?
A
M1,3,5 - Gq pathway (IP3 -> more Ca+; DAG -> PKC)
M2,4 - Gi pathway (inhibits cAMP production and K+ channel opens causing hyperpolarization).
a1 - Gq pathway; Major function is vasoconstriction due to its location (various smooth muscle, heart, liver)
a2 - Gi pathway
b1,2,3 - Gs pathway (increase cAMP through adenylyl cyclase; kinase activity)
9
Q
What are the differences between the sympathetic and parasympathetic control of the eye (pupillary size, lens refractive power, aqueous humor production and flow)?
A
Pupillary size - SNS dilates, PSNS constricts
Lens refraction - ??
Aqueous humor secretion- SNS increases aqueous humor through ciliary epithelium (b2)
Aqueous drainage (flow) - SNS ciliary body a2 receptor inhibits production of aqueous humor and increases the outflow of it; PSNS contracts ciliary muscle, increasing flow.
10
Q
How can you predict the effects of a given drug on pupillary size (miosis v. mydriasis) based on knowledge of the radial and circular muscles?
A
If the drug is an agonist or antagonist of these receptors, the following things will happen:
Miosis - pupillary constriction through the circular muscle (PSNS); m3 receptor.
Mydriasis - pupillary dilation by radial muscle (SNS); a1 receptor.
11
Q
What are the major pharmacologic manipulations of the cholinergic system?
A
Muscarinic receptor agonist
AChE inhibitor
12
Q
How can you identify the major structural features of a drug to determine what is responsible for its activity? (In terms of charge and structure for AChE binding)
A
- charged molecules can’t pass BBB
- no acetyl group would ensure that it wouldn’t get hydrolyzed by AChE
- 4º amine ensures it will bind to anionic site in AChE
13
Q
How can you determine what the effect of a chemical modification will do to a molecule’s activity/sensitivity to acetylcholinesterase?
A
Acetylcholinesterase hydrolyzes ACh extremely fast, so decreasing ACh’s sensitivity to AChE will increase the binding of ACh to its receptor.
In this case, it’ll further stimulate muscarinic receptors that have various effects.
14
Q
What is the molecular basis for the interactions of acetylcholine and related drugs with muscarinic receptors (esp. on stereochemical requirements of drugs)?
A
The muscarinic receptor is steroselective.
ACh assumes a particular formation when it binds to the muscarinic receptor. The derivaties of ACh mimic that stereochemistry (even tho ACh doesn’t have a chiral center, the derivatives do).
15
Q
How can you choose the appropriate cholinergic agonist to treat various clinical conditions? (Bethanechol, methacholine, carbachol, pilocarpine)
A
Bethanechol - GI stimulation & treatment of urinary retention
Methacholine - Provocative test for hyperreactive airways
Carbachol - Ocular surgery & glaucoma
Pilocarpine - glaucoma & hypoproduction of saliva
16
Q
What’s the difference between acetylcholinesterase and plasma cholinesterase?
A
Plasma ChE has a much broader range of selectivety than AChE (hydrolyzes ACh, Succinylcholine, and local anesthetics)
Plasma ChE is not neuronal (it’s in plasma), but AChE is (in synapse).
17
Q
What are the direct and indirect mechanisms of acting parasympathomimetic drugs?
A
Direct - Binds to muscarinic receptor
Indirect - Inhibits AChE
18
Q
What are the roles that the AAs at the esteratic and anionic sites play in the catalytic steps associated with the actions of acetylcholinesterase?
A
The 4º amine binds to anionic site, and the ester binds in the catalytic triad. Then, the OH on the serine attacks the ester and the ACh splits. Serine is now attached to acetate. Then, water comes in an attacks the acetate, and it is now released. Once the acetate is release, the enzyme is reactivated and restarts the cycle.
19
Q
What are the differences between the structures and molecular interactions of the reversible cholinesterase inhibitors with acetylcholinesterase? (Edrophonium, Neostigmine/Pyridostigmine, Pyridostigmine)
A
Edrophonium - An alcohol and a quat. amine. This binds to the anionic site of AChE, but can’t be hydrolyzed, so it blocks the site.
Pyridostigmine & Neostigmine - A carbamate & quat. amine. Causes covalent modification to AChE. Hydrolyzed slower than ACh, so slows down AChE.
Physostigmine - A carbamate, but no quat. amine, so more likely to cross the BBB. Causes covalent modification to AChE. Hydrolyzed slower than ACh, so slows down AChE. (Still can be pos. charged at phys. pH)
20
Q
How can you choose the appropriate acetylcholinesterase inhibitor to treat various clinical conditions? (Edrophonium, Pyridostigmine, Neostigmine, Physostigmine)
A
Edrophonium - Diagnosis of Myasthenia Gravis; Very short acting.
Pyridostigmine - Treatment of MG, pretreatment for potential nerve gas exposure, reversal of non-depolarizing neuromuscular blockade
Neostigmine - MG, reversal of non-depolarizing neuromuscular blockade, post-op urinary retention
Physostigmine - Glaucoma, Alzheimer’s, & Antidote to antimuscarinic poisoning because it can cross the BBB.
21
Q
What’s the difference between the mechanism of organophosphates (inc. aging effect) and the reversible inhibitors of acetylcholinesterase?
A
Organophosphates have a phosphate that permanently covalent bond to Serine’s functional group (usually, H2O can come and kick out the covalent bond, but the phosphate bond is too strong).
When the phosphate binds to serine, it can later form an anion (process called aging), which is extremely poisonous.
In the reversible inhibitors, the compounds get hydrolyzed and released as water replaces the transient covalent bond.
22
Q
What’s the difference in toxicity of Malathion and Diazinon in mammals and insects?
A
Malathion is rapidly inactivated to its acid form in mammals due to a carboxyesterase enzyme that we have, but insects do not have this capability, so it’s toxic for them.
Diazinon - ??
23
Q
Why shouldn’t parasympathomimetic drugs be used in asthma, peptic ulcer, or bowel and urinary obstructions?
A
The parasympathomimetic drugs stimulate the PSNS, which is responsible for bronchoconstriction and for simulating digestion/urination. It increases acid secretion, and increased contractions don’t necessarily remove the obstructions.
24
Q
What are the signs and symptoms of parasympathomimetic toxicity and how can you determine the appropriate treatment?
A
Signs/Symptoms - DUMBBELS (essentially consequences of overstimulations of cholinergic receptors); SLUD (salivation, lacrimation, urination, defecation)
2-PAM (Pralidoxime) - Antidote of organophosphate toxicity. Must be combined with atropine for BBB access.
Atropine - Cholinergic receptor antagonist, doesn’t need to be with 2-PAM if it’s not necessary.
25
What are the cholinergic agents used to treat Alzheimer's dementia? (4)
All reversible:
Tacrine (Cognex) - Binds to anion site to prevent ACh binding; Enhances cognitive ability, but doesn't slow the progression of the disease
Rivastigmine (Exelon) - 3º amine; Enhances cognitive ability, but loses effectiveness as disease progresses; Side effects include nausea, vomiting, anorexia, and weight loss.
Galantamine (Razadyne) - Natural product that loses effectiveness as disease progresses
Memantine (Namenda) - NMDA receptor antagonist, which decreases stimulation in CNS by glutamate in areas associated with cognition and memory, which may slow the progression of the disease.
26
What are the side effects of Cholinergic agonists? DUMBBELS
```
Diarrhea
Urination
Miosis
Bradycardia
Bronchoconstriction
Emesis
Lacrimation
Sweating/Salivation
```
27
What are the various clinical uses of antimuscarinic drugs? What are examples of drugs used for each clinical purpose?
Treatment of motion sickness - Scopolamine
Mydriasis, cycloplegia - Homatropine, Tropicamide (short-lasting)
Parkinsons Disease - Benztropine
COPD - 4º amines; Ipratropium
GI disorders - 4º amines; Glycopyrrolate, Probanthine
OAB - Tolterodine
28
What are the clinical outcomes of antimuscarinic drugs in terms of the functional properties of M1, M2, and M3 muscarinic receptors?
M1 - Responsible for postganglionic functions (depolarization); Not many things target M1
M2 - Responsible for the heart (slowing beat, reducing force); When targeted, pulse raises, force increases.
M3 - Responsible for smooth muscle (contractions), exocrine glands (secretions) and endothelium (relaxation); This can be targeted to reduce constriction (ex. asthma treatment, COPD), reduce secretions (ex. Pre-op GI surgery)
29
What are the pharmacophore characteristics of antimuscarinic drugs?
Antimuscarinic drugs are mainly tertiary or quaternary amines.
They also have an ester, mimicking the acetyl moiety of ACh.
30
How does the clinical use of antimuscarinic drugs depend on the drug's duration of action?
Long acting - Used for longer term issues like Parkinson's, GI disorders, motion sickness
Short acting - Used in optical applications like cycloplegia and mydriasis
Ex. We don't want to use a long acting drug on something that'll affect the patient's vision.
31
Why are antimuscarinic drugs with a quaternary amine group suitable for some clinical purposes but not others?
Having a quaternary amine results in a permanent positive charge. A positive charge makes it impossible for the compound to pass the BBB. So, if CNS assess is needed, then a quaternary amine would NOT be suitable.
Quaternary amines are used in GI tract and other peripheral applications, and tertiary amines are used in ocular and CNS appications.
32
What is the chemical and biological rationale for the anticholinergic effects of drugs that were not designed to target muscarinic receptors?
This one, she said it's more general like we have to be aware of the anticholinergic effects of drugs to make sure it's okay to give to the patient.
33
What are the clinical uses of ganglionic and neuromuscular blockers? What are examples of drugs used in each clinical purpose?
Skeletal muscle relaxation during anesthesia - Tubocurarine (Curare), Succinylcholine
Muscle spasm issues - Botulinum Toxin
HTN - Hexamethonium (not anymore tho)
34
What are the clinical outcomes of ganglionic and neuromuscular blockers in terms of the functional properties of nicotinic receptors?
N skeletal - Responsible for motor end-plate depolarization and contraction; Can be targeted to prevent the contraction.
N neural - Responsible for depolarization and catecholamine secretion; When targeted, can block SNS and PSNS activity.
35
What are the pharmacophore characteristics of ganglionic and neuromuscular blockers (ex mono and bis-quaternary motifs)?
Neuromuscular blockers look like ACh, but they don't have the acetyl group, so they can't be hydrolyzed by AChE.
36
What are the different modes of action of depolarizing vs. non-depolarizing ganglionic and neuromuscular blockers?
Depolarizing blockade - Ensures that the channel never resets by keeping the agonist bound to the receptor, so the channel stays inactive. A depolarizing blocker is one that binds and activates nicotinic receptor once, but then blocks it. (ex. Succinylcholine)
Non-depolarizing - Binds to active site of nicotinic receptor and blocks it without every activating it (ex. Tubocurarine)
37
What are the key structural features of anti-muscarinic drugs and ganglionic and neuromuscular blockers?
They all mimic ACh. They either have 3º or 4º amine.
Anti-muscarinic - have acetyl moiety.
Ganglionic/neuromuscular blockers - Look like ACh, but can't be hydrolyzed by AChE because they lack the acetyl moiety.
38
What are the differences between the major pharmacologic mechanisms that alter adrenergic system function?
??
39
What are the major steps in catecholamine synthesis and metabolism?
1. Tyrosine (single -OH, NH2, COOH)
2. Tyrosine converted to L-DOPA by tyrosine hydroxylase (Adds an -OH, now is a catechol)
3. L-DOPA converted to Dopamine through AA Decarboxylase (Takes off carboxyl (-COOH))
4. Dopamine converted to NE by Dopamine b-Hydroxylase (adds -OH to beta carbon)
5. NE converted to E by N-methyltransferase (adds CH3)
40
What are the different adrenergic receptor subtypes (in terms of signaling pathways and location)?
a1 - Gq pathway
a2 - Gi pathway, in CNS
b1 - Gs pathway
b2 - Gs pathway
41
What is needed in the structure of NE to bind to adrenergic receptors?
NE has one chiral center (R orientation), and that is what is important for direct binding to the adrenergic receptors.
42
What are the effects of structural changes in an adrenergic receptor agonist w/ regards to receptor selectivity, activity (agonist v. antagonist), mechanism of action (direct v. indirect), lipophilicity, and metabolism?
Receptor selectivity - The bulkier the group (on α carbon), the more likely it'll bind to b2 receptors (order from least bulky to most bulky: a -> b1 -> b2); Moving one of the -OH from the catechol makes it selective for b2, whereas removing one -OH makes it selective for a1
Activity -
MOA -
Lipophilicity - As the R group on α carbon gets bulkier, it is more likely to be lipophilic (adding more carbons)
Metabolism - As the R group (on α carbon) gets bulkier, the less likely it is to be metabolized by MAO.
43
How can you determine the receptor selectivity of adrenergic receptor agonists through dose-response curves?
In a dose-response curve, the left-most curve (indicating lowest value) means the drug is most selective for that receptor.
Ex. Phenylephrine will be left-most on a graph that is indicating a1 receptor activation.
44
Given data on the effects of adrenergic agonists on the CV system, how can you predict what adrenergic receptor(s) the drug is acting on?
b1 receptor is known for cardiac stimulation, which results in increased heart rate and force of contraction
a1 receptor is known to facilitate vasoconstriction; An agonist would cause vasoconstriction, raising BP
b2 receptor is known to facilitate uninnervated vasodilation; Agonist would lead to fall in BP and bronchodilation
45
What are the pharmacologic properties, adverse effects, and clinical uses of different selective and non-selective a-adrenergic receptor agonists? (NE, E, D, Phenylephrine, Naphazoline/Tetrahydrozoline/Oxymetazoline, Clonidine, Guanabenz/Guanfacine, Methyldopa, Brimonidine, Apraclonidine, Tizanidine)
Norepinephrine - direct, non-selective, raises blood pressure
Epinephrine - direct, non-selective, used for anaphylaxis (b2), glaucoma, and in combination with anesthetics
Dopamine - direct D1, b1, and a1 agonist, used for shock and CHF
Phenylephrine - direct a1, mydriasis, pressor, nasal decongestant
Naphazoline/Tetrahydrozoline/Oxymetazoline - direct a1 partial agonist, used for local vasoconstriction with nasal and ophthalmic decongestants
Clonidine - a2 agonist, used for HTN, opiate withdrawal, and ADHD
Guanabenz/Guanfacine - a2 agonist, used for HTN and ADHD
Methyldopa - a2 agonist (prodrug), active metabolite used for HTN
Brimonidine - a2 agonist, used for glaucoma
Apraclonidine - a2, Glaucoma
Tizanidine - a2, Muscle spasticity
46
What are the general structural features of imidazoline-based a-adrenergic receptor agonists?
Imidazoline: 5 membered ring with 2 nitrogens
- results in e- dispersion due to resonance, thus stabilizing the charge
- more basic due to this stability
47
What are the differences in the effects of changes in a2-adrenergic receptor agonist structure on cardiovascular response and receptor affinity?
The a2 receptor is in the CNS and antagonizes the a1 receptor functions. It decreases the release of NE, and therefore decreases the sympathetic tone of the SNS.
In order to increase CNS, you want the pKa to be lower (ex. pKa of 8) so that it's not protonated (don't want + charge). The goal is to be non-ionized at physiological pH, but still mimic imidazoline.
48
What are the differences in pharmacologic properties, adverse effects, and clinical uses of selective and non-selective b-adrenergic receptor agonists? (Isoproterenol, Terbutaline/Metaproterenol, Albuterol/Salmeterol, Formoterol, Dobutamine, Mirabegron)
Isoproterenol - non-selective, used for asthma, COPD, and cardiostimulant
Metaproterenol/Terbutaline - b2 agonist, used for asthma, COPD (terbutaline also used to prevent premature labor)
Albuterol/Salmeterol - b2 agonist, used for asthma, COPD (Salmeterol used for long term asthma)
Formoterol - b2 agonist, used for long term asthma
Dobutamine - mixed b1 (and a1) agonist, strong inotropic effect results in use for acute heart failure and shock
Mirabegron - b3 agonist, used for OAB
49
What structural changes in b-adrenergic receptor agonists lead to increased b2 receptor selectivity and resistance to MAO and COMT?
- increase in bulky R group off of amine group increases selectivity for b2 receptor and lessens MAO activity
- changing from catechol to resorcinol or meta-hydroxymethyl makes compound selective for b2
50
How does the racemic mixture of dobutamine lead to a selective inotropic effect on the heart?
The (+) enantiomer is a b1 agonist and an a1 antagonist, and the (-) enantiomer is an a1 agonist and the potency for b receptors is reduced x10. This results in a strong inotropic effect, but little chronotropic effect.
51
What are the differences in the major mechanisms of indirect-acting sympathomimetics from the direct receptor agonists?
Direct binds to the actual adrenergic receptors.
Indirect-acting sympathomimetics bind to receptors that are in charge of NT reuptake and either inhibit them, or alter the pre-synaptic conc. of the NT. There are also MAOIs that increase the amount of NT circulating by inhibiting MAO, which usually metabolizes the NT.
Ex. NET blocked by cocaine
52
For amphetamine and related drugs, what are the pharmacologic actions that contribute to and promote release of catecholamines from neurons?
Through the actions of the plasma membrane transporter, the extra drug makes the pre-synaptic cell think there is more NT inside than there actually is, so it pumps out more NT. This results in excess NT in the synapse.
53
What are the pharmacologic properties, adverse effects, and clinical uses of the different selective and non selective a-adrenergic receptor antagonists? (Phenoxybenzamine, Phentolamine, Terazosin/Doxazosin, Tamsulosin/Prazosin)
Phenoxybenzamine - a1 & a2; Used for pheochromocytoma, hypertensive crisis
Phentolamine - a1 & a2; Used for pheochromocytoma, hypertensive crisis, and male impotence
Terazosin, Doxazosin - a1; Used for HTN, benign prostatic hypertrophy (BPH)
Tamsulosin & Prazosin - a1; Used for HTN, BPH, and Reynaud's disease
Side effects of a1 receptor antagonists: orthostatic hypotension, inhibition of ejaculation, nasal stuffiness, tachycardia
54
What is the mechanism by which phenoxybenzamine irreversibly inactivates adrenergic receptors?
Phenoxybenzamine is a b-Haloalkylamine that has a Cl as the X group. This Cl forms a covalent bond with the receptor, making it irreversible.
The covalent bond is formed by making a highly reactive intermediate called Aziridinium ion, which is then used to make the bond with the receptor.
-It also blocks ACh, Histamine, and Serotonin receptors.
55
What are the general structural features of selective and non-selective a-adrenergic receptor antagonists?
Non-selective: b-Haloalkylamines that have an alkyl group on one end and an aromatic or alkyl attached to the nitrogen on the other end. Also imidazolines (5 membered ring with 2 nitrogens)
a1 selectivity: Quinazolines that have 2 aromatic rings (one with 2 nitrogens, the other has ethers attached)
a2 selectivity: Indole alkaloid
56
How can you predict effects on dose-response curves of combinations of adrenergic agonists and antagonists?
A competitive antagonist will push the curve to the right (lower affinity).
An irreversible antagonist will lower the max binding, and thus lower potency.
57
What are the differences in pharmacologic properties, adverse effects, contraindications, and clinical uses of non-selective b-adrenergic receptor antagonists? (Propanolol, Nadolol, Timolol, Pindolol, Carteolol)
b-blockers common indications: decreased CO and HR, reduced renin release (& BP), Increase VLDL, Decrease HDL, Inhibit lipolysis, Inhibit glycogenolysis/glucose release, Increase bronchoconstriction
b-blocker clinical use: HTN, angina, cardiac arrhythmias, migraine, stage fright, thyrotoxicosis, glaucoma, CHF.
blocking b2 is contraindicated with asthma due to bronchoconstriction
Propanolol - non-selective, has local anesthetic properties
Nadolol - non-selective, HTN, agina, migraine, contraindicated in kindey disease pts.
Timolol - non-selective, Glaucoma, hypertension, angina, migraine
Pindolol - non-selective, Has intrinsic sympathomimetic activity, making it a partial agonist. It is less likely to cause bradycardia/lipid abnormalities. Used for HTN, angina, migraine.
Carteolol - non-selective, Has ISA, so partial agonist. Used in HTN and glaucoma
58
What are the general structural features of selective and non-selective b-adrenergic receptor antagonists?
Non-selective: Aryloxypropanolamines which have a non-carbon atom in the side chain attached to an aromatic ring and a bulky alkyl group attached to the nitrogen.
b1 selective: para-substited phenyl derivatives. These have a group on the para position on the aryl group.
59
How can you differentiate partial agonists from antagonists and full agonists using dose-response curves?
Partial agonists decrease the affinity and potency. An antagonist would take the response to 0%, but the partial could take it from 100 to 50%.
60
What was the development of b-adrenergic receptor upregulation and how has it potentially contributed to b-blocker withdrawal syndrome?
When taking b-blockers, the body may eventually make more adrenergic receptors, so when the b-blocker is no longer being taken, there are too many adrenergic receptors. This increases morbidity and mortality
61
What are the differences in contributions of the mixed adrenergic antagonist enantiomers in terms of receptor selectivity, physiological responses, and therapeutic advantages?
Receptors: non-selective b and a1 blocker.
Advantage - One enantiomer is a b-blocker, the other is a1 blocker. The b-blocking prevents the tachycardia reflex that usually happens when a1 is blocked.
Labetalol - Phenylethylamine derivative,
This is used for HTN and in hypertensive crises.
Carvedilol - Aryloxypropylamine, Used for HTN and CHF
62
What are the mechanisms of different direct and indirect acting sympatholytic drugs?
Metyrosine - Indirect; This inhibits the first step of NT synthesis (tyrosine hydroxylase). It's very potent and by inhibiting NT synthesis, adrenergic receptors don't get activated. Used for perioperative management of pheochromocytoma.
Reserpine - Catecholamine depleter; Blocks vesicular monoamine transporters, thus depleting the vesicular pool of NE/catecholamines. Used in treatment of HTN, but rarely used.
Bretylium, guanethidine - Indirect; 4º amine; Mechanism isn't very well understood, but this inhibits the release of NE and depleted NE storage. Used for antiarrhythmic purposes.
63
What are these used for and what is their main issue? (Metyrosine, Reserpine, Bretylium)
Metyrosine - Used for perioperative management of pheochromocytoma. Problem is that it depletes catecholamines everywhere.
Reserpine - Used for HTN. Problem is that it depletes catecholamines everywhere.
Bretylium - Used as an antiarryhthmic. Problem is that it depletes catecholamines everywhere.
64
Why does the antihypertensive effect of reserpine not evoke a baroreceptor response?
Because it also blocks a2, which is responsible for the tachycardia effects.
65
What are the 5 cardiovascular indications of beta blockers?
```
Angina
Cardiac arrhythmia
Post-myocardial infarction
Hypertension
Congestive heart failure
```
66
What are the differences in pharmacologic properties, adverse effects, contraindications, and clinical uses of selective b-adrenergic receptor antagonists? (Metoprolol/Bisprolol, Atenolol, Esmolol, Nebivolol)
Metoprolol & Bisprolol - b1; less bronchoconstriction; Used for HTN, angina, antiarrhythmic, CHF
Atenolol - b1, "water-soluble metoprolol"; Used for HTN and angina.
Esmolol - b1, Rapidly hydrolyzed by esterases, so it has a really short half life. This is used in pre-op HTN, Supraventricular tachycardia, and a-fib/flutter.
Nebivolol - b1, Derivative of phenylethylamine; Helps HTN due to vasodilation from nitric oxide production.
67
Side effects of beta blockers? (5)
Contraindications? (3)
```
AV block
Sedation
Bradycardia
Mask symptoms of hypoglycemia
Withdrawal syndrome
```
COPD
Asthma
CHF
68
What are some characteristics of endocrine signaling?
There are 5 modes of communication: Juxtacrine (direct), endocrine (through blood vessels over long distance), paracrine (travels short distance), synaptic/neuronal (NT travels very short distance and it goes really fast), and autocrine (made and functions in the same cell).
There are intracellular and extracellular receptors.
69
What are the differences in structural and chemical properties of hormones depending on the type of their receptor? (ex. intracellular receptors v. cell surface receptors)
Intracellular - hydrophobic, small, unionized
Extracellular - large, charged, hydrophilic, growth factors
70
How can you distinguish the structures of cortisol, aldosterone, progesterone, testosterone, and 17b-estradiol?
Cortisol - Almost testosterone, but has additional ketone attachment on carbon 17/20, and an addition -OH on carbon 11.
Aldosterone - Almost exactly Cortisol, but has additional ketone attachment on carbon 13/18 and no -OH on carbon 17.
Progesterone - Almost exactly testosterone, but instead of an -OH on carbon 17, there is a ketone attachment.
Testosterone - Similar to cholesterol, but exchange the -OH on carbon 3 or a ketone, move the double bond, and switch out the squalene for another -OH.
17β-estradiol - Similar to cholesterol, but the 1st ring is now aromatic, there is no methyl group on carbon 10, and the squalene was replaced by an -OH.
71
What are the common features in the structures and the mechanisms of steroid hormone receptors?
All steroid receptors are intracellular. They all have a common DNA-binding domain and hormone-binding domain.
These receptors bind steroid hormones and regulate transcription of a specific set of genes. They also belong to the nuclear receptor family.
Mechanism - Hormone binds intracellularly to the hormone receptor. Heat shock proteins bind and stabilize the other proteins. This complex enters the nucleus. The hormone receptors dimerize and bind to a specific region of DNA. This promotes transcription of mRNA which is translated into the desired proteins.
72
What is the order of the intermediates in the steroid synthesis pathways?
There are lots of pathways that could use a different order, but here's a general:
1. P450scc
2. 3β-Dehydrogenase Isomerase (17α-Hydroxylase &/or 17,20-Lyase may be used before or after this)
3. 21-Hydroxylase (These are only for Aldosterol and Cortisol from now on)
4. 11β-Hydroxylase (if 17α-Hydroxylase was used, this would make Cortisol)
5. Converted to Aldosterone
For Testosterone and 17β-Estradiol
3. 17α-Hydroxylase & 17,20-Lyase, and 3β-Dehydrogenase Isomerase must have already been used.
4. 17β-Hydroxysteroid dehydrogenase (this makes testosterone)
5. Aromatase (this makes 17β-Estradiol)
73
What are the major organs responsible for steroid synthesis?
Adrenal glands, ovaries, testes
74
What are the effects of these genetic disorders in steroid synthesis on the levels of each steroid hormone? (17α-hydroxylase deficiency & 21-Hydroxylase deficiency)
17α-hydroxylase deficiency - Aldosterone would be the only steroid hormone that would be made.
21-Hydroxylase deficiency - No aldosterone or cortisol, overproduction of testosterone
75
What are the drugs used to regulate steroid synthesis?
Aminoglutethimide (Cytadren) - Inhibits aromatase and P450scc (which turns cholesterol -> pregnenolone), thus blocking steroid production in some hormone-dependent tumors.
Ketoconazole - At a high conc. this inhibits P450scc, 17α-hydroxylase, and 11β-Hydroxylase, so this treats hyperglucocorticoid states. At lower conc. this is used as an antifungal.
76
What are the 5 major steroid hormones in our body?
Progesterone - Menstrual cycle, pregnancy, embryogenesis
17β-Estradiol - Estrogen, female hormone
Testosterone - Androgen, male hormone
Cortisol - Stress hormone, anti-inflammation
Aldosterone - Regulator of Na+ uptake in kidney, raises BP and blood volume
77
What is the order of the negative feedback loop of the hypothalamic-pituitary-adrenal (HPA) axis?
Stress on the hypothalamus causes secretion of corticotropin releasing hormone (CRH). That stimulates adrenocorticotropic hormone (ACTH) secretion from the pituitary gland. This stimulates secretion of cortisol from the adrenal gland. This causes the physiological response.
The ACTH and Cortisol both are involved in a negative feedback loop.
78
What is the regulation of testosterone synthesis?
Testosterone has feedback inhibition, meaning once it is produced by the Leydig cells in the testes, the testosterone inhibits the production of itself by targeting the hypothalamus (responsible for GnRH) and the anterior pituitary gland (responsible for LH and FSH).
79
What is the role of LH and FSH in testosterone synthesis and spermatogenesis?
LH and FSH are secreted by the anterior pituitary. LH stimulates Leydig cells which go on to produce testosterone. FSH stimulates Sertoli cells which go on to stimulate spermatogenesis.
80
What is the role of 5α-reductase in testosterone action?
5α-reductase is involved in the metabolism of testosterone. 5α-reductase is in target tissues and removes the double bond of ring 1 of testosterone, adding a hydrogen. The product of this metabolism is 5α-Dihydrotestosterone, which is more potent and more active.
In a way, testosterone is a prodrug.
81
What are some physiological effects of testosterone?
- Responsible for changes during puberty
- Growth-promoting properties, such as penile/scrotal growth, change in the skin; More hair growth, esp. beard hair; Deepening of the voice; Skeletal growth followed by epiphyseal closure; Increased lean body mass due to positive nitrogen balance
- Stimulation and maintenance of sexual function
- Stimulation of erythrocyte production (increases # of RBCs, which enhances athlete performance)
- Decrease HDL levels (bad!!)
82
What are the structures of synthetic androgens? (Methyltestosterone, Testosterone ananthate, Testosterone cypionante)
Methyltestosterone - methyl on carbon 17.
Testosterone enanthate - Prodrug that has ester on 17 carbon. Needs to by hydrolyzed to the -OH.
Testosterone cypionate - Prodrug that has ester on 17 carbon. Needs to by hydrolyzed to the -OH.
83
What are the effects of different structural modifications in synthetic androgens?
Synthetic androgens are androgens that are modified on carbon 17.
Alkylation makes them much more orally available.
17-ester forms have prolonged absorption time and greater activity in IM injections.
84
What are the adverse effects of androgens?
When taken by pregnant women, can cause major sexual development disturbances.
Women: Hirsutism, acne, amenorrhea (no menstruation), clitoral enlargement, deepening of the voice.
Men: Acne, sleep apnea, gynecomastia (breast development), testicular atrophy and azoospermia, increases agressiveness and psychotic symptoms.
85
What are the pharmacological uses of antiandrogens?
5α-reductase inhibitors:
- Male pattern baldness
- Hirsutism
- Benign prostatic hyperplasia
Steroidal androgen receptor inhibitors:
- Hirsutism
- Excessive sexual drive (men)
- Acne
Non-Steroidal androgen receptor inhibitors:
- Prostate cancer
- Metastatic castration-resistant prostate caner
86
What are the types of antiandrogens?
5α-reductase inhibitors - Blocks the conversion of testosterone to 5α-Dihydrotestosterone, inhibiting the more potent and active form of testosterone to be produced.
Androgen receptor inhibitors - Block the binding of androgens to the receptor or blocking the activation of the receptors. Ex. steroidal inhibitors and non-steroidal inhibitors.
87
How is arachidonic acid released from the membranes?
Arachidonic acid is release from the membrane phospholipids by phospholipase A2 (PLA2 (aggregation)).
Corticosteroids suppress the production of PLA2, thus reducing arachidonic acid, thus suppressing inflammation.
88
What are the different physiological roles of eicosanoids in different organs? (PGE, PGF, PGI, TXA)
PGE (Gs; expand): dilation of blood vessels, dilation of bronchi, oxytocic dilation of uterus
PGF (Gq; fasten): constriction of blood vessels, constriction of bronchi, oxytocic constriction of uterus.
PGI (inhibit): dilation of blood vessels, inhibits aggregation of plateletes
TXA (aggregation): constriction of blood vessels, stimulates aggregation of plateletes.
Ex. of Eicosanoids: Prostaglandins, leukotrienes, lipoxins
89
What are the end products of the cyclooxygenase and lipoxygenase pathways?
Both of these pathways are stimulated by arachidonic acid.
Cyclooxygenase -> Prostaglandins & Thromboxanes
Lipoxygenase -> HPETEs, Leukotrienes, & Lipoxins
90
What are the distinct physiological roles of COX1 and COX2?
COX1 - aka PGH synthase 1; Responsible for house keeping. It is constitutively expressed in various tissues. Ex. of function: gastric cytoprotection
COX2 - aka PGH synthase 2; Responsible for inflammation. It is expressed upon stimulus in inflammation and immune cells. It is stimulated by growth factors, tumor promoters, and cytokines.
Both COX1 & COX2 are inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs).
91
What are the functions of the therapeutic prostaglandins? (Alprostadil, misoprostol, latanoprost, prostacyclin)
Alprostadil - PGE (dilation), relaxes smooth muscles and expands blood vessels. It's used for erectile dysfunction by injection or as a suppository.
Misoprostol - PGE (dilation), cytoprotective, prevents peptic ulcer, also terminates pregnancy if used with mifepristone.
Latanoprost - PGF (constrict), constricts blood vessels, used in opthalmology to treat high pressure inside the eye (ex. glaucoma)
Prostacyclin - PGI (inhibit), vasodilators and inhibitor of aggregation, used to treat pulmonary arterial HTN by IV injection or inhalation, but shouldn't be used with anticoagulants
92
What are the pharmacological activities of NSAIDs?
Anti-inflammatory
Analgesic
Antipyretic
Used in treatment of moderate pain, fever, and inflammation from acute inflammation. Also used in treatment of early-stage rheumatoid arthritis and osteoarthritis. Also used in cancer prevention
93
What is the mechanism of actions of NSAIDs?
NSAIDs inhibit prostaglandin endoperoxide H synthase (PGHS or COX), which catalyzes the formation of prostaglandins. Many NSAIDs inhibit both COX-1 and COX-2.
94
What is the mechanism of gastric bleeding by NSAIDs?
1. NSAIDs are usually pretty acidic, which already isn't good for the stomach
2. The inhibition of synthesis of the cytoprotective prostaglandins (PGEs) in the gastric mucosa causes the stomach lining to not have enough protection.
3. Inhibition of platelet aggregation causes increased tendency of bleeding.
All three of these lead to increased gastric bleeding.
95
What is the mechanism of the inhibition of blood coagulation by aspirin?
Aspirin is known to prolong bleeding time due to irreversible inhibition of platelet COX-1, which reduces the formation of thromboxane (which is known for platelet aggregation).
This is why aspirin should not be used before surgery or tooth extraction, but it can be used in patients with some CV diseases.
96
What is Reye's syndrome and what is the precaution in the use of aspirin by children?
Reye's syndrome - Rare, acute, life-threatening condition characterized by vomiting, delirium, and coma (20-30% mortality). Brain damage is common in survivors.
This occurs in children who have had the flu or chicken pox, so Aspirin should not be given to anyone under 12 who has a fever.
97
What is the main cause of drug interactions of NSAIDs?
NSAIDs are highly bound to serum albumin. Many other drugs also bind to serum albumin, so NSAIDs compete with that. When NSAIDs are taken with oral anticoagulants, for example, it increases the plasma conc. of the free anticoagulant, which causes more bleeding.
It would mean that the other drugs we are taking should probably have a lowered dose if we are going to start an NSAID.
98
What are the classes of NSAIDs?
```
Salicylates
Arylacetic acids
Arylpropionic acids
Non-carboxylate NSAIDs
COX-2 selective NSAIDs
```
99
What is the role of α-methyl group in the structure activity relationship of arylpropionic acids?
If an α-methyl group is added, the activity increases greatly.
Also adding an alkyl/aromatic that isn't planar with the ring enhances activity.
100
What are the clinical uses of testosterone?
- Androgen replacement therapy
- Gynecologic disorders
- Protein anabolic agents (reverses protein loss after trauma)
- Andropause
101
What are the changes in estrogen and progesterone levels during the menstrual cycle?
Estrogen drops right before menstruation, then it is produced a lot until ovulation. Then, it drops again, and gradually grows until the next menstruation.
Progesterone stays really low until ovulation, when the corpus luteum appears. Then it drops fast along with estrogen right before the period.
102
What is the regulation of estrogen and progesterone synthesis during the menstrual cycle?
As the follicle grows, the more granulosa cells are produced. These are the cells that produce lots of estrogen. As the corpus luteum takes over, it produces estrogen AND progesterone.
103
What are the physiological effects of estrogens? (female maturation, endometrial effects, metabolic and CV effects, etc.)
- Female maturation: development of sex organs and growth of breasts, accelerate growth phase & epiphyseal closure, growth of axillary and pubic hair, alteration in distribution of body fat to produce female contours, pigmentation in skin (nipples, areolae, genital region)
- Endometrial effects: Development of endometrial lining during menstrual cycles, prolonged exposure leads to hyperplasia of endometrium and abnormal bleeding.
- Metabolic/CV: Decrease in rate of resportion of bone (this is good), more transcortin and SHBG (bind to sex hormones), increase in HDLs.
- Etc: Enhanced blood coagulation, increase/decrease of mood.
104
What are the clinical uses of estrogens?
- Hormone replacement therapy in postmenopausal women (causes relief of CNS disturbances, symptoms, and psychological effects)
- Post-menopausal osteoporosis
- Hormonal contraception
- Replacement therapy in patients with hydogonadism (ex. Turner syndrome, castration, or failure of ovary development)
105
What are the adverse effects of estrogens?
- Uterine bleeding
- Endometrial carcinoma
- Breast cancer
- Nausea, headache, fluid retention, weight gain
106
What are the structural characteristics responsible for the variance in drug properties in steroidal and non-steroidal estrogens?
Steroidal:
17β OH group - required for activity
17α R group - ethynyl substituent blocks metabolism and allows for oral activity.
16-OH - decreases activity
Aromaticity is required, 3-OH is essential for activity.
- This OH can be masked as an ether to then be hydrolyzed in vivo.
Non-Steroidal:
- "5th" aromatic ring interferes with helix-12 conformation, leading to antagonist/SERM activity
- Amine-substituted side chain on "5th" ring blocks helix-12, leading to antagonist/SERM activity
- Hydroxyl at "3rd" carbon enhances activity (mimicks 3-OH of estradiol)
- OH at "17th" carbon is required.
- Rigid core is required to maintain proper space between the aromatic rings.
107
What are the structural characteristics responsible for the variance in drug properties in steroidal and non-steroidal estrogens?
Steroidal:
17β OH group - required for activity
17α R group - ethynyl substituent blocks metabolism and allows for oral activity.
16-OH - decreases activity
Aromaticity is required, 3-OH is essential for activity.
- This OH can be masked as an ether to then be hydrolyzed in vivo.
Non-Steroidal:
- "5th" aromatic ring interferes with helix-12 conformation, leading to antagonist/SERM activity
- Amine-substituted side chain on "5th" ring blocks helix-12, leading to antagonist/SERM activity
- Hydroxyl at "3rd" carbon enhances activity (mimicks 3-OH of estradiol)
- OH at "17th" carbon is required.
- Rigid core is required to maintain proper space between the aromatic rings.
108
What are the clinical uses of non-steroidal estrogens?
Agonist:
- Advanced prostate cancer
- Postpartum breast engorgement
- Menopause symptoms
- Prostate cancer
Partial agonists: Have estrogen and antiestrogen effects.
- Treatment/prevention of breast cancer
- Prevents osteoporosis in post-menopausal women
- Stimulate ovulation
109
What are the pharmacological uses of aromatase inhibitors?
These block the biosynthesis of estrogens and are effective in some pts whose breast cancer has become resistant to tamoxifen.
Off label use is to induce ovulation
110
What are the clinical uses of non-steroidal estrogens?
Agonist:
- Advanced prostate cancer
- Postpartum breast engorgement
- Menopause symptoms
- Prostate cancer
Partial agonists:
- Treatment/prevention of breast cancer
- Dyspareunia in post-menopausal women
- Prevents osteoporosis
- Decreases LDL levels
- Increases risk of blood clots (bad)
- Decreases risk for breast cancer
- Stimulated ovulation in women with oligomenorrhea or amenorrhea
- Polycystic ovary syndrome (PCOS)
111
What are the physiological effects of progesterone?
Menstrual cycle: Causes maturation and secretory changes in the endometrium following ovulation
Metabolic: Increases insulin levels and the insulin response to glucose; Promotes glycogen storage in the liver.
Interference with aldosterone: Competes with aldosterone for the mineralocorticoid receptor bc it has some amount of structural similarity; Causes decrease in Na+ reabsorption leading to an increase in aldosterone secretion in adrenal cortex
Depressant/hypnotic effects
112
What are the clinical uses of progestins?
- Hormonal contraception
- Hormone replacement therapy in combo with estrogens (prevents some adverse effects of estrogens)
- Endometriosis (suppress the growth of endometrial cells)
- Dysmenorrhea
- Bleeding disorders
113
What are the structural characteristics responsible for the variance in drug properties in progestins?
Required: C-18 methyl group, C-3 ketone
6-Me group would enhance the activity.
17α-ethynyl moiety leads to oral activity.
Exchanging native acetyl moiety for 17β-OH/ester would make it more orally available.
C-19 methyl group can be replaced by H or double bond and still be fine. Rings 2, 3, and 4 can be unsaturated or saturated.
Aromatic/amine substituent on ring 3 leads to antagonist.
114
What is the mechanism of action of hormonal contraceptives?
Combination therapy: Here we inhibit pituitary function. Because it's all a cycle, when we give combination therapy, there's no cycle anymore, thus inhibiting ovulation.
- Progestin-only doesn't always inhibit ovulation bc there's still a cycle
They also suppress ovarian function and change the cervical mucus in the uterine endometrium.
115
What are the types of hormonal contraceptives?
Combinations of estrogens (ex. ethynyl estradiol or mestranol) or progestins only.
- Pts will have 21 days on active compounds, then 7 days on placebo where withdrawal bleeding is present.
- There is mono-, di-, and tri- phasic doses (essentially increase of dose x amount of times)
Delivery is mostly oral and at the same time everyday, but there are implants, IUDs, or depot injections.
116
What are the adverse effects of oral contraceptives?
Mild: Due to estrogens -> Nausea, HTN, edema, breast fullness; Due to progestins -> Increased appetite, fatigue, breast regression
Moderate: Irregularities in menstruation, weight gain, acne, hirsutism, amenorrhea
Severe: Venous thromboembolic disease (estrogens); Myocardial infarction (androgenic activity of progestins)
Can be dangerous in women over 35 who smoke
117
What are the components of combinatorial oral contraceptives?
Estrogens and progestins
Ex of monophasic: Alesse - ethinyl estradiol 20mcg + levonorgestrel 100mcg
118
What is Drospirenone?
- 3rd generation progestin.
- It has relatively weak progestogenic activity, and also has antimineralocorticoid activity. This negates the side effects of ethynyl estradiol in combination therapy.
- Has much milder side effects because the androgen effect is much lower.
119
What is special about Ella and Mifepristone? (Not the same special characteristic)
Ella - emergency contraceptive that can be used for up to 5 days, which is longer than the usual 3 days
Mifepristone - can terminate a pregnancy, but has serious consequences
120
What are the 5 signs of inflammation?
```
Heat (calor)
Redness (rubor)
Swelling (tumor)
Pain (dolor)
Loss of function (functio laesa)
```
121
What are options when we want to prevent the GI side effects of NSAIDs?
Misoprostol - Used to prevent NSAID-induced gastric ulcers in pts at high risk.
Proton pump inhibitors - Greatly reduce acid secretion in the stomach and protect against ulceration in the absence of COX-1 activity (takes over for the constitutive cytoprotective activity that COX-1 has)
Combination products are also an option! ex. Naproxen/esomeprazole
122
What are functions of some Salicylates? (Salicylic acid, aspirin, salsalate, diflunisal)
Salicylic acid - Inhibits COX-1 and COX-2 reversibly, slightly acidic, absorbed as an ionic form from the small intestine.
Aspirin - The only NSAID that irreversibly inhibits COX by acetylating a serine residue in the active site. It is rapidly hydrolyzed in vivo. It blocks TXA effectively, which increases risk of bleeding but also reduces the risk of myocardial infarction.
Salsalate - Dimer of salicylic acid. It's a produg, so it doesn't mess with the stomach and therefore doesn't cause GI bleeding.
Diflunisal - More potent analgesic than aspirin, but produces fewer side effects. Less antipyretic than aspirin. Much longer 1/2 life than aspirin.
123
What are the functions of some arylacetic acids? (Indomethacin, Sulindac, Etodolac, Diclofenac)
Indomethacin - One of the most potent NSAIDs in use. Not suitable for long-term use due to the side effects.
Sulindac - Prodrug, so less GI side effects, suitable for long-term use to treat chronic inflammation.
Etodolac - As potent as indomethacin, but pretty selective for COX2, which is good bc less GI side effects. Due to that, this is suitable for long-term use to manage osteoarthritis.
Diclofenac - Most widely used NSAID in the word. It's just as potent as indomethacin, but bc it's somewhat selective for COX-2, it has less side effects. It inhibits both COX and lipoxygenase pathways (reduces lots of prostaglandins).
124
What are the functions of some Arylpropionic acids? (Ibuprofen, Naproxen, Ketorolac)
Ibuprofen - OTC analgesic that is more potent than aspirin, but less than indomethacin. It has moderate degrees of gastric irritation. The a-Methyl group enhances its activity and reduces many side effects. It's a racemic mixture.
Naproxen - S-(+)-enantiomer that is more potent than ibuprofen. It has moderate degrees of gastric irritation and is used to treat rheumatoid arthritis and osteoarthritis (good for long term use).
Ketorolac - Used for short term management of moderate to severe pain becuase it's so strong as an analgesic. It's widely accepted as an alternative to narcotic analgesics. But bad for long term use due to side effects.
125
What is the difference in the mechanism of action of acetaminophen from that of NSAIDs?
Acetaminophen scavenges the peroxynitrite that is required for PGH synthase activity. Peroxynitrite is the major oxidant for PGH synthase activity in the CNS.
So it's like an indirect inhibition of prostaglandin synthesis. With NSAIDs, they inhibit the actual producer of the prostaglandins.
126
What is the structural basis of selective COX-2 inhibitors?
COX-2 selective drugs have a valine in the NSAID binding site (instead of isoleucine in COX-1).
This makes it selective because the extra methyl causes steric hindrance
127
What is the mechanism of the side effects of selective COX-2 inhibitors?
Constitutive COX-2 function is needed to produce PGI, which inhibits aggregation. When COX-2 inhibition no longer balances out the aggregation from TXA by COX-1. This atherogenesis may result in heart attack and stroke.
Side effects: elevated blood pressure, accelerated atherogenesis.
128
How do the hypothalamus and the pituitary regulate the biosynthesis of cortisol?
Hypothalamus-pituitary-adrenal (HPA) axis:
Stress signals (like pain, noise, and emotional reactions) on the hypothalamus stimulate CRH (corticotropin releasing hormone), which causes the pituitary to produce ACTH (adrenocorticotropic hormone), which then causes the adrenal gland to produce cortisol.
This also involves a feedback loop.
129
What is the difference in regulation of synthesis of glucocorticoids and mineralocoritcoids?
The pituitary does not affect aldosterone/mineralocorticoids. Mineralocorticoids are regulated by the renin-angiotensin-aldosterone system:
the liver produces Angiotensinogen -> Renin, produced by the kidney, cleaves angiotensinogen into Angiotensin I -> Angiotensin converting enzyme (ACE) cleaves Angiotensin I to Angiotensin II -> Angiotensin II goes to the adrenal glands and gets turned into Aldosterone.
130
What are the structural differences between glucocorticoids and mineralocorticoids?
Glucocorticoids - Have 17α-OH group and a methyl on C-13.
Mineralocorticoids - Have no 17α-OH group and have a ketone on C-13.
131
What are the two different mechanisms of actions in glucocorticoids?
1. Hormone response elements - The DNA-binding domain binders bind to the Glucocorticoid Responsive Elements (GRE). This binding alters the rate of transcription. Glucocorticoids up-regulate enzymes for gluconeogenesis (PEP carboxykinase) and anti-inflammatory (lipcortin I - suppresses PLA) proteins.
2. Immunosuppression - The activated glucocorticoid receptor binds to NFkB and prevents the binding of NFkB to its response element. This causes the transcription of cytokine genes to be repressed, thus suppressing the immune cell function.
132
What are the physiological effects of glucocorticoids?
All of this is to increase blood glucose levels:
Liver - Increase gluconeogenesis and glycogen storage (getting ready to supply glucose when needed)
Muscle - Promote protein degradation, decrease protein synthesis, and decrease sensitivity to insulin.
Adipose tissue - Promote lipolysis and decrease sensitivity to insulin.
These deal with immune system:
Immunosuppression - Blocks the synthesis of cytokines
Anti-inflammation - Inhibit the production of eicosanoids
133
What are the different causes in Addison's disease and Cushing's disease from the levels of cortisol, ACTH, and CRH?
Addison's disease - Hypoadrenalism. Caused by the destruction of the cortex, so there's no cortisol or aldosterone. There is a build up of CRH and ACTH due to no feedback control.
- Primary (adrenal defect) = CRH↑ and ACTH↑; Cortisol & Aldosterone low)
- Secondary (pituitary defect) = CRH↑ (everything else low).
- Tertiary (hypothalamic defect) = everything low.
Cushing's disease - Hyperadrenalism (too much cortisol). Tumors in the adrenal cortex causes adrenal Cushing's disease (cortisol↑). Increased production of ACTH due to pituitary carcinoma causes pituitary Cushing's disease (Cortisol↑ and ACTH↑). Increased ACTH due to non-pituitary carcinoma causes ectopic Cushing's disease (Cortisol↑ and Ectopic ACTH↑).
134
What are the structural features responsible for drug properties in synthetic glucocorticoids? (Carbon 1/2, 6, 9, 16, 17, 21)
C1,2-double bond adds five-fold enhancement to glucocorticoid activity.
6α-CH3 or F also enhances GR/MR ratio.
9α-F or Cl enhances GR & MR potency.
16α-CH3 or 16β-CH3 or O substituent decreases MR activity.
17α-O is required for GR activity (it can be part of an acetonide ring or ester)
21-OH,F,Cl is required for GR/MR activity; an ester prodrug must by hydrolyzed to OH for maximum activity.
135
What are the differences in potency levels of synthetic glucocorticoids?
There are short-acting, intermediate-acting, and long-acting corticosteroids.
The short-acing ones, like cortisol, have the least potency.
The long-acting ones, like Dexamethasone and Betamethasone are extremely potent
136
What are the structural and chemical characteristics of systemic, inhaled, and topical glucocorticoids?
Systemic - 21-OH, 11β-OH, and other things to increase the GR/MR ratio. We want these to be selective.
Inhaled - Very lipophilic, low oral availability, and rapid clearance.
Topical - High lipophilicity for fast absorption, minimal systemic effect, prolonged action. Halogenated analogues (F, Cl) are good for potent topical glucocoriticoids. Acetonide & ester forms are good for topicals. Adding Cl instead of 21-OH enhances anti-inflammatory activity.
137
What are the desired properties of inhaled glucocorticoids?
- High potency
- Minimal systemic effects (we want low half life, so it should be hydrolyzed as soon as it's systemic)
- Prolonged action
138
What are the side effects of Addison's disease?
```
Extreme weakness
Anorexia, anemia, nausea, and vomiting
Low blood pressure
Hyperpigmentation of skin
Mental depression
```
139
What are the traits of different 21-esters in glucocorticoids?
These all must be hydrolyzed to -OH before being active.
Acetate/Butyrate - Increased lipophilicity causes prolonged action upon IM injection due to flow diffusion.
Succinate - Soluble, so it's good when we need to injects lots of glucocorticoid into the body
Phosphate - Increased solubility due to rapid hydrolysis by phosphatases. We use this for IV or IM injection in emergency conditions.
140
What is the etiology and incidence of osteoarthritis?
Etiology - Wear and tear. Genetics, age, gender, race, hormonal static, overuse, and obesity, etc. are huge factors when it comes to getting OA.
Incidence - Observed more commonly in oder patients (10-15% of people of over 50 have it, and almost 85% of patients are over 75 years old). It's more common in females.
141
What is the pathophysiology, clinical presentation, potential complications of osteoarthritis (OA)?
Pathophysiology - OA occurs due to degenerative changes that occur in cartilage and the associated bone. It's characterized by the increased destruction and subsequent proliferation of cartilage and bone.
Presentation - Occurs in unilateral distal interphalangeal joint, hips, and knees. The pt could experience joint pain, AM stiffness, crepitus, inflammation, muscle atrophy, and it's especially asymmetric. Herberden's or Bouchard's nodes are seen, as well.
Complications - Complications can be seen as the disease worsens. The joint will most likely need to be replaced as the disease continues.
142
What are pharmacologic and non-pharmacologic options for OA patients?
Drug therapy - Based on whether it's the hand, knee/hip, there are topical therapies, oral agents, supplements, and injectables. Oral NSAIDs are strongly recommended for hand/knee/hip OA. Topicals should only be used for the hand and knee. There are charts that show the recommended treatment depending on the OA site & medical history.
- Dosing of NSAIDs will be different depending on if it's for analgesic or anti-inflammatory purposes.
- NSAIDs, COX-2 inhibitors, combination of NSAID + gastro-protective drug
- Can also use opioid analgesics for breakthrough pain
- Intra-Articular corticosteroid injection can be used for isolated joints
Non-pharm - Exercise regularly, lose weight if obese, go to physical therapy
143
What are the adverse effects for NSAID therapy? (6)
```
GI upset
Renal dysfunction
Ulcers
Bleeding
Increase BP
Increased risk of stroke, MI, and death
```
144
Who's at the greatest risk for NSAID adverse effects?
- It's dose dependent, so higher dose for long periods of time is more likely to cause adverse effects.
- Older than 75 years old
- History of GI bleeds or Peptic Ulcer Disease (PUD)
- Taking anticoagulants, antiplatelets, or glucocorticoids
145
What patients are at greatest risk for nephrotoxicity with NSAIDs? Cardiovascular AE's?
Nephrotoxicity - Pts with CHF, HTN, renal dysfunction, and dehydration
Cardiovascular AEs - CHF, CVD
146
What is the goal of therapy and education points for osteoarthritis treatment?
Goal of therapy - To relieve pain and discomfort & maintain function of joint and strength.
Education - For topicals, it's important to educate the patient on where the topical should go and how often to take it. Topicals usually take a couple weeks to work, so that's another education point. Also, with some of the analgesics, it's important to know that patients shouldn't be "chasing the pain."
147
What are opioid analgesics used for with OA and how is it dosed? What AEs should we look out for?
Used PRN for breakthrough pain
Start dosing low and go slow.
AEs: Nausea, somnolence (sleepy, drowsy), constipation, and dizziness
148
What can we monitor while a pt is taking NSAIDs OR while their disease progresses?
Monitoring when pt is on NSAIDs - Want to monitor BP, due to increased risk of HTN. Monitor signs of edema or weight gain, due to fluid retention. BUN/SCr every 3 months to monitor kidneys. Hgb/Hct every 6-12 months, due to risk of increased bleeding. Lastly, monitor for signs fo dehydration.
Monitoring progression of OA -
- Pain at rest?
- Joint stability and function?
- Risk of fall?
- Range of motion?
- Degree of disability?
- Quality of life?
- Take X rays
