Opt 226B Pharmacology Lectures 8-15

Front 1

Excitatory neurotransmitters

Back 1

Glu
ACh
D1 & D5 (DA)
ATP

Front 2

Inhibitory neurotransmitters

Back 2

GABA
D2, D3, D4 (DA)
Glycine
Adenosine

Front 3

Alzheimer's disease

Deficiency of ___

Back 3

ACh

Front 4

Parkinson's disease

Imbalance of ____
Excess of ___

Back 4

Excess ACh [deficiency of DA]

(imbalance of DA/ACh)

Front 5

Schizophrenia

Imbalance of ___
Excess of ___

Back 5

Excess of DA [deficiency of ACh]

(imbalance of DA/ACh)

Front 6

Drugs for anxiety disorders

Back 6

1. Benzodiazepines (-zepam, -zam, -lam)
2. 5-HT partial agonist (buspirone)
3. Beta blockers (social phobias & performance-related problems)
4. Antidepressants
(TCAs, SSRIs, MAOIs for panic, phobias, OCD)
(MAOIs for social anxiety disorders)

Front 7

MOA of benzodiazepines

Back 7

Potentiate action of GABA (thus increasing inhibition; decreasing excitability)

Front 8

Benzodiazepines used in anterograde amnesia

Back 8

Diazepam
Lorazepam

Front 9

Therapeutic effects of anti-depressant drugs

Back 9

1. Enhanced CNS monoamine levels & transmission (N.B. 5-HT)
2. Enhanced intracellular signaling
3. Regulation CRH production (+upregulation CNS CORT receptors?)
4. Antagonism of NMDA (glu) receptor action

Front 10

Drugs for depression

Back 10

1. T/PCAs
2. SSRIs
3. MAOIs
4. Buproprion (DA uptake inhibitor for quitting smoking, depression, anxiety)
5. Trazodone (weak 5HT uptake inhibitor, receptor blockade)
6. Mirtazapine (5HT2A & alpha-2; anti-H1)

Front 11

MOA for T/PCAs
Ocular SEs

Back 11

Block pre-synaptic reuptake of monoamines (NE, 5HT, DA) to keep them in cleft longer, improve monoamine transmission

Ocular SEs (2° anti-muscarinic, anti-adrenergic actions)

DO NOT use with decongestants

Front 12

MOA for SSRIs
Ocular SEs

Back 12

Inhibit reuptake of 5-HT to keep it in synaptic cleft; decreased inhibitory feedback, improved transmission

Ocular SEs:
-increase IOP (fluoxetine)
-ONH neuropathy (sertraline)

Front 13

Amblyopia therapy

Back 13

Bupivacaine (strengthens EOMs)

SSRIs? (fluoxetine increases cortical plasticity)

Apomorphine (DA agonist, improves vision in amblyopic eyes)

Front 14

MOA for MAOIs
Ocular SEs

Back 14

Inhibit MAO breakdown of NE to keep NE levels up in cytoplasm (MAO-A effect more important)

Phenelzine non-selective & irreversible
Moclobemide selective for MAO-A & reversible

Ocular SEs:
-pupil & maybe accommodation

AVOID sympathomimetics (decongestants) and tyramine-containing food (hypertensive crisis)

Front 15

Drugs for Mania, Bipolar Depression, and Mood Stabilization

Back 15

1. Lithium salts
2. Carbamazepine
3. Valproate

Front 16

MOA of Lithium Salts
Adverse SEs

Back 16

Interference with IP3 signaling pathways (decrease IP3 levels); neuroprotection; increased neurogenesis

Very toxic (long half-life, narrow TI, easily substitutes for Na+ & K+ in body)

Adverse SEs:
-polyuria, diabetes insipidus
-GI, CNS, thirst, cardiac arrhythmia, convulsion, hypothyroidism
-blurred vision

DO NOT give with NSAIDs

Front 17

Drugs for Schizophrenia

Back 17

1. Phenothiazines (-azine)
2. Butyrophenones (haloperidol)
3. Thioxanthenes (flupentixol)
4. Atypical (rispieridone, clozapine, olanzapine)

Front 18

MOA of schizophrenia & neuroleptic drugs

Adverse SEs

Back 18

Inhibition of mesocortical pathway; multiple receptor interactions

Adverse SEs:
-oculogyric crisis
-Parkisonian SEs (nigrostriatal pathway)
-antimuscarinic effects (glaucoma!)
-lens (star-shaped cataract from chlorpromazine)
-retinopathy (thioridazine)
-postural hypotension
-photosensitivity

Front 19

Neural pathways involved in schizophrenia
1. Mesocortical pathway
2. Mesolimbic pathway
3. Nigrostriatal pathway

Back 19

1. Mesocortical release of DA inhibited in schiz -- negative Sx (flat affect, apathy); 5-HT receptor blockers increase release of DA to alleviate

2. Mesolimbic release of DA active in schiz -- positive Sx (delusions, hallucinations); D2 receptor blockers inhibit DA release to alleviate

3. Nigrostriatal -- causes adverse effects (parkinsonism); inhibited DA release results in loss of inhibition of excitatory ACh neurons

Front 20

Drugs for Epilepsy

Back 20

Carbamazepine
Phenytoin
Lamotrigine
Sodium valproate
Gabapentin
Topiramate
Vigabatrin (serious SEs)
Benzodiazepines (-zepam)
Ethosuximide

Front 21

MOAs of anti-epilepsy drugs

Back 21

1. Enhancing inhibitory GABA influences (or preventing GABA breakdown)
2. Dampening excitatory Glu influence
3. Inhibition of Ca2+ T channels (blockade)
4. Na+ channel blockade

Front 22

Ocular SEs of anti-epilepsy drugs

Back 22

Diplopia (carbamazepine)
AACG (topiramate)
Nystagmus (vigabatrin)
Peripheral VF defects (vigabatrin)
Photophobia (ethosuximide)
Steven's Johnson's Syndrome (ethosuximide)

Front 23

Drugs for Parkinson's Disease & MOA

Back 23

1. Levodopa (--> DA)
2. Enzyme inhibitors to reverse DA deficiency and increase DA activity:
--DOPA decarboxylase inhibitors (carbidopa, benserazide)
--MAO-B inhibitor (selegiline)
--COMT inhibitor (entacapone)
3. DA agonists (apomorphine, bromocriptine, pergolide)
4. Amantidine (DA reuptake inhibitor, increased release)
5. Antimuscarinics to restore ACh/DA balance (benztropine, trihexyphenidyl HCl)

Front 24

Ocular SEs of Parkinson's Disease drugs

Back 24

Levodopa most problematic
Pupil, lid, eye movement, and vision effects (incl. oculogyric crisis)
Antimuscarinic effects

Apomorphine improves vision in amblyopic eyes

Front 25

Drugs for Alzheimer's Disease & MOAs

Back 25

1. Anticholinesterase inhibitors to increase ACh level (donepezil, rivastigmine, galantamine)

2. Non-competitive Glu antagonist for neuroprotection (memantine)

3. Statins, prophylactic prevention

4. Antipsychotics

Front 26

Ocular SEs of anticholinesterase inhibitors used as Alzheimer's drugs

Back 26

-miosis
-decreased accommodation (if any)
-ciliary muscle spasm (decrease IOP, but increased risk of RD)
-increased tearing (good SE)

Front 27

Similarity between Alzheimer's Disease & glaucoma

Back 27

Both have lower CSF pressure than normal people. May increase risk of damage at lamina cribrosa.

Front 28

MOA of Verteporfin (Visudyne)

Back 28

Dye injected in liposome form --> attaches to LDLs in abnormal BVs at neovascularization sites or in tumors --> laser activation of dye --> release of cytotoxic oxygen species --> endothelial cell damage --> platelet activation --> thrombosis --> vascular occlusion

Front 29

Alternative Tx for neovascularization and/or AMD

Back 29

1. Anti-oxidants
2. Macugen (pegaptanib) -- anti-VEGF aptamer
3. Lucentis (ranibizumab) -- anti-VEGF monoclonal ab
4. Infliximab

Front 30

What are the components of Metabolic Syndrome

Back 30

Overweight
HTN
High cholesterol
Sedentary lifestyle
Insulin insensitivity

Front 31

Insulin Release Pathway

Back 31

Triggered by levels of blood glucose --> GLUT2 transports glucose into cells --> incr. ATP --> closes K+ channels --> depolarization --> activates Ca2+ channels --> incr. Ca2+ influx --> triggers insulin exocytosis --> insulin released as hexamers

Front 32

Insulin Degradation

Back 32

60% metabolized by liver, 35-40% by kidney. Plasma half-life 3-5 min.

Front 33

What kind of receptor is the insulin receptor?

Back 33

Tyrosine kinase

Front 34

Mechanism of insulin receptor

Back 34

Insulin binds receptor --> 2 beta subunits phosphorylate each other --> receptor phosphorylates IRS --> activates MAP kinase pathway

Front 35

Function of GLUT 2, and what tissues it's on

Back 35

B cells of pancreas, liver, kidney, gut

Regulation of insulin release and other aspects of glucose homeostasis

Front 36

Function of GLUT 4, and what tissues it's on

Back 36

Muscle, adipose

Insulin-mediated uptake of glucose to decr. blood glucose. Insulin stimulates translocation of GLUT 4 to plasma mb.

Front 37

Rapid-Acting Insulins

Back 37

Insulin Lispro, Aspart, Glulisine (all monomers)

Front 38

Short-Acting Insulins

Back 38

Regular Novolin R, Regular Humulin R, Velosulin BR (pump), Regular Exubera (inhaled)

Should only be administered by IV. (SC injection results in 3 different rates of absorption due to size)

Front 39

Intermediate-Acting Insulins

Back 39

NPH Humulin N, NPH Novolin N, Lente

Front 40

Pre-Mixed Insulins (%NPH/%regular)

Back 40

Combo of short & intermediate-acting

• Novolin 70/30
• Humulin 70/30 and 50/50
• 50/50 NPL, Lispro
• 75/25 NPL, Lispro
• 70/30 NPA, Aspart

Front 41

Long-Acting Insulins

Back 41

Insulin detemir (Levemir)
Insulin glargine (Lantus)

Used to establish baseline insulin levels (separate injection only)

Front 42

Nighttime sensitivity to insulin is ______?

Back 42

3-5x higher

Front 43

4 categories of oral antidiabetic (DM2) agents

Back 43

1. Insulin Secretagogues (sulfonylurea, meglitinides, D-phenylalanine derivatives)

2. Biguanides

3. Thiazolidinediones (Tzds, PPAR α agonists, Rosiglitazone, Pioglitazone)

4. α-glucosidase inhibitors

Front 44

MOA of Sulfonylureas (-amide, -ide)

Back 44

Inhibition of ATP-sensitive K+ channels --> opens Ca2+ channels --> incr. Ca2+ --> incr. fusion of insulin granulae with beta-cell mb --> enhance response to glucose

Also:
-increase insulin receptor number
-reduced hepatic glucose output
-decreased glucagon

Front 45

MOA of Meglitinides (-glinide)

Back 45

Modulates insulin release by effect on K+ channels. Insulin release is GLUCOSE-DEPENDENT (enhances insulin secretion when glucose is present). Does not cause insulin exocytosis.

Front 46

Why are meglitinides superior?

Back 46

They only work when you are eating a meal and glucose incr -- then they will enhance the physiologic response to glucose. Rapid onset, short duration, administered before meals.

They do not completely block the channel if there is no glucose present. Do not contain sulfur (ok for sulfur allergies).

2 shared binding sites with sulfonylureas, 1 unique binding site.
-highly selective for pancreas ion channel
-low affinity for heart/muscle

Front 47

MOA of Biguanides (-formin)

Back 47

Targets insulin resistance rather than insulin release. Also decreases plasma TGs and cholesterol, decreases weight, and increases HDL. "No hypoglycemia"

Front 48

MOA of Thiazolidinediones/Tzds (-glitazone)

Back 48

1. Post-receptor insulin-mimetic activity (increases insulin receptor kinase activity)
2. Activates PPARγ and PPARα (pioglitazone)
3. Does not affect insulin release, simply increases activity of receptor

Front 49

What is the drug of choice for someone with Metabolic Syndrome?

Back 49

Biguanides or Tzds.

1. High blood glucose
2. High insulin
3. Insulin resistance

Front 50

MOA of α-Glucosidase Inhibitors (acarbose, miglitol)

Back 50

Inhibits glucosidase (breakdown of complex starches, etc), prevents absorption in small intestine, and attenuates prandial (meal-time) increase in blood glucose

Front 51

What is glucagon used for?

Back 51

Emergency treatment of severe hypoglycemic reaction in Type 1 DM. Cuases rapid release of glucose from muscle --> get them out of hypoglycemic coma.

Front 52

What are the protective circuits for GI?

Back 52

1. Mucus lining
2. Bicarbonate secretion (buffer)
3. Prostaglandins (increase mucus and bicarbonate, decrease H+ secretion)
4. Blood flow delivers bicarbonate to the system

Front 53

Mechanism of bicarbonate buffering

Back 53

CO2 --> H2CO3 (via CA in parietal cells) --> HCO3- + H+

HCO3- --> blood plasma --> lungs --> H2CO3 --> CO2 (exhaled)

H+ --> stomach (via H+/K+ ATPase)

Front 54

Physiological control of H+ ion secretion (pathway)

Back 54

Food --> stimulates gastrin release --> stimulates G(CCK-B) receptors on parietal cells and ECL (chromaffin) cells

ECL --> releases histamine --> binds H2 receptors on parietal cells --> incr. cAMP --> secretion of H+ into stomach (H+/K+ ATPase)

Enteric system direct muscarinic innervation:
-M1 on ECL cells
-M3 on parietal cells

Front 55

Main ways to counter excessive acid-pepsin in the gastric lumen

Back 55

1. Neutralize acid (antacids)
2. Reduce acid secretion (anticholinergics, H2 receptor antagonists, PPIs, prostaglandin analog misoprostol)
3. Protect tissue from further damage (bismuth, sucralfate)
4. Enhance cytoprotective mechanism (PGE2 analog - misoprostol; stimulates EP3, which completely turns off proton pump)
5. Eradicate H. pylori (Abx)

Front 56

Anticholinergics used for GI

Back 56

M1 antagonists
-pirenzepine
-telenezepine

Rarely used due to major SEs

Front 57

Triple therapy for ulcers

Back 57

2 abx (amoxicillin, clarithromycin) + PPI (omeprazole) or bismuth (bismuth citrate)

Front 58

H2 Receptor Blockers for GI

Back 58

-tidine

Reduce acid secretion to most stimulants. Good safety track record; highly effective and safe drugs. SEs mainly for cimetidine.

Front 59

PPIs for GI

Back 59

-prazole (all prodrugs activated locally by acid)

H+/K+ ATPase inhibitors (final step in acid secretion). 1° Tx - potent, highly selective, effective, safe.

Front 60

Treatment of Diarrhea

Back 60

1. Opiates (diphenoxylate/Lomotil, loperamide/Imodium)
2. Bismuth subsalicylate (Pepto-Bismol) - antibacterial and anti-inflammatory
3. Kaolin and Pectin (often combined with opiates, binds bacteria, toxins, fluid)

Front 61

Why is the eye a high risk site for OARs? (5 reasons)

Back 61

1. Rich blood supply (choroid)
2. Relatively small volume
3. Good concentrating powers (melanin)
4. Multitude of transmitters
5. Finely-tuned autonomic control mxms (e.g. pupil)

Front 62

Detecting adverse drug reactions -- proof of causality?

1. Reactions may ___ ____ ____
2. Timing
3. Ocular tissues critically dependent on ________ are more susceptible
4. Must report any suspected OARs to ____

Back 62

Detecting adverse drug reactions -- proof of causality?

1. Reactions may mimic natural disease
2. Timing -- reaction vs. start of drug use
3. Ocular tissues critically dependent on ion and/or water balance more susceptible (cornea, lens, retina)
4. Must report any suspected OARs to FDA

Front 63

Naranjo's Criteria for Causality

Back 63

1. Frequently described event that is well documented
2. Event improves on withdrawal of drug
3. Other possible causes can be excluded
4. Events become more severe with ↑ dose
5. Adverse event documented by objective evidence
6. Similar effects occur in a given patient with similar drugs
7. Even reoccurs on rechallenge with suspected drug

Front 64

What is tamsulosin?

Back 64

Treatment of BPH (benign prostate hyperplasia). Prone to a complication known as intraoperative floppy iris syndrome during cataract surgery. Choroidal detachment.

Front 65

What is Cymbalta? What does it increase risk for?

Back 65

Duloxetine - SSNRI
Increased risk of glaucoma

Front 66

Regarding parietal cell receptors, which are stimulatory/inhibitory?

M3, H2, EP3

Back 66

□ M3 -- ↑ proton pump via Ca2+ pathway
□ H2 -- ↑ proton pump via cAMP pathway
□ EP3 -- turns off proton pump via cAMP pathway

Front 67

Treatment options for high cholesterol (5 groups)

Back 67

1. HMG CoA3 reductase inhibitors
2. Niacin
3. Fibrates (PPAR agonists)
4. Bile acid binding resins
5. Inhibitors of sterol absorption

Front 68

Cholesterol pathway

Back 68

Fat & C in diet --> fatty acids + glycerol + C --> pkged into chylomicrons --> bloodstream --> LPL on vascular endothelium frees fatty acids from chylomicrons --> FFAs enter cells

Chylomicron remnant goes to liver --> TG and CE re-packaged into VLDLs --> bloodstream --> LPL frees fatty acids

Remainder is LDL (the main way cholesterol is transported in blood) --> LDL receptors on liver bind and take up cholesterol

Front 69

What decreases synthesis of cholesterol?
What increases LDL receptor uptake of LDL?
What decreases VLDL secretion?
What enhances lipoprotein lipase and reduces LDL?
What binds bile acids?

Back 69

What decreases synthesis of cholesterol? Statins (partially).
What increases LDL receptor uptake of LDL? Statins, resins, fibrates.
What decreases VLDL secretion? Fibrates, Niacin (Vit B3).
What enhances lipoprotein lipase and reduces LDL? Fibrates.
What binds bile acids? Resins.

Front 70

What are the lipoproteins in order by size from largest to smallest?

Back 70

Chylomicrons > VLDL > IDL > LDL > HDL

Front 71

What proteins are associated with each of the lipoproteins?

Back 71

Apolipoprotein A -- LDL, IDL, VLDL

Apolipoprotein B -- HDL

Front 72

Ideal values of cholesterol, LDL, HDL, TG

Back 72

Total C < 200 (240 dangerous)
LDL C < 130 (160)
HDL C > 45 (40)
TG < 150 (200)

Front 73

What is Tangier disease?

Back 73

Extremely low levels of HDL --> massive atherosclerosis --> cloudy cornea --> die at early age

Front 74

Which is more efficient at emulsifying fat, bile acids or bile salts?

Back 74

Bile SALTS (conjugated form) more efficient than bile acids (unconjugated form) at emulsifying fat.

Front 75

Serious drug reaction from cerivastatin

Back 75

Rhabdomyolysis (muscle wasting) from increased creatine kinase. Cerivastatin has serious drug interactions esp. when combined with fibrates.

Front 76

MOA of fibrates

(gemfibrozil, fenofibrate)

Back 76

Stimulate LPL --> decr. plasma TGs and VLDL
PPARα agonist --> lipid metabolism

Front 77

MOA of bile acid binding resins

(cholestyramine, colestipol)

Back 77

Inhibits bile acid transporter --> decr. GI absorption and recycling of cholesterol
Upregulates LDL receptors --> decr. plasma LDLs
Increase fecal elimination of bile acids

Front 78

MOA of ezetimibe (combo therapy with statins)

Back 78

Inhibits cholesterol uptake from SI
Upregulates LDL receptors --> decr. plasma LDLs

Front 79

MOA of niacin

(nicotinic acid, vit. B3)

Back 79

Decr. production and/or secretion of TGs, VLDL, LDL, cholesterol.

Effect enhanced by omega-3 fish oils

Front 80

Actions of omega-3 fatty acids

Back 80

Reduces plasma TGs and VLDLs***
Produce TG-poor LDL
Slight increase in LDL and HDL
Reduced plasma fibrinogen
Impairs platelet aggregation
Retardation of plaque formation
Promotes NO-mediated vasodilation
Anti-inflammatory (reduces risk of CVD)

Front 81

4 Alternative Strategies for Gene Therapy

Back 81

1. Gene replacement
2. Gene silencing
3. Gene addition
4. Gene correction

Front 82

4 Advantages of Eye wrt Gene Therapy

Back 82

1. Compartmentalization (local targeting, low risk of systemic SEs)
2. Small, non-mitotic (not rapidly dividing) cell populations
3. Immune responses generally attenuated (immune-privileged sites)
4. Amenable to non-invasive phenotypic investigation of gene expression (fluorescent tag with BIO, SLE, gonio)

Front 83

4 Pre-Reqs for Viral Vectors

Back 83

1. Broad "tropism" (able to infect many cell types)
2. Can deliver genes to cells in vivo
3. Gene expression persists for years (except in retinoblastoma). Can use tetracyclines to switch gene expression on/off.
4. Viral serotype influences cell type affected

Front 84

3 Types of Viral Vectors in Use

Back 84

1. Nonintegrating (vector genome lost in rapidly dividing cells) -- Adenovirus, AAV
2. Integrating (stable, long-term transduction in dividing/nondividing cells) -- lentivirus (incl. HIV-derived), gamma-retrovirus
3. Alternative Lipid/Cationic Carriers (for naked nucleic acids) -- siRNA

Front 85

Which herbal med/rec. drug has anti-muscarinic action?

Back 85

Datura (gypsum weed) - causes dry eye, mydriasis, cycloplegia

Front 86

Which herbal med/rec. drug(s) has sympathomimetic action?

Back 86

Cocaine, crystal meth (mydriasis)

Front 87

Which herbal med/rec. drug causes changes in EOMs & eye movements? Eso shifts?

Back 87

Cocaine, crystal meth, marijuana, additives to injectibles

Eso shifts with marijuana or after heroin withdrawal (heroin induces exo)

Front 88

Which herbal med/rec. drug have effects on IOP?

Back 88

Datura (incr. IOP --> AACG)
Marijuana (decr. IOP --> hypotension)

Front 89

How do recreational drugs alter color vision?

Back 89

Marijuana (blue-green)
Cocaine (blue-yellow)
Heroin (blue-purple)

Front 90

Which herbal/rec. drugs cause MYDRIASIS?

Back 90

- Datura
- Cocaine (antimuscarinic)
- Crystal meth (sympathomimetic)
- Ecstasy
- Marijuana (decr. pupillary constriction amplitude)

Front 91

Which herbal/rec. drugs cause MIOSIS?

Back 91

Heroin