Block I Pharmacology

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How do platinum compounds work?: The N in each strand of DNA forms cross-links
What is the most emetic chemotherapeutic agent?: Cisplatin
How does folate enter the cell?: reduced folate carrier
What happens to folate when it enters the cell?: It it metabolized to have glutamates added to it
How does MTX work?: It enters the cell through RFC
Gets glutamated
Blocks the Folic acid + DHFR reaction whcih normally --> THF --> AA + NTs
How does fluoruracil work? What is specifically inhibited?: It inhibits thymidylate synthase when 5-FU --> FdUMP
Specifically inhibits DNA synthesis- RNA synth not affected
How does Arabinoside work?: It poisons topoisomerase (it's a pro-drug, must be comverted to Ara-CTP)
How does GEM work?: It's a pro-drug
It inhibits DNA synthesis/repair, by incorpating itself into DNA
How do 6MP and 6TG work?: They inhibit purine synthesis
What is a side effect of 6TG?: Hepatic veno-occulsive disease
How does hydroxyurea work?: Inhibits riboNT --> deoxyNT
How does L-asparaginase work?: Doesn't enter tumor cells
Tumor cells can't make Asp (although it's not normally an essential AA in healthy tissue)
As a result, protein synthesis is inhibited
How do the -rubicins work?: Creates free radicals
Inhibits topo II
promotes strand breaks
Blocks DNA/RNA synthesis
What other drug is in the -rubicin family?: Etoposide
What is one of the major toxicities of the -rubicins?: Cardiotoxicity
How does Irinotecan/Topotecan work?: Inhibits Topo I
How do the vincas and taxanes work?: They inhibit MTs
They affect metaphase
What is the major side effect of the vincas/taxanes?: Neurotoxicity
What does tamoxifen/toremifene do?: treats breast CA
What are the drugs that are SERMS?: Tamoxifen
Toremifene
Raloxifene
Faslodex
What does SERMS stand for?: Selective estrogen receptor modulators
What do aromatase inhibitors do?: Inhibits the conversion of androgens --> estrogens
What are the antigonadotropins?: Leuprolide
Goserelin
What do leuprolide and goserelin do?: Inhibit LH and FSH release from pituitary
What does leuprolide/goserelin treat?: prostate CA
What are the anti-androgen drugs?: Flutamide
Bicalutamide
What do flutamide and bicalutamide treat?: prostate CA
What is trastuzumab? What does it treat?: mAB for HER2 + breast CA
What is the main toxicity with trastuzumab?: cardiotoxicity
What is elevated in many types of epithelial cancers?: EGFR (Her1)
What is cituximab? What does it treat?: mAB to EGFR receptor
Colon CA
Side effect of cituximab?: rash
How does ERlotinib work?: Inhibits EGFR kinase
Inhibits intracellular phosphorylation of TK associated with EGFR
What is another name for imatinib mesylate?: Gleevac
What is imatinib mesylate used to treat? Mechanism?: CML
Inhibits abl kinase
What is dasatinib?: Effective against mutant forms of abl, in case there is resistance to imatinib mesylate
What is the major toxicity for imatinib mesylate?: mostly edema... very low toxicity
What is bevacizumab?: mAB to VEGF
What are the toxicities associated with bevacizumab?: minimal: HTN, proteinuria
What drugs are VEGFR inhibitors?: Sunitinib
Soraenib
What do sunitinib/sorafenib inhibit?: VEGFR
Raf kinase
HOw does bortezomib work?: proteasome inhibitor
What are the toxicities associated with L-asparaginase?: Allergic reaction (it's bacterially derived) --> anaphylaxis
Toxic to lymphoblasts...
Decreased synthesis of clotting factors adn clotting inhibitors --> thrombosis/hemorrhage
Hyperglycemia d/t decreased insulin production
Cerebral dysfxn
Pancreatitis
Examples of adenosine analogs?: Fludarabine
pentostatin
cladribine
What does fludarabine treat?: CLL
Hairy cell leukemia
Non-Hodgkin's
How does pentostatin work?: It inhibits adenosine deaminase (ADA) --> accumulation of deoxyadenosine and dATP, which exerts negative feedback on riboNT reductase --> imbalance in deoxynNT pools --> toxic to lymphocytes
Side effects from pentostatin?: Neurotoxicity
Somnolence
Confusion
Coma
What is not a common side effect for adenosine analogs?: N/V although it does occur
What enzyme does hydroxyurea inhibit?: RiboNT reductase
Which is the only rubicin drug that can be given orally?: Idarubicin
All the others require IV
What happens during phase I trials?: Way to determine doses
What happens during phase II trials?: Treat pts with the doses det previously in order to determine the efficacy of the drug
What happens during phase III?: New drug is compared to standard therapies for particular cancers
Randomized trials are performed
What are the -parin drugs?: LMWH
What is the MOA of -parins?: Doesn't inhibit thrombin
Enhances activity of ATIII (breaks down IX, X, XI, XII)
What is fondaparinux?: LMWH that doesn't cause HIT
MOA of hirudin?: inactivates fibrin bound to thrombin found in clots
Causes no thrombocytopenia
How is hirudin administered? monitered?: IV
PTT
MOA of bivalirudin?: Inhibits platelet aggregation
What is bivalirudin used to treat?: Cariac angioplasty
MOA of argatroban?: Blocks and binds thrombin
How is argatroban metabolized?: Metabolized in liver, excreted in bile
MOA of melagotran?: Binds and blocks thrombin
Advantage of melagotran over argatroban?: No p450 interations with other drugs
MOA of streptokinase?: Activates plasminogen specifially found on clots
MOA of anistreplase?: Activates plasminogen everywhere (breaks down good and bad clots)
MOA of alteplase, reteplase, tenecteplase?: Activates plasminogen bound to clots; doesn't cause allergy and good for ppl who are allergic to streptokinase
Where does urokinase come from?: Synthesized in kidney
MOA of urokinase?: Converts plasminogen to plasmin
Breaks down good and bad clots
MOA of clopidogrel?: Inhibits binding of ADP to platelet receptors (thsi inhibits platelet aggregation)
MOA of ticlopidine?: Inhibits binding of ADP to platelet receptors (thsi inhibits platelet aggregation)
Adverse effects of clipidogrel and ticlopidine?: Rash
Diarrhea
Abdominal pain
Intracranial hemorrhage
(Clopidogrel has less adverse effects)
MOA of abciximab?: mab against GPIIb/IIIa
Adverse effect of abciximab?: Acute coronary syndrome
MOA of eptifimab?: mab against GPIIb/IIIa
MOA of tirofban?: mab against GPIIb/IIIa
MOA of dipyradimol?: vasodilator that inhibits adenosine and cGMP phosphodiesterase activity
What is dipyradimol used with?: Aspirin to prevent TIA
MOA of cilostazil?: Phosphodiesterase inhibitor that promotes vasodilation and inhibits platelet aggregation
MOA of aminocaproic acid (EACA)?: Synthetic inhibitor of fibrinolysis
What is Tranexamic acid?: Analog of EACA
What is tranexamic acid used to treat?: Hemophilia
Prevents post-surgical bleeding
Stops hemorrage secondary to radiation and drug induced cystitis (possibly from cyclophosphamide?! :))
Where are the alpha-1 receptors found?: Vascular smooth muscle of skin and splanchnic
GI, bladder sphincters
Iris
Where are the alpha-2 receptors found?: Presynaptic nerve terminals
Platelets
Fat Cells
GI walls
Where are the beta-1 receptors found?: AV/SA node
LV
Where are the beta-2 receptors found?: Vascular smooth muscle of skeletal muscle
Bronchial smooth muscle
GI, bladder walls
Describe the parasympathetic nerve signal conduction?: long presynaptic --> nicotinic receptor --> short postsynaptic nerve --> muscarinic receptor
Describe sympathetic nerve signal conduction?: short presynaptic --> nicotinic r --> long postsynaptic --> alpha/beta r
Describe somatic nerve conduction?: 1 long nerve, uses ACh on nicotinic receptors
Receptor speciificity for Epi?: all are =
Receptor specificity for NorE? Uses?: A1=A2, B1>B2
BP control
Receptor specificity for Dobutamine? Uses?: B1>B2 >>> A
Inotropes, CHF
Receptor specificity for Isoproterenol?: B1=B2 >>>> A
Heart block
Receptor specificity for DA?: D1=D2 >>> B1 >>>> A
Uses for low doses of DA?: At low doses, vasodilation of renal, mesenteric, and coronary beds
Receptor specificity for phenylephrine?: A1>A2 >>> B
Receptor specificity for clonidine?: A2>A1 >>> B
Receptor specificity for Albuterol?: B2 > B1 >>>> A
Receptor specificity for Ritodrine?: B2 > B1 >>>> A
What are the effects of clonidine?: Inhibits sympathetic output
bradycardia, hypotension, sedation
What effect does albuterol/ritodrine have on teh uterus?: It relaxes it, prevents premature labor
What are examples of direct non-catecholamines?: Clonidine
Phenylephrine
Ritodrine
Albuterol
What are direct catecholamine examples?: DA
NorE
Epi
Isoproterenol
Dobutamine
What are examples of indirect non-catecholamines?: Cocaine
Amphetamine
Tyramine
What class of drugs is ephedrine in?: Mixed non-catecholamien (direct and indirect)
Receptor specificity for phenoxybenzamine? Used to treat?: A1 + A2 antagonist
Pheo
Receptor specificity for Phentolamine? Used to treat?: A1 + A2 antagonist
Pheo
Hypertensive crisis
What are the alpha-1 blockers?: Prazosin
Terazosin
Tamsulosin
What are the alpha 1 blockers used to treat?: HTN
BPH
Why is tamsulosin a good drug?: A1a specific...
Promotes urine flow in BPH w/o BP effects
What are the pharmacokinetic properties of carbechol?: Resistant to hydrolysis
Long duration of action
What does carbechol treat?: Glaucoma
What are the pharmacokinetic properties of bethanechol?: Resistant to hydrolysis
Long duration of action
What does bethanechol treat?: Relief of urinary retention post-op
GI paralysis
Increase tone of LES
What are the pharmacokinetic properties of pilocarpine?: Tertiary amine
What does pilocarpine treat?: sialogogue
glaucoma
miosis q
What is structure of neostigmine? What does it degrade to?: Tertiary amine
Alcohol + carbamoyated enzyme
What does neostigmine treat?: AChE inhibitor
MG, ileus, NM blockade
Neostigmine is poorly absorbed through...?: Skin, eyes, lungs
What class of drug is physostigmine? Structure?: AChE inhibitor
Tertiary amine
What does physostigmine treat?: MG
Glaucoma
What are the adverse effects from physostigmine?: Weakness
Abdominal cramps
Diarrhea
What is structure of echothiophate? Drug Class?: Organophosphate
AChE inhibitor
What does echothiophate treat?: Glaucoma
What is parathion?: Organophosphate
What effects are seen from parathion and malthion?: DUMBBELSS
Diarrhea
Urination
Miosis
Bradycardia
Bronchoconstriction
Excitation of skel muscle
Lacrimation
Salivation
Sweating
How are the effects of parathion and malthion overcome?: Atropine (for the muscarinic effects)
Praloxime (for the nicotinic effects)
What class of drug is ambenonium?: AChE inhibitor
What does ambenonium treat?: MG
What drug class is demarcarium?: AChE inhibitor
What does demarcarium treat?: Glaucoma
What are the different types of drugs that can treat glaucoma?: Beta blockers
Muscarinic mimetics
Physostigmine
Echothiophate
Demarcarium
Pilocarpine
What type of drug is pyridostigmine?: AChE inhibitor
What does pyridostigmine treat?: MG
What are the drugs that treat MG?: Neostigmine
Physostigmine
Ambenonium
Pyridostigmine
What type of drug is atropine?: Anti-muscarinic
What effects does atropine have?: Midriasis
Decreased GI activity
Decreased bladder activity
Bradycardia (at low doses)
Tachycardia (at high doses)
What is atropine used to treat?: Antispasmotic for GI and bladder
Antidote for cholinergic agonists (insecticides)
What are the common side effects from atropine?: Dry mouth
Flushing
Mydriasis
Delirium
Tachycardia
"Dry as a bone, blind as a bat, red as a beet, mad as a hatter"
What type of drug is scopolamine?: Anti-muscarinic
Long-acting
Treats motion sickness
**If given topically --> mydriasis and cycloplegia**
Blocks short-term memory
What type fo drug is propantheline?: Quarternary amine
Anti-muscarinic
What does propatheline treat?: Peptic disease
Hypermotility
What does glycopyrrolate treat?: Peptic disease
Hypermotility
Traveler's diarrhea
What type of drug is tolterodine?: Tertiary amine
Anti-muscarinic with M3 selectivity
What does tolterodine treat?: Urinary incontinence
What type of drug is ipratropium?: Quarternary amine
Anti-muscarinic
What does ipratropium treat?: Asthma and COPD
MOA of ipratropium?: Relaxes bronchial smooth muscle, minimal systemic absorption b/c it's quarternary amine
What is the structure of tubocurarine?: Quarternary amine
NM blocking agent
What are the adverse effects of tubocurarine?: Bronchoconstriction through release of histamine
Where is the M1 receptor found?: CNS neurons
Sympathetic postganglionic neurons
Sometimes presynaptic
Where is M2 receptors found?: Myocardium
Smooth msucle
Some presynaptic sites
Where is M3 found?: Exocrine glands
Smoooth muscle
BV
Which muscarinic receptors utilize IP3/DAG?: M1 and M3
How does IP3/DAG work?: Increases intracellular Ca
Which muscarinic recpetors ultilize K channels?: M2
How does M2 send it's signal: It opens K channels which inhibits adenylate cyclase
How does ACh released from parasympathetic nerves interact wiht M receptors on nerve terminals?: It inhibits the release of their neurotransmission
What controlls the pupillary dilator muscle?: alpha receptors
What controls pupillary constrictor muscles?: muscarinic receptors
What controls ciliary musce?: Muscarinic receptors
What controls ciliary epithelium?: Beta receptors
What secretes aqueous humor?: epithelium of ciliary body
How do muscarinic cholinomimetics work in the eye?: They mediate teh contraction of the ciliary muscle and the circular pupillary constrictor muscle --> miosis
Miosis puts tension on trabcular meshwork, facilitating outflow, reducing intraocular pressure
How long does atropine last?: 7-10 days
How long does tropicamide last?: .25 days (6 hrs)
When is the ONLY time antimuscarinics should be used for mydriasis?: If cycloplegia (weakening of ciliary muscles) results in loss of ability to accommodate
What class of drug is sildenafil?: Organic nitrate
How does sildenafil work?: Blocks PDE5, a phosphodiesterase that converts cGMP --> GMP

Increases cGMP, enhancing erections by increasing myosin light chain that is not bound by phosphate (--> smooth muscle relaxation)
How does verdemafil work?: Same way that sildenafil works:

inhibit the conversion of cGMP --> GMP, this increases cGMP, which enhances erection by increasing the amount of mysosin unbound to phosphate --> relaxation
What type of drug is veramapil?: Ca channel blocker, binds to open L channel, preventing further Ca influx
How does veramapil work?: Moderate vasodilation
Moderate direct cardiac suppression
Moderate reflex cardiac activation
Results: vasodilation with moderate cardiac suppression
CO and HR are only modestly decreased
How does Nifedipine work?: Binds to closed L-channel
Decreases frequency that it will be open

Strong vasodilation
Direct cardiac suppression
Reflex cardiac activation

Results: Vasodilation with modest cardiac stimulation
systemic vasodilation of resistance
What are the advantages of nifedepine over veramapil?: no aggravation of diabetes, peripheral vascular disease, bronchospasm, blood profiles of lipids, glucose or K

No tolerance develops!
What are the effects of nitroglycerine: No overall increase in coronary blood flow, but redistributes the blood to endocardium (preferential dilation of larger vessels)
Venodilation
Reflex cardiac stimulation of rate and contractility
What drug is diltiazem similar to?: Verapamil
d: d
What effect does NO have on cells?: It activates guanylate cyclase whihc increases cGMP which ultimately leads to dephosphorylation of myosin light chain --> muscle relaxation
What happens to nitrates in the liver?: They are inactivated by nitrate reductase
They are not deactivated in other tissues
B/c of this though, it is possible to gain tolerance
Which preparation of isosorbide dinitrate is short acting? long acting?: Sublingual
Oral
Which preparation fo nitroglycerine is short acing? long acting?: Sublingual
Oral, sustained action
Important thigns about diltiazem?: Similar to verapamil, but less suppressive heart effects
What do calcium blockers do in angina?: Increase coronary blood flow
Which is a stronger vasodilator: nifedifine or verapamil?: NIfedipine
Which provides more cardiac stimulation: nifedipine or verapamil?: Verapamil
Why do the oral preps of nitro and isosorbide dinitrate have such long action times?: Orally they have low bioavailability (<20%), but once absorbed, the nitrate compounds have very short half lives.

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