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1

Michaelis Menten graph and key variables

Velocity vs. substrate, MM = hyperbolic curve

Km = inversely related to enzyme's affinity for substrate, is equal to [substrate] at 50% Vmax) ie as affinity increases, [substrate] needed to reach 50% decreases!

Vmax = directly proportional to enzyme concentration

2

Lineweaver-Burk plot and intercept meanings

1/V vs. 1/S
used to show relationships of inhibitors

y-intercept = 1/Vmax (therefore, incr. y-intercept = decr. Vmax)
x-intercept = 1/Km (therefore, closer to 0 = incr. Km = decr. affinity)

3

Inhibitors and their effects on Vmax and Km

Competitive, reversible: no change on Vmax, incr. Km
leads to decr. potency of a drug

Comp., irreversible: decr. Vmax, no change on Km
leads to decr. efficacy of a drug

Noncompetitive: decr. Vmax, no change on Km
leads to decr. efficacy

4

Volume of distribution

give formula for Vd

- for protein-bound drugs, this volume can be affected by liver or renal disease (decr. protein binding = incr. volume)

- Vd = amount of drug in body / plasma drug concentration

5

Clearance of a drug

give formula

volume of plasma cleared of drug per unit time. IT'S A VOLUME!

CL = rate of elimination / plasma drug concentration = Vd x Ke (elim constant)

6

Half-life

4-5 half-lives to reach steady state
3.3 half-lives to reach 90% steady state

7

Dosage calculations

Loading dose, maintenance dose

Loading dose = Cp x Vd / F
Maintenance = Cp x CL x r / F

F = bioavailability (100 for IV dose)
Cp = target plasma concentration
r = dosage interval (time)

8

Zero-order elimination

constant rate of elimination (no effect of target plasma conc.), therefore linear decrease in conc. with time

aka. capacity dependent

Ex: phenytoin, ethanol, aspirin

9

First-order elimination

rate of elimination is proportional to drug concentration, therefore exponential decrease in conc. with time

aka. flow dependent

10

Weak acid overdose

ex. phenobarbital, methotrexate, ASPIRIN

Get trapped in basic environment (when they are ionized), therefore treat with bicarbonate

11

Weak base overdose

ex. amphetamines

Trapped in acidic environment, therefore treat with ammonium chloride

12

Drug metabolism Phase 1 (modification)

Reduction, oxidation, hydrolysis with cytochrome p450

Yields slightly polar, still-active metabolites

Lost first in old people

13

Drug metabolism Phase 2 (conjugation)

Glucoronidation, Acetylation, Sulfation

Yields very polar, inactive metabolites (renally excreted)

14

Definition of efficacy

maximal effect a drug can produce

represented by Vmax

partial agonists < full agonists

15

Definition of potency

amount of drug needed for a given effect

represented by EC50 (effective concentration)

16

Competitive antagonist effects

Decreased potency

Overcome by increasing concentration of agonist substrate

17

Noncompetitive antagonist

Decreased efficacy

18

Partial agonist

Lowers the maximal effect of the full agonist

Note: potency is an independent variable, though generally, a partial agonist is designed to have a higher potency

19

Therapeutic index

TD50/ED50 = median toxic dose/median effective dose

Safe drugs have higher TI values (means there is more wiggle room between the efficacious dose and possibly going up to the toxic dose)

20

Nicotinic Ach receptors

Ligand-gated Na/K channels

21

Muscarinic Ach receptors

G-protein coupled receptors that act through 2nd messengers

22

What is special about the sweat glands and adrenal medulla vs. all other autonomic nervous systems organs?

They are innervated by the SYMPATHETIC nervous system, but are innervated by CHOLINERGIC (sweat glands have muscarinic receptors, but adrenal medulla has nicotinic)

23

Give the G-protein class for the appropriate sympathetic receptor

Alpha1
Alpha2
Beta1
Beta2

Alpha1: Gq (IP3)
Alpha2: Gi (decr. cAMP)
Beta1: Gs (incr. cAMP)
Beta2: Gs (incr. cAMP)

24

Describe the major functions of the sympathetic receptors

Alpha1
Alpha2
Beta1
Beta2

Alpha1: vascular smooth muscle contraction, sphincter contraction, pupillary dilator
Alpha2: decr. symp. outflow
Beta1: incr. heart rate, contractility, incr. renin release
Beta2: vasodilation, bronchodilation, tocolysis

25

Give the G protein class for the parasympathetic receptors

M1: Gq
M2: Gi
M3: Gq

Gq = h1, a1, V1, M1, M3

26

Describe the major functions of the parasympathetic receptors

M1: CNS, enteric nervous system
M2: decr. heart rate and contractility of atria
M3: incr. exocrine secretions, incr. peristalsis, bladder contraction, close pupil

27

Describe the general roles of dopamine in the body

D1: relaxes renal vascular smooth muscle
D2: modulates transmitter release

28

Describe the general roles of histamine in the body

H1: mucus production, allergic response
H2: gastric acid production

29

Gq pathway

Receptor --> phospholipase C
1.) ---> DAG ---> protein kinase C
2.) ---> IP3 ---> incr. in [Ca] (smooth muscle contraction)

30

Gs pathway

Gi opposes this from happening

adenylyl cyclase --> (ATP to cAMP) --> protein kinase A
--> heart [Ca] incr.
--> smooth muscle relaxation

31

Notable cholinergic drugs and specific mechanisms

Botulinum: block Ach-granule release
AChE inhibitor (-stigmines, donepezil): block breakdown of choline in the synaptic cleft

32

Notable noradrenergic drugs and specific mechanisms

Reserpine: block transport of dopamine into granule (for converstion to NE)
Amphetamine/ephedrine: promote NE release into cleft
Cocaine/TCAs/amphetamine: inhibition of NE re-uptake

33

Direct cholinergic memetics

bethanecol: activates bowel/bladder smooth muscle
pilocarpine: stimulate sweat/tears/saliva, glaucoma

34

Indirect Ach agonists, anticholinesterase inhibitors

All increase Ach!

donepezil: Alzheimer
edrophonium: test for MG
neostigmine: urinary retention, MG
"phys"ostigmine: "phyxes" atropine overdose (note: crosses CNS barrier)
py"rid"ostigmine: gets "rid" of MG

35

Indirect Ach agonist (AChEi) poisoning
Aka Organophosphates

tx: atropine! (ACh antag)

DUMBBELSS:
diarrhea, urination, miosis, brochospasm, bradycardia, excitation of muscle, lacrimation, sweating, salivation

36

Muscarinic antagonists (block Ach)

aka anticholinergics

atropine: mydriasis (dilation)
benztropine: parkinson dz (park my benz), dystonia
glycopyrrolate: reduce airway secretions
ipratropium: COPD, asthma
oxybutynin: reduce bladder spasms, overactive bladder
scopolamine: motion sickness

37

Atropine toxicity

Hot, Dry, Red, Blind, Mad

can cause...
- acute angle glaucoma due to mydriasis
- urinary retention w/ prostatic hyperplasia
- hyperthermia in infants

38

Fish toxins

Pufferfish: tetrodotoxin (binds fast voltage-gated Na, prevent depol)

Reef fish: ciguatoxin (opens Na channels, causing depol)

Dark-meat fish: histamine build-up (aka scombroid)

39

Lipid-lowering therapies

HMG-CoA reductase inhibitors
Bile acid resins (cholestyramine)
Ezetimibe
Fibrates
Niacin

40

Gastric acid suppresion therapy

histamine inhibitors (octreotide, ECL cell)

H2 receptor blockers (ranitidine, parietal cell)

PPIs

mucus layer enhancers (misoprostol, bismuth)

antacids

41

Heparin vs. warfarin

heparin = large, acts in blood, acute onset, PTT, no placenta crossing

warfarin = small, acts in liver, long onset, PT/INR, can be teratogenic

42

Cancer chemotherapeutics and the cell cycle

Mitosis: microtubule inhibitors (taxols, vinca alkaloids)

G1/G0 inhibs: carmustine, cisplatin

S phase: antimetabolites (azathioprine/6-MP, 5-FU, hydroxyurea, MTX)

G2 inhib: bleomycin

43

Inflammatory mediators

LTB4 - neutrophil chemotaxis
PGI2 - inhibits plt. aggregation (Plt Gathering Inhibitor)

Steroids basically block synthesis of arachidonic acid

44

Glaucoma treatment

goal: decr. intraocular pressure (decr. aqueous humor)

decr. aq humor synthesis: alpha agonists (via vasoconstriction) epinephrine, b-blockers timolol, acetazolomide

incr. aq humor outflow (opening of meshwork): direct/indirect cholinergic agonist (use pilocarpine in emergencies), prostaglandin

45

Opioid analgesics mechanism

open K channels, close Ca channels --> decr. synaptic transmission

mu = morphine
delta = enkephalin
kappa = dynorphin

46

Anesthetics

decr. blood solubility = rapid induction and recovery

incr. lipid solubility = incr. potency 1/MAC

eg. NO. incr. blood/lipid solubility = slow induction, high potency

halothane: high lipid/blood solubility = high potency, slow induction

47

Malignant hyperthermia

Caused by inhaled anesthetics and succinylcholine

often defect in the sarcoplasmic reticulum ryanodine receptor

tx: dantrolene (inhibits Ca flux through ryanodine receptor)

48

Local anesthetics

Esters vs. amides

variables for rate of analgesia

block activated Na channels by binding to receptors on inner portion of channel (most effective in rapidly firing neurons)

Esters = procaine, cocaine
Amides = 2 I's in the name (eg. lidocaine, bupivicaine)

infected tissue requires more anesthetic

small diameter/myelinated fibers affected before large diameter/unmyelinated fibers (size matters more than myelination)

lose pain, then temp, then touch

49

Parkinson's drugs

BALSA: increase dopamine and decrease cholinergics

Bromocriptine
Amantadine
Levodopa
Selegiline
Antimuscarinics

50

Diuretics: order of location of action

PCT: acetazolomide
Thin descending limb: mannitol
Thick ascending limb: loop diuretics
DCT: thiazides
Collecting tubule: K sparing diuretics
Medullary CT: ADH antagnonists

51

Electrolyte changes with diuretics

acidemia: CA inhibs, K sparing
alkalemia: loops, thiazides (volume contraction alkalosis, K loss)

urine Ca incr. w/ loop (decr. paracellular reabsorption!)
urine Ca decr. w/ thiazides (enhanced Ca reabsorption in DCT)

52

Centrally acting reproductive drugs

Clomiphene - activates GnRH
GnRH antagonists
GnRH agonists

53

Location of female reproductive drugs

OCPs - ovary
Danazol - cytochrome p450c17 (synthesis of androstenedione/testosterone)
Anastrozole - block aromatase
SERMs - block estrogen reception in sensitive cells

54

Location of male reproductive drugs

Spironolactone - block synthesis of testosterone
Finasteride - 5a-reductase
Flutamide - blocks androgen-receptor complex

55

Asthma treatment basics

Exposure --> antigen and IgE complex on mast cells --> mediators (leukotrienes, histamine) --> 1.) bronchoconstriction 2.) inflammation

Steroids block release of mediators
Early response tx: B-agonists, theophylline, muscarinic antagonists
Late response tx: steroids, anti-leukotrienes