Z - Pharmacology Part I

Front 1

Tachyphylaxis

Back 1

Tolerance develops rapidly after administration of only a few doses of a drug.


**allergies = hypersensitivity**

Front 2

Radioligand binding studies

Back 2

used to determine if a drug will have selective effects.

- binding curve is hyperbolic (like an enzyme-substrate curve)

**can be used to "count" # receptors/receptor density (Bmax)

Front 3

Dose-Response Relationships

- Characterizing parameters

Back 3

Graded (follow a continuum) = Systematic relationships

Parameters:
1. Potency: location along the dose (x) axis
2. Maximal Efficacy: same as maximal effect (y axis)
3. Slope: steep is BAD
4. Variability: vertical bracket = variability with a given dose; horizontal = variability of doses for given response.

Front 4

Drug-Receptor Interactions & Elicited Effects
- Full Agonist
-Partial Agonist
- Antagonist
- Inverse Agonist

**has to do with preferred equilibrium states of the drug**

Back 4

[agonist]/ ([agon]x Kd) X efficacy X [receptor]

FULL: Binds to produce MAX possible reponse

PARTIAL: less than a maximally activated receptor population

ANTAGONIST: NO OVERALL EFFECT (useless)
- prefers EQUAL # of activated & inactivated receptors

INVERSE AGONIST: prefers overall population to be INACTIVE
**opposite effect of an agonist**

Front 5

Graded Dose-Response Curves for Agonists alone vs. Agonists + Antagonist

- competitive
- noncompetitive

Back 5

Agonist + Competitive antagonist (aka equilibrium comp, reversible comp):
NO change in efficay, DECREASES potency (right-shift)

Agonist + Noncompetitive Antagonist
(aka non-equil or irrev comp)
- DECREASES POTENCY & EFFICACY
(right-shift and down-shift due to decreased # receptors)

Front 6

BIOAVAILABILITY

Back 6

Fraction of drug that reaches the blood stream UNALTERED

(AUCoral/AUCiv) x 100
*auc = area under the curve

P.O. is cheapest & convenient, but has limited bioavailability due to 1st pass effect

Front 7

FIRST PASS METABOLISM/EFFECT

Back 7

Fraction of the drug metabolized after absorption before it reaches the circulation.
(liver and mucosal metabolism)

Front 8

Benefits of Sublingual, buccal, and rectal administrations

Back 8

sublingual & buccal administrations avoid 1st pass metabolism by the liver
- absorbed directly into capillary network

Rectal: avoids nausea & vomiting of oral admin
- reduces 1st pass metab b/c 50% venous drainage avoids liver.

Front 9

PARENTERAL MODES OF ADMIN

Back 9

(Bypasses the alimentary tract)
IV: immediate response, precise control (good for low TI)
- needs to be water soluble so it doesn't precipitate in the blood

IM & SC: Absorption dep. on perfusion rates.
- good for sustained release (precipitates & desolves slowly)

Transdermal: good for cont. admin

Intrathecal/Intraventricular: for drugs that don't cross BBB

Front 10

Misc. Routes of Admin

Back 10

Inhalation: almost as fast as IV
- lungs have large surface area 4 fast absorption

Topical: little systemic absorption.

Front 11

DRUG PREPARATION


**prodrugs**

Back 11

1. Solution: fastest oral absorption
- already disintegrated & dissolved
- gastric emptying is rate-limitng step
2. Suspension
- disintegration isn't required for drug release
3. CAPSULES
4. Tablets:
-Dissolution is the rate-limiting step in delivery
5. Coated tabs
- Enteric coated = delay disintegration & can cause ^ variation in absorption
6. Oral prolonged release
- multiple layers in a pill
7. Parenteral Prolonged release

Front 12

4 TYPES OF PARENTERAL PROLONGED-RELEASE MEDICATIONS

Back 12

1. Injection of slowly dissolving drug suspension IV or SC

2. Solid pellet implants
- low MW LIPOPHILIC drug
- constant diffusion rate out of capsule

4. Portable/implantable pumps
- ex// insulin or heparin ("fake pancreas")

Front 13

DRUG ABSORPTION
- general

Back 13

Absorption = transfer of drug from site of admin to BLOOD STREAM

VIA: simple / facilitated diffusion, filtration, active transport, endocytosis, etc.

Front 14

SIMPLE DIFFUSION ABSORPTIONG
- principles
- increasing it

Back 14

Fickes law: Diffusion depends on [diffusing thing], surface area of diffusing barrier, & intrinsic diffusion coefficient

PASSIVE

INCREASE DIFFUSION BY:
1. Increasing magnitude of the [gradient]
2. Decreasing the distance traversed
3. Increasing surface area
4. Increase temp
5. Increase lipid solubility
- determined by measuring the oil/water partition coefficient
6. Decrease MW & CHARGE
- molecules need to be UN-IONIZED to pass through

Front 15

WEAK ACIDS & BASES - ABSORPTION

Back 15

ONLY UN-IONIZED MOLECULES CAN PASS:

HA (at low pH) and B (at high pH)

**ACIDIC DRUGS: acidification = INCREASE in un-ionized drug = INCREASE absorption/reabs (in kidneys) --> more goes to brain**
- in general, a given pH change will have its largest effect when starting pH is similar to the pKa of the drug

pH - pKa = log B/HB or A/HA

(divide (pH-pKa) with 1+result)

Front 16

DRUG ABS - FILTRATION & Facilitated diffusion

Back 16

FILTRATION:
INVOLVES BULK FLOW OF SOLVENT (WATER) & SOLUTES

- through pores
- passive

FAC. DIFFUSION
- Saturable
- still down a concentration gradient

Front 17

FACTORS INFLUENCING DRUG ABSORPTION FROM THE GI TRACT

Back 17

1. PARTITION COEFFICIENT: ionization state, lipid solubility, pH
2. LOCAL BLOOD FLOW: ^ = ^ abs
3. INTESTINAL SURFACE AREA
4. INTESTINAL MOTILITY: fast is bad
5. METABOLISM: bacteria
6. SLOWER GASTRIC EMPTYING: slow abs
7. INCREASE GASTRIC EMPTYING
- AChase Inhibs, Cholinergic agonists, & drugs interfering with adrenergic nn.

Front 18

DRUG DISTRIBUTION IN THE BODY:
VOLUME OF DISTRIBUTION

Back 18

Vd = Dose injected (mg) / Initial plasma [ ] (mg/L)

" apparent volume of distribution*

REGIONS OF THE BODY:
1. Intracell: 28 L
2. Interstitial: 10 L
3. Plasma: 4 L
4. Extracell: 14 L
5. Total body water: 42 L
6. Fat: 11 L
**If Vd is > total body water, drug is also in the fat**

Front 19

TI = THERAPEUTIC INDEX

Back 19

TI = LD50/ED50
- lethal dose for 50% divided by effective dose for 50%

HIGH TI & far apart curves for effective and lethal dose range = GOOD (safer drug)

Front 20

Phases of Drug Distribution


*keep in mind only FREE unbound drug is free to distribute (competition)*

Back 20

Phase I: distribution reflects regional blood flow pattern
- highly perfused organs initially receives most of the drug.

Phase II: Depends on ability of drug to leave plasma
- if diffusion is immediate, distribution is FLOW-limited (big Vd)
- Meningitis & inflamm increases the perm of capillaries (esp in BBB & blood-testis barrier)

Front 21

DRUG STORAGE DEPOTS

Back 21

= fat or plasma proteins

- "stored" drug is in equilibrium with free circulating drug

ex// " twilight anesthesia " = thiopental stored in fat slowly enters plasma

Front 22

Clinical Distribution of drugs

- distribution phase
- elimination phase

- 1 compartment vs. 2 comp models

Back 22

Drugs are actually eliminated starting at the time of admin & before distribution is complete

1 COMPARTMENT: not most drugs
- distribution is UNIFORM and occurs rapidly compared w/ absorption

2 COMPARTMENT MODEL: most drugs
- separates the drug into distribbution and elimination phases
- two comp = plasma vs. all others
- board Q: what was initial concentration?
- A: extrapolate the line line of the elimination phase to t0

**multi-compartment models include storage depots**

Front 23

DRUG ELIMINATION

Back 23

metabolism, storage, and excretion

- renal excretion is the most important route (after drug is made more water-soluble)

Front 24

PHASE 1 & 2 REACTIONS OF DRUG METABOLISM/BIOTRANSFORMATION



**appendix 1 rxns**

Back 24

1. OXIDATION, REDUCTION, HYDROLYSIS
- Add Oxygen (OH) or remove alkyl group to make drug MORE POLAR
- inactivate or alter activity

2. CONJUGATION, SYNTHETIC RXN
- make it VERY POLAR by adding glucuronide or sulfate groups
- ALWAYS inactivates drug --> excrete

Front 25

MAJOR SITES OF BIOTRANSFORMATION

Back 25

LIVER IS #1

- KIDNEY
- LUNGS
- INTESTINAL WALLS
- PLASMA
- INTESTINAL BACTERIA

Front 26

LIVER P450 SYSTEM

- part of microsome (rough & smooth ER)
- affects 90% of drugs

Back 26

CARRY OUT PHASE I reaction: mixed fxn oxidase

1. Cytochrome P450 Reductase: Reduces the flavoprotein using NADPH
2. Cytochrome P450: adds sulfate group, reduces it, and then replaces it with OH
- NADPH = cofactor that is reduced

Drug + O2 + NADPH + H+ --> Ox'd Drug + NADP+ + H2O

Front 27

INDUCERS OF CYTOCHROME P450

Back 27

INDUCTION = increased synthesis and INCREASES ELIMINATION/METABOLISM

(LEFT-shift = ^ metab. rate)


ex// smoking, anticonvulsants, etc.

Front 28

INHIBITORS OF CYTOCHROME P450

Back 28

Inhibit by forming tight binding complexes with P450 HEME

= iNCREASED DRUG EFFECT

1. Imidazole or pyridine rings
ex// tagamet

2. Alkenes & alkynes
ex// some birth control, some anti-arrythmics

Front 29

KINETICS OF BIOTRANSFORMATION

Back 29

1st Order: [drug] is small relative to the amt of enzymes
- rate of metabolism is proportional to [drug]
- most drugs

Zero-Order: BAD
- [drug] is LARGE compared to at. of P450/enzyme
- constant amt of drug metabolized/unit time bc enzyme is saturated

** with zero-order, you can shift the curve up (increase metab. rate) by giving a P450 inducer

Front 30

THREE MAJOR MECHANISMS OF RENAL CLEARANCE

Back 30

1. GLOMERULAR FILTRATION
- free drug
- GFR = 125 ml/min
- NOT influenced by pH or lipid solubility

2. ACTIVE proximal tubular secretion
- requires energy
- 2 organic cation & anion transport systems
- subject to competition

3. Passive Distal Tubular Reabsorption
- UN-IONIZED drug (lipid sol)
- HIGHLY dep on pH

**to excrete weak acids, ALKALINIZE urine with Na+HCO3-, for weak bases, ACIDIFY with ammonium chloride, hippuric acid, or vit. c.

Front 31

OTHER PATHWAYS OF DRUG EXCRETION

Back 31

1. hepatic/biliary excretion
- REABSORBED vis enterohepatic circulation
- conjugation enchances biliary excretion
- subject to liver dz

* Extraction ratio = Amt. removed / amt entering *
(ER of 1 = completely extracted from blood by the liver)

2. Pulmonary
- volatile drugs
- Low solubility of drug = ^ exc rate.

3. Sweat & saliva

4. Milk: Basic drugs concentrate here (pH = 6.5)
- alcohol

Front 32

CLEARANCE

Back 32

Cltotal = Clr + Clh + Clp + Clo

- renal, hepatic, pulm, other

Front 33

Renal Clearance

Back 33

Clr = UV/P = mL/min

1. Filtration alone GFR = 130 mL/min
ex// inulin

2. Filtration & complete secretion = RPF = 650 ml/min
ex// PAH acid

3. Filtration + secretion w/ partial reabsorption
= 130-650 mL/min

**kidney disease will RIGHT SHIFT the drug concentration or elimination curve**

Front 34

PHARMACOKINETICS VS. P-DYNAMICS

Back 34

P-KINETICS: effect the patient has on the drug
- study of drug and metabolite [ ]s in the blood & body fluids.
- local [ ]s


P-DYNAMICS: effect the drug has on the pt.

Front 35

LOADING DOSE

Back 35

Amount of drug initially given to fill the volume of distribution with drug

LD = ( Desired Cp x Vd ) / F

- Cp = plasma concentration (mg/L)
- F = bioavailability = assumed 1
- Vd = in L

Front 36

TIME VARIATION IN THE CONCENTRATION AFTER THE INITIAL DOSE

Back 36

Most drugs follow 1st order elimination kinetics:

EXPONENTIAL DECAY as described by t1/2 (half life) or Ke

Ke = rate coefficient that multiplies the concentration setting by the rate of disappearance of the drug

Ke = ALL the elimination processes

Front 37

Calculation of Ke and t1/2

Back 37

ke = Clearance / Vd

t1/2 = 0.693 / ke

.693 = ln 2

Front 38

TIME VARIATION OF [ ] WITH CONSTANT IV INFUSION

- maintenance rate

Back 38

The concentration will increase exponentially toward a steady-state value in about FOUR HALF LIVES

- stop infusion = 1st order decay

*Achieved [plasma] is dependent on infusion rate*
- infusion rate depends on desired plateau & how fast u want to get there

Ra = ( Cl x Cpss) / F

Cl = clearance
Cpss = steady state [plasma]
F = bioavailability = 1

Front 39

MULTIPLE DOSAGE ADMINISTRATION


* changing the dose size or the dosing rate changes the Cpss, but NOT the time required to achieve steady steate

Back 39

Doses of equal size are added to a single compartment at regular intervals

- [plasma] rises like a constant infusion, but in a SAW TOOTH PATTERN
- steady state still achieved after 4 half lives
- fluctuations are proprotional to interval/half time

*multiply Ra by time interval b/w doses*

Ra = (Cl x Cpss x t) / f

**you don't want big fluctuations, but you want to increase patient compliance = balance**

Front 40

TYPES OF BONDS IN DRUG-RECEPTOR BONDING

L/- isomers are used by our bodies

Back 40

WEAK: h-bonds, ionic, vdw,

strong: covalent
ex// MAOIs, phenoxybenzamine

*stereochemistry is important in terms of generating the most contact points*

Front 41

Selective binding

Back 41

No ligand has 100% specificity

- specificity is dose-dependent

Front 42

Receptor types

--> subtypes

Back 42

1. Ligand-regulated transmembrane enzyme receptors: RTKs
2. Ion channels
3. G-protein coupled / 2nd msger - R
4. Transcription factors / intracellular

Front 43

INTRACELLULAR RECEPTORS

Back 43

- Drugs are lipid soluble

ex// NO --> gunaylyl cyclase --> cGMP
- steroids
- vit D
- T3, T4

Front 44

LIGAND-REGULATED TRANSMEMBRANE ENZYME RECEPTORS

Back 44

- Intracellular enzyme domain
- TK, Ser Kinase, Guanylyl cyclase

ex// insulin, EGF, PDGF, ANF, TGFb

Front 45

G PROTEIN/2ND MSGER RECEPTORS

Back 45

G proteins = a,b,y subunits
- a subunit = GTPase
- ai = Gi (inhibitory protein)
- a2 = Gs (stimulatory protein)

cAMP, PIP2 & IP3, cGMP

= AMPLIFICATION

Front 46

RECEPTOR REGULATION

Back 46

Desensitized: via downregulation of receptor or decline in signaling cascase

ex// morphine, bronchodilators

Supersensitivity: abrupt withdrawal of chronically used receptor agonist

ex// b-blockers

Front 47

P450

Back 47

oxidized (Fe3+) P450 combines with a drug substrate to form a binary complex (step 1). NADPH donates an electron to the flavoprotein P450 reductase, which in turn reduces the oxidized P450-drug complex (step 2). A second electron is introduced from NADPH via the same P450 reductase, which serves to reduce molecular oxygen and to form an "activated oxygen"-P450-substrate complex (step 3). This complex in turn transfers activated oxygen to the drug substrate to form the oxidized product (step 4).