Ga-Pcom Pharmocology-Owen

Front 1

Factors influencing Bioavailability

Back 1

Very Hydrophilic drugs are poorly absorbed because they cant cross the lipid-rich cell membranes.

(Extremes arent good)

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Enteral Absorption

Back 2

Oral
Rectal
Sublingual

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Parenteral Absorption

Back 3

Ex: Penicillin, Insulin

Intravascular (IV injection)
Intramuscular
Subcutaneous (patches)
Other: Inhalation
Intranasal
Intra-Thecal (CSP)
Topical (for local Therapy only...But if you give a high enough [] it can get into systemic circulation
Transdermal

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Bioequivilance

Back 4

Similar Bioavailability

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Therapeutic Equivilance

Back 5

If similar efficacy and safety, and Bioequivilance.

Not every bio= is therapy=
but therapy= are bio=

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Vd= Volume of Distribution

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Vd= the Dose (mg)/
[Plasma Concentration] (Mg/mL)

Drug in Blood/Drug in Body

[[in the absence of elimination]]

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Large , Charged mol. are trapped in the plasma compartment

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Plasma Compartment.

Front 8

Small but hydrophilic mol. can move from plasma to ExtraCellular fluid via endothelial slit junctions

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Extracellular fluid

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Small and Hydrophobic can move through slit junctions AND cell membranes through passive diffusion

Back 9

Total Body water
small Hydrophobic (un-ionized)

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Extrememly lipid soluble drugs--> may have unusual high volumns of distribution

Ex: thiopental in pregnancy

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Very lipid soluble drugs have high Vd.

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Two phases of Drug concentrations
1. Distribution Phase
2. Elimination Phase

Can be linear or log scale

Back 11

can be linear or log scale

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FREE drugs are pharmogologically ACTIVE

BOUND are BUSY = cant do anything.

Back 12

Albumin- A1-acid Glycoprotein (AGP)
are binding proteins

Strongest for weak acids (not neutral drugs)

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Drug Classes

1. Less Dose More Binding
2. More Dose Less Binding

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Class 2 displaces Class 1 drugs.

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Large Vd means that most of the drug is in the Extraplasmic space (not in the plasma).

If the drug is not in the plasma it will not be cleared as easily, because it is not carried to the Liver and Kidneys...thus increasing its t1/2

Back 14

extending t1/2

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Biotransformation= chem. changing a drug to a Metabolite

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Usually changed from nonpolor hydrophobic, to a polor hydrophilic ..... now easier to excrete in urine.

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First order Elimination= Concentration Dependent

Log scale= linear
Constant t1/2
(= 0.693/ke..imp. for excretion rate)

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Not clearance (the amount of fluid cleared of a drug per time)

Elimination= Weight of drug removed per unit time

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Zero order Elimination= Concentration Independent

Ex: aspirin, ethanol

Constant amount of drug is lost per time, (not a % of the amt. of drug left like in 1st order)

Log Scale=curved
Changing t1/2

Back 17

The higher the Concentration the longer the t1/2 (one way to get higher concent. is to have drug reasborption through enterohepatic circulation) Ppt. Abnormality may also effect t1/2 of drug ex. kidney failure.

Zero Order=
Nonlinear=
Dose-Dependent (Concentration Independent!)

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Drug Metabolism

Ph. 1= P-450 system
Ph. 2= Conjugations, Glucuronide

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Ph.1 = lipophylic--> polar mol.via P-450 microsomal enzymes. (endogenous and exogenous subst.)

Ph. 2 = adding acetyl, hydroxyl or AA, to make drug more polar...and excreted by kidney (when phase 1 wasnt enough!)
***Most important= GLUCORONIDATION

but neonates are deficient in this, & morphine-6-gluconeride is twice as potent, so they are vunerable to this.

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CYP3A4- is a P-450 enzyme that is often targeted because it plays a role in metabolism for 50% of drugs prescribed
(can be Induced or Inhibited (ex. Warfarin)).
(Ph.1)

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ex. CYP2D6
mutated by Genetic Polymorphism to be activated.??
-->Codiene

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RENAL Excretion

Glomerulus
Proximal Tube
Distal Tube

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Glomerulus- Drug flows from body into urine (size matters here)
Proximal Tube- Drugs can be actively secreted into here.( they are secreted out by Active transport---because there is low specificity, Competition can our btw drugs)
Distal Tube- Uncharged drugs diffuse out back into the body, Changing the pH can ionize more drugs and cause them to be peed out (they cant sneak back across membrane into the body anymore)

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Ecretion Ratio= c2/c1

C2= [excreted] from kidneys
C1= [entering] the kidneys

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Extraction Rate= clearance x [plasma]

Total Body Clearance= Vd x ke

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Steady-state Concentration= Css

Css is DIRECTLY prop. to Infusion rate!

Css is INVERSE to Clearance rate!

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If something decreases the clearance of a drug, the Steady-state concnt. will be Higher!

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IV infusion to Css = by 1st order

It takes 3.3 to 5 t1/2's to reach steady state

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the rise to Css is exponential.

Time required to reach Css = f= 1- e^(-ket)

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Fixed doeses at Fixed times (opposed to cont. infusion)

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But this can result in time-dependent fluctuations in the circulating level of the drug.

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Orally taken drugs on fixed time and fixed doses

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Css= 1 / ke x Vd = (dose)(Bioavailability)/ dosage interval (time)

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Pharmacokinetic- delivery of a drug

Pharmacodynamic-response of a drug

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kinetic action- GI, Plasma, Liver, Kidney

dynamic action-target organ

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*****Antacids and Iron supplements reduce the absorption of expensice and potentially life saving antibiotics-->

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Carafate and Zithromax, Cipro

Prilosec changes pH and solubility of other drugs

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Protein "bumping" in serum causes increased amt. of free drug

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EFFECTS-
lots of things

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**** Microsomal Enzymes:

Cytochrome 450
FMO3 (flavin mono-oxygenase)

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Phase I metabolism in Liver to convert lipid soluble to water soluble (polar) and easily excreted.

Almost all do Phase I
Not all drugs need Phase II

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Nomeclature:

CYP2D6

CYP=cytochrome P450
2=genetic family
D= gen. sub family
6=specific gene

Back 30

Cytochrome P450 3A =metabolizes largerst number of drugs after 2D6

Found in Liver and GI


Polymorphic Dist= when there is a differiental distribution in less than 1% of popn.

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2D6- Codiene
2C6- Warfarin, NSAIDS
1A2- induced by smoking

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Can be inhibited and induced and will effect the levels of any other drug that is metabolized by these enzymes.

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P-glycoprotein = best studied drug transporter

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inhibitors raise the drug plasma [] of the drug transported by it.

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Warfarin is an example of Pharmacodynamic interactions with other drugs.
Bleeding could be increased.

Herbals have an interaction with drugs too
Ex: St. Johns Wart

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Food and Drug:

Tetracycline and milk
Warfarin and Vitamin K
Grapefruit juice.

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The dose makes the Poison

No drug is so selective in its pharmacotherapeutic action that is produces no undesired (adverse) effects

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The degree of injury increases as the dose increases.

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LD50 is the Lethal dose that kills 50% of the popn that used it.

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Therapeutic Index=

Ld50/Ed50= the larger the ratio the better.

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Drug toxicity in humans
1. Mild= annoying
2. Toxic= severe effects, potentially fatal
3. Drug Allergy= drug acts as an antigen (not related to dose, and only in susceptable person)

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1. Ex: drowsiness
2. Ex: Seizure
3. Ex: hypersensitivity to drug.

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Iatrogenic = Physician induced


(You want to treat Poisoning at the Effector Site!)

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Corticosteroids= loss of bone

Prevention of Poisoning=
Vomiting (within 1 hr)
Ipecac root (enteric tract irritant)
Lavage (within 60 min. contra= if physic. damage to esoph, stomach etc.
Chemical Absorption (absorbed by charcoal)

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To enhance Elimination of Toxic drug=

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Reduce t1/2
Increase pH
Hemodialysis - to remove agents from blood.

Front 39

Toxin:

1.Arsenic
2.Benzo-dia-zepines
3.Carbone Monoxide
4.Coumadin
5.Lead
6.Organophosphates

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Antidotes:

1.BAL
2.Flu-mazenil
3.Oxygen
4.Vit. K
5.Dimer-caprol, Succimer, Penicillamine
6.Atropin, Pralioxime

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Children and Drugs

Tetracyclines = discolored teeth

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Caffeine used to treat Apnea of prematurity

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To achieve Steady state condition...for fluctuating dosing and to stay in therapeutic interval

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Give drug interval 4-5 t1/2's

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Addiction= Compulsive, doing it, using it
(before chronic use)

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Physical Dependence= begins with tolerance from the body.
(after chronic use)

Withdrawal rxns:
When drug is used in lowered dosage or is stopped.

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Drug Testing:

Determination of Use- A Quantitative assessment
Determination of Assessment- Quantitative is NOT good enough....Must do BLOOD or BREATH test.

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Thalidomide = Teratogen in Humans
Aspirin is in Rats but not in Humans...studies arent reliable

Front 44

Proven Human Tetratogens:

Alcohol
Carbamazipine
Cocaine
Coumarin
Folic acid Antagonists
Lithium
Misoprostol
Tetracyclines
Thalidomide

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Studies
1. 20-100 ppl healthy vol.
2. 100s ppts.
3. 100s-10000s ppts


Recalls:
1.Exposure to drug will cause serious adverse effects (temp. removal from market)
2. Cause medically or temporarilly adverse health consqu. Possibly serious
3. Likely to cause Serious adverse effects and health consq. Ex: quantity packaging error