Basics of Pharmacology

Pharmacokinetics vs pharmacodynamics

What the body does to the drug vs. what the drug does to the body

Four pharmacokinetic processes

absorption, distribution, metabolism, excretion

Route of administration is determined by

properties of the drug and therapeutic objectives

Enteral administration

Administration of drugs by way of the alimentary canal.

enteric-coated preparations

enteric coating - chem envelope that protects from gastric acids (dissolves in intestine)

extended-release preparations

special coatings and ingredients that control how fast the drug is released from the pill into the body

ER formulations (extended-release) are used for drugs w/

short half-lives (ex morphine)

Siblingual/buccal administration

diffuse into capillary network + direct entry to systemic circ.

Siblingual/buccal administration bypasses

harsh GI enviro + first-pass metabolism

parenteral administration

directly into systemic circ., for drugs not absorbed by GI tract, have highest bioavailability

Major parenteral routes

intravascular, intramuscular, subcutaneous

If IV administered as an IV infusion, drugs is infused over long period of time :

lower peak plasma concentrations + increased duration of circulating drug levels

________ permits rapid effect + max degree of control over amount

IV delivery

Intramuscular (IM) administration - types of preps

in aq solutions (absorbed rapidly) or specialized depot preparations (absorbed slowly)

Subcutaneous administration

absorption via simple diffusion, slow, not for drugs w/ tissue irritation

Oral inhalation

rapid delivery across large SA of mucosa + pul. epithelium

Intrathecal/intraventricular administration

directly to csf, bypasses blood-brain barrier

transdermal administration usually used for

sustained drug delivery

because 50% of drainage of rectum bypasses portal circ, the biotransformation of drugs:

by liver is minimized

Mechanisms of absorption from the GI tract

Passive diffusion, facilitated diffusion, active transport, endocytosis/exocytosis

Factors influencing absorption

- effect of ph

- blood flow to site

- total SA available

- contact time

- P-glycoprotein expression

A drug passes thru membranes more readily if it's

uncharged

The intestines receive ______ blood flow+ SA than stomach

more

P-glycoprotein

Transmembrane protein that transports drugs across cell membranes + associated w/ multidrug resistance

Bioavailability

the rate at and the extent to which drug reaches systemic circ

bioavailability is determined by comparing

plasma levels of drug after a particular administration route

total AUC

extent of absorption of drug

Factors influencing bioavailability

First pass metabolism, drug solubility, drug stability, drug formation

When drug absorbed from GI tract, it enters ________ before entering systemic circulation

portal circ

____ + ______ are poorly absorbed bcus of their inability to cross lipid-rich membranes + insoluble

hydrophilic, lipophilic

Bioequivalence

if 2 drugs have same bioavailability + times to achieve peak blood conc

Drug distribution

process of drug reversibly leaving circ + entering extracell fluid + tissue

drug distribution depends on

-Blood flow

-Capillary permeability

-Drug structure (lipophilicity)

capillary permeability is due to

fraction of BM exposed by slit jxns bw endothelial cells

what organ has no slit jxns and therefore continuous capillary structure

brain

binding to plasma proteins (albumin) consequences

drugs - nondiffusable, slows transfer out vasc compartment

drugs may ______ as result of binding to tissue proteins

accumulate

volume of distribution

fluid volume required to contain drug in body at the same conc in plasma

Distriution of drug into water compartments in body

- plasma compartment

- extracell fluid

- total body water

drug trapped within plasma compartment if

drug has high molecular weight or protein bound, too large

if drug has _____ + is ____ it can move thru extracell fluid to total body water (intracell fluid)

low molecular weight, lipophilic

Apparent volume of distribution

volume in which drugs distribute

first order

Constant fraction of drug eliminated per unit time

if drug has high Vd,

most of drug in extraplasmic space

first-order kinetics: rate of drug metabolism and elimination directly proportional to

conc of free drug

zero-order kinetics

constant rate of metabolism regardless of concentration of drug

since kidney can't eliminate lipophilic drugs, they are metabolized into _______ in ______

hydrophilic substances, liver

Phase I

convert lipophilic drugs into polar molecules

variations in P450 activity may altert

drug efficacy + risk of adverse events

consequences of increased drug metabolism

-Decreased plasma concentrations

-Decreased drug activity if metabolite is inactive

-Increased drug activity if the metabolite is active

-Decreased therapeutic drug effect

Phase I rxns w/ P450 system

catalyses metabolism of endogenous compounds + biotransformation of exogenous substances

Phase I rxns w/o P450 system

amine oxidation, alcohol dehydrogenation, esterases and hydrolysis

Phase II

a subsequent conjugation rxns w/ endogenous substrate, using glucuronidation

Drugs must be sufficiently _ to be eliminated from body thru kidneys to urine

polar

Renal Elimination of Drugs

glomerular filtration, tubular secretion (active), tubular reabsorption (passive)

what affects passage of drugs into glomerular filtrate

variations if GFR and protein binding

secretion in proximal tubules occurs in 2 active transport systems:

one for anions and one for cations

elimination of weak bases may be increased by

acidification of urine, process called ion trapping

what drugs are eliminated in feces

drugs not absorbed after oral administration

drugs secreted directly to intestines or bile

total body clearance

Sum of the clearances from organs involved in drug metabolism and elimination

patients have __________ if 1. diminished renal/hepatic flow 2. decreased ability to extract drug from plasma

increase in drug half-life

continuous infusion regimens results in

accumulation of drug until steady state occurs

steady-state concentration

The point where drug accumulation equals drug elimination

fixed-dose regimens result in

time-dependent fluctuations in circulating level of drug

loading dose

use of a higher dose than what is usually used for treatment to allow the drug to reach the plasma level sooner, used for drugs w/ long half-life

the magnitude of the response is proportional to the number of

drug-receptor complexes (active receptors)

binding of agonists cause eq to shift from

inactive to active, in order to produce effect

antagonists occupy the receptor but don't increase the

fraction of active receptor

Hydrophilic vs hydrophic ligands (how they interact w/ receptors)

hydrophilic - w/ receptors on cell surface

hydrophobic - w/ receptors inside cell

Transmembrane ligand-gated ion channels

receptor activated briefly by agonist

causes neurotransmission, cardiac conduction and muscle contraction

Transmembrane G protein-coupled receptors

extracell has ligand-binding area, intracell interacts w/ G protein

Activate second messengers - signal cascade effect

intracell receptors

ligand (liposoluble) must diffuse into cell to interact w/ receptor, causes transcription factors in nucleus

features of signal transduction

- amplifies small signals

- mechanisms that protect cell from overstimulation

signal amplification

only a part of total receptors for a ligand need to be occupied to elicit a response

down-regulation of receptors

repeated administration of agonist causes diminished effect

As concentration of drug increases, the effect also increases until

all receptors occupied

potency

Measure of the amount of drug necessary to produce an effect

efficacy

magnitude of response a drug causes when it interacts w/ receptor

full agonist

ligand that binds & produces the full effect

partial agonist

a drug that binds to a receptor and causes a response that is less than that caused by a full agonist (acts as antagonist of full agonist)

inverse agonist

causes inactive form of receptors and exert opposite effects of agonists

Antagonist

bind to receptor w/ high affinity, blocks drug's ability to bind to/activate receptor

competitive antagonist

prevents agonist from binding to receptor, receptor stays inactive

irreversible antagonist

bind to active site of receptor, reducing # receptors for agonist