Basics of Pharmacology (Lectures 1-3)

pharmacology

study of the effects of chemical substances on living systems through chemical processes (activating or inhibiting) to produce beneficial therapeutic effect

bind to regulatory molecules, modification of receptor

how does pharmacology differ from pharmacy

pharmacy uses the principles learned from pharmacology in clinical settings; mainly in a dispensing or clinical care role

when was pharmacology named

~200 - 250 years ago

early stages of pharmacology was:

herbal remedies >3000 years ago

earliest: important plants by indian and egyptian scholars (15th and 6th century BC)

who played major roles in prevalent clinical practices

religious authorities

limitations of crude plant-derived materials

outcome was uncertain

knowledge of normal and abnormal functioning of the body was very limited

disease and death was semi-sacred subjects

other prevalent remedies

not based on rationale principles (limited use)

allopathy - emetics and purgatives (effectiveness not clear)

homeopathy - guided principles like cures, and the effect of a drug is enhanced by dilution (more dilution = more potent?)

3 main pillars forming the foundation of modern pharmacology

physiology, pathology, chemistry

cell theory from 1858

1. all living organisms are composed of one or more cells

2. cell is the basic unit of structure and organization of organisms

3. cells arise form pre-existing cells

major events of 1868 and 1878

first description of strucutral formula and synthesis of an organic compound (urea)

discovery of bacteria as the cause of disease by Pasteur

progress of biochemistry 20th century

discoveries of enzymes and chemical pathways - provided the framework for understanding the precise effect of various drugs

biotech and genomic era

mid 1980 to present

use of biotech for the production of antibodies, enzymes, growth factors, hormones, gene therapy ex. insulin

previously needed to purify, limited product, extensive process before obtaining pure

controlled clinical trials

use of a control group (receive either placebo, another treatment, no treatment) in clinical studies

introduced 70 years ago

allows evaluation of clinical effectiveness of any substance

core areas of pharmacology

drug absorption, metabolism, effect on living organisms, how effects can be applied to therapeutics

define biotechnology

products made by genetic engineering or recombinant DNA technologies

pharmacology wheel

Drug dosage

must be adjusted to each individual need

define a drug

any substance causing change in biological function through chemical interactions that is therpeutically useful

examples of solid, liquid, gas drugs

aspirin

nicotine, ethanol

nitrous oxide (at room temp)

what do physical natures of drug determine

route of administration, therapeutic effect, rate of absorption, distribution, and elimination in the body

cascade initiated once a drug is given

how can drugs be synthesized

hormones can be synthesized in the body

produced outside the body synthetically

how do most drugs work

interact with a specific receptor molecules and alter the receptor’s biochemical or biophysical activities

2 categories of drug body interaction

pharmacokinetics and pharmacodynamics

pharmacokinetics

what body does to the drug (absorption. distribution, metabolism and elimination)

pharmacodynamics

actions of the drug on the body (different chemical processes to bring about effect)

range of molecular drug size

7Da to 59050Da, but majority 100-1000Da

importance of the lower limit of a drug

for the need of specificity, should be large enough to be unique in shape, charge, etc to prevent non-specific binding to other receptors

importance of the upper limit of a drug

determined by the ability of molecules to diffuse between compartments of the body, large drugs will not diffuse readily in body compartments - often administered directly to the compartments in which they exert their effect

aim of drug therapy (pharmacokinetics)

prevent, control, or cure diseases

requires delivery of adequate (therapeutic) doses of the drug to the target tissue at levels that are generally non-toxic

consideration of barriers such as lipid membranes, drug elimination

determines the concentration of a drug at its sites of action

barriers within mechanism of drugs absorption, distribution, permeation

lipid membranes, drug elimination

knowledge of pharmacokinetics allows for

prediction of route of administration, doses, dosage regimens

Drug movement in the body

site of administration
plasma (distribution)
tissue (metabolism)
output (elimination)

2 main categories of routes of drug administration

enteral and parenteral

enteral administration

all or large portion of the drug passes through the gastrointestial tract (GI)

oral, rectal, sublingual

parenteral administration

GI tract mostly avoided

intravenous, intramuscular, subcutaneous

other routes of drug administration

inhalation, topical, intranasal, transdermal

enteral route

mouth, esophagus, stomach, small intestine, anus

oral administration

most common, amount of drug that enters the system is affected by its absorption and by the drug metabolism in the liver

sublingual administration

under the tongue, absorbed through capillaries, >50% of drug bypasses first-pass metabolism in liver, 50% passes to GI tract

nitroglycerin >90% inactivated by first pass metabolism

rectal administration

absorption through blood vessels in the rectum, >50% bypasses the liver, metabolism is minimized

useful in cases where drug is inactivated by acidic pH of the stomach or intestinal enzymes

also for drugs that induce vomiting or if patient is already vomiting

commonly used for antiemetic drugs, allows for administration outside a clinical setting

reasons for parenteral administration

drugs can be unstable, inactivated or metabolism by GI tract, poorly absorbed by oral administration, could be charged molecule or hydrophobic, rapid effect

intravenous administration

100% reaches the bloodstream

most control over doses, generally administered in hospital setting

if administered by IV it cannot be easily reversed by emesis (vomiting)

must be administered slowly, concentration cannot be too high

can also lead to bacterial contamination or infection inadvertently

will eventually be inactivated in the blood, but will take time

intramuscular administration

some in this form given in depot form (suspension in non-aqueous solvent like polyethylene glycol)

as solvent diffuses, drug dissolves at site of injection, providing a sustained release of the drug for extended duration (drug will dissolve slowly, longer term effects)

drug effective once it has dissolved, therefore concentration at the site is not an issue

mainly vaccines and single injection of drugs

subcutaneous administration

requires absorption and is slower than IV

contraceptive capsules for long term activity, can be implanted

allows embedment of programmable devices (mechanical pumps to deliver insulin to diabetic patients)

subcutaneous vs intramuscular injection

difference in angle of injection

inhalation administration

absorption through mucous membranes

drugs in gaseous form (anesthetics) or an aerosol

useful in respiratory conditions (asthma), drug delivered right to site of action (not system wide)

topical administration

application on the skin (ointment, cream)

not system wide effect (local)

first pass metabolism

in the liver (and often kidneys) before entering circulation via absorption from stomach and duodenum

can greatly limit the system availability of the drug

how much of the drug will bypass the liver when deliveryed by rectal or sublingual

50%

what increases the duration of a drug in the stomach

presence of food (can also affect metabolism and absorption) ex. penicillin inactivated by acid

what is absorption

transfer of a drug from its site of administration to the bloodstream (dependent on route of administration)

absorption via intravenous delivery

intravenous has close to 100% bioavailability and doesn’t have to be absorbed in the same manner as other routes of administration because all given dose reaches the systemic circulation

what is bioavailability

fraction of the administered drug that reaches the systemic circulation from where it has access to the site of its action

most important mechanism for drug absorption

passive diffusion across a lipid bilayer

various aqueous body compartments are separated from each other by lipid barriers

most drugs will have to cross multiple anatomical barriers before reaching their sites of action

where are drugs taken orally absorbed to produce an affect on nervous system

walls of the intestine

walls of the capillary that perfuse the gut

blood brain barrier

walls of the capillaries that perfuse the brain

components of a lipid bilayer

polar heads, hydrophobic tails

aqueous parition coefficient

determines how easily drugs move between aqueous and lipid media

lipid diffusion depends on:

soluability of the drug

charge of most drugs

weak acids or weak bases (charged states and lipid soluability varies with the pH of the medium)

passive diffusion

driven by a concentration gradient (in the body, contains larger aqueous compartments)

what compounds will not allow drugs to pass through the basal membrane

binding to larger proteins, limiting factor

pores in capillary cell walls permit passage of molecules as large as 20-30 kDa

what law defines passive flux across a concentration gradient

Fick’s Law

Flux equation

(C1-C2)*(area x permeability coefficient)/thickness)

C1: higher concentration

C2: lower concentration

Area: area across which diffusion is occuring

permability coefficient: measure of mobility of drug in particular medium

thickness: length of diffusion path

effect of pH on drug absorption

uncharged form of the drug passes through the membrane more readily, relative concentration of the 2 forms is dependent upon pH at the site of absorption and pKA of the acid or base

weak acid: binds to H+ to be neutral and passes through

weak base: gives up its H+ to be neutral and passes through

henderson-hasselback equation

ratio of protonated to unprotonated molecules of a drug with certain pKA, in a medium of given pH

more weakly acidic drugs will be in lipid soluable form at ____ pHs

acidic

more weakly basic drugs will be in lipid soluable form at ___ pHs

basic

when pH is less than pKa, the ______ forms of ___ and ___ predominate

protonated forms of HA and BH+ predominate (ionized form, can be trapped)

more H+ in the environment = more HA and BH+ protonated forms

when pH is greater than pKA, the _____ forms of ___ and ___ predominate

unprotonated forms A- and B predominate (unionized form, won’t be trapped)

less H+ in the environment means more A- and B unprotonated form, therefore easier to transport and absorb

when pH = pKA,

HA = A- and BH+ = B

the unionized form will be the same on both sides of the membrane

pHs of the 2 compartments will determine how much total drug will be on each side

the compartment where the degree of ionization is

what may cause trapping of a drug into certain compartments

pH of some bodily fluids; different from the blood

will be due to a greater concentration of the drug due to its ionization

effect of pH on drug distribution in body compartments

aspirin example of pH dependence

aspirin is highly unionized in the gastric juices

accumulates to high concentrations inside the cells of the stomach mucous membrane (have close to neutral pH)

leads to adverse effects as gastritis or gastric ulcers because in the mucous membrane it ioninzes and cannot extract

increases concentration of aspirin in the stomach

how can you increase absorption of ionic drugs

mask the charged groups

ex. heroin is morphine + 2 ester groups which are cleaved upon entry into the body by esterases, and releases morphine

ex. the ester groups of bacampicillin can be cleaved to release ampicillin after uptake into the intestinal epithelium

what is carrier-mediated membrane transport

active and facilitated transport including molecules that can transport drugs across a membrane

active is dependent upon metabolic energy

what types of drugs are transported via carrier-mediated membrane transport

molecules that have similar structures to peptides, nucleosides, nucleotides, and are related to natural substrates

acting on central nervous system (e.g. L-dopa, L-a-methyldopa, GABA), and oral beta-lactams (amoxicillin, cephalexin)

2 types of carrier mediated transports

active and facilitated (only active is dependent on metabolic energy)

define active transport

energy dependent and is driven by the hydrolysis of ATP (or by ion gradient) capable of drug transport against a concentration gradient

Such carriers are saturable (reaches maximum velocity at high substrate levels) and inhibited in the same manner as enzyme-catalyzed reactions

characteristics of facilitated diffusion

1. Requires a carrier to mediate transport of drugs/molecules that will diffuse too slowly through membrane. Examples; different types of ion channels

2. Does not require energy input

3. Cannot occur against a concentration gradient. Shows greater temperature dependency

endocytosis/pinocytosis of drugs

Mechanism used for absorption of drugs

100 kDa such as proteins, toxins, antigens etc., Uptake of vitamin B12, complexed with a binding protein, across the gut wall; Uptake of iron bound to the protein transferrin by hemoglobin synthesizing cells

Molecules are engulfed by cell membrane and carried into the cell by pinching off of the newly formed vesicle;

Exocytosis: reverse of endocytosis- e.g. release of neurotransmitters

what are the physical factors influencing drug absorption

1. blood flow to the absorption site - Blood flow to the intestine is much greater than to the stomach, so absorption from the intestine is favored

2. total surface area available for absorption - Generally the rate and quantity of drug absorbed is directly proportional to area available for absorption. Intestine surface is rich in villi and microvilli increasing its surface area about 1000 fold more than that of stomach

3. contact time at the absorption surface - Greater contact time = more absorption

   If a drug moves through the GI tract rapidly as in diarrhea, it is not well absorbed

   anything that delays the transport of the drug from stomach to the
   intestine (food in the stomach) delays the rate of absorption of the drug or its entrance into the general circulation.

general pathway of drug absorption

passive diffusion across the epithelial cell layer lining the intestine and from there to blood capillaries (another single cell layer); unabsorbed drugs or nutrients are excreted in feces

Blood capillaries drain their contents into hepatic portal veins leading to liver

From liver the blood goes to general circulation in the body

determination fo bioavailability

Comparing plasma levels of a drug after a particular route of administration with
plasma drug levels achieved by IV injection (of the same drug dosage), in which all of the given drug enters the circulation

factors that influence bioavailability of orally administered drugs

• Absorption from the Gut

• Solubility of drug: very hydrophilic drugs poorly absorbed; extremely hydrophobic drugs insoluble in aqueous body fluids.

• Chemical instability

• Nature of the drug formulation e.g. particle size, binders that can affect
  its dissolution.

• First pass Metabolism (extraction ratio)

bioavailability equation

100 x (AUC Oral / AUC IV)

what is bioequivalence

Two related drugs which show comparable bioavailability and similar times to achieve peak blood concentrations

what is therapeutic equivalence

Two similar drugs which have comparable efficacy and safety