intro to pharmacology i - class notes

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Introduction To Pharmacology

September 1999

Last updated 09/06/01 08:53 PM

PHARMACOLOGY

Give a drug to effect change for desired outcome( NS, HR, bioelectric process), and effect a pathophysiological process(medical pharm is a reason to treat, diagnose, prevent a fundamental purpose

A drug is a substance that interacts with a biological process, and interact with a receptor molecule, on the cell membrane

or in the cell. Drugs are formulated for action and for delivery. Its concidered a ligand which is a substance that interacts

with a biological process by fitting into a receptor molecule.

Nutriti onal substances are drugs which do not und ergo rigorous testing

How to get drug to target site solubility(water or lipid) & where receptor is

Solubility concider route if the target isnt in the GI then drug needs to cross gut membrane, so the process involves

absorption of drug into the compartment of the body its designed for.

Process of absorption

PHARMACOKINETICS - solubility, absorption, distribution, elimination( metabolism & excretion), active ingredient &

formulation such that it augments

WHAT THE BODY DOES TO THE DRUG

PHARMACODYNAMICS - WHAT THE DRUG DOES TO THE BODY

Ligands size- small size increases specificity and distribution

Shape- inc specificity, isomers (levo & dextro) used in racemic mixtures but the inc in the selectivity is in one shape orthe other RT where it fits this inc specificity.

Heparin is a big molecule 50K Daltons, and therefore it does not distribute into the intracellular space. Think of heparin

vs lovenox.(low molecular weight)

electrical properties( extent of ionization) interactions with, receptor types, facilitate absorption and distribution. There

are agonists & antagonists. Competitive antagonists, non competitive antagonist, mass action . Ligands can directly

interact with ion on the nicotinic receptors

Receptor specific affect or cascade of effects. There are spare, desensitizing, upregulating, downregulating

Know the classification of drugs, and side effects related to the calsses

Graphs linear, logarithmic, efficacy, potency, response, EC50, Emax, therapeutic goals related to EC50,

Toxicity, potency, rt shift

Integrate text to give us a foundation @ how drugs work, get in. Learn @ concepts and relate them to clinico pharmaco

therapeutics

This course is rote memorization. Katzung is good its in the library

FIGURE 2 8 ligands bind to receptor and receptor now interacts with another molecule such as an enzyme( JAK,STAT)

Ligand binds to a receptorcascade pf eventscellular response IE ach binds to channelchannel opensNa goes

into cellaction potential vs NO or steroid enter the cell and then interact via cascade effectturn on genes and causeits effect (this one is longer lasting and also takes longer to act)

FIGURE 2.6 ligands interact with receptor to activate or inhibit.

Ligands agonist form- binds to receptor and activates a process direct effect such as opening a Na channel & indirect


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effect like G protein activatedadenylate cyclasestimulates c AMP from ATPacts as a 2ndmessanger

(amplification)

Antagonist blocker b inds to a receptor and blocks o r prevents event receptor acitivation

Radio or histo chamicals label ligands and trace where they go.

We need to learn how to look at graphs FIG 1

MI patient beta block and nervous patient overcomes beta blockade via endog enous chatech release

Non competative

Max response altered with dec # receptors to hook with drug, but EC50 is the same

Efficacy prop to # receptors blocked, but EC50 not affected secondary tp diminished mass action response, spare

receptors??????????? Dose dependent . If knock out 20% of the receptors then knock out 20% or the response, this

relationship is proportional.

FIG 5

Graded dose response curve looks at biological cells as opposed to a group of study participants.

Agonists stimulate binded receptors Full agonist

Partial agonist stimulates receptors but not as well as FA, see inc HR but not as well as with max response. FIG 6

Agonist if FA or PA depending on its affinity and whether phosphoralation is saturated

Cascade and amplification determine whether agonist is FA or PA see pg 10 CPMRS

Fig 7

O conc partial agonist competes with FA but doesnt elicit full response, but dampens the effect of the FA, check HR in

presence of i nc conc. Mass action plays a role

Antagonist (blocker), CA usually reversable, NCA usually 1 block, RA reversable, IA irreversable

CA - competes with some binding site as agonist weak bonds and mass action

NA weak bon ds, come onn and off. Doesnt compete with some sites as agon ists usu irreversabl e

blo cker, covalent bon din g means hig h affinity

Alpha, AR phenoxybenzamide high affinity, not reversable, receptors need to be downgraded


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regulated. So NC IBdowngrading so new receptors need to be made.

Inderal is a CA and there is no change in EMAX FIG

Fig 9 B = blocker

Look and compare the NCB it takes away the # of receptors in process and no change in affinity occurs so the EC50 isthe same

Dose response curve is good at comparing the different concentrations of drugs.

Therapeutic Index - TI

Quantal response it is or it isnt FIG 2 19 in handout

TI. Potency for individual, check for partial conc graded dose response curve vs. Quantel dose effect, QDE. Potency is

graded on DR Curve. QDR curve ~ population and looks at different drugs comparatively.

GDR potency individual drug, selectivity, drug x vs cough supression look at response close to receptors. Max effect yes

QDE potency pop drug drug,

selectivity sense of marker relationship to dose.

Max effect no b ecause one may or may not have a headache at a specific conc

Titration occurs and start woth lower dose 1 st this gives some sense of what variability of how

Respondants react

Reasons why drugs ?????????

NC ag oni st EC50 the same, max response is

Can swithc to see what does what antagonist to agonist and visa, check EC50, efficacy, potency, and what changes, what

parameters are affected ..

PHARMACOKINETICS goal is to get drug to receptors. Most drugs are designed toward specific receptors but

exceptions do exist mannitol osmotic diuretic, but it changes osmolarity by pulling water out of bloodurine excr

there is an end effect.

Most drugs have affinity for a specific receptor so as to ellicit a specific response ie B2 inc HR and bronchodilates

Absorption is affected by molecule size( usu < 1 KD) , type of transport across the cell membrane(SD, AT, CMT) PCN is

via AT thru renal tubules, solubility lipo, hydro

HENDERSON H eq (HA = weak acid)

HA < H+ + A- this is for a weak acid where HA gives up a proton, (becomes charged)

>

BH+ < H+ + B (the B gives up the H charged part of the molecule, now its not charged)

>

An acid in > acidic environment is uncharged

A base in > basic environment is uncharged

Get drug across cell membrane, make it uncharged


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A charged molecule attracts water because its polar, so give drug which works in blood a charge

Water goes to an acid with a charge A-

Water goes to a base BH+ with a charge

Ionization constants most drugs are weak bases

Most weak acids have low pKa but not tylenol

HA, if pH is lower than pKa , then there is > uncharged molecules, more drug is unionized

If HA is in a > acidic environment, then the pKa is low and > molecules are uncharged, the acid is

protonated

The further away the pH is from the Pka there is a higher # of charged molecules present.

PH < pKacharged

PH > pKauncharged & bases end up uncharged

FIG 11

Distribution is influenced by blood flow brain, heart, liver is determined by the

bld flow,

by cap perm (placental or BBB vs kid ney or sp leen fenestration s/junction s in cap walls)

by plasma p rotein bin din g, maj or o nes ( albumin, g lob ulin, l ipo protein, RBC s)

drug reaches target place if free from PP- inc PP binding keeps drug in circulatory system.

PP bound drug has inc life and a changed rate of clearance, there are enzymes in the lung and

blo od. Drugs boun d to PP are not filtered by the kid ney . HA hav e inc affinity to PP, ASA coumadin

Weak bases have low affinity - ethanol.

Pts with dec albumin need to change dose ie burns and dec albumin CL = clearance

Metabolism = biotransformation changes soluability of parent compound from lipid to aq soluability,so it will be

excreted from the kidney. Lipid soluble doesnt get filtered out of kidney so phase 1 and phase 2 reactions are necessary.

Metabolic activity varies precursor-prodrug maintain parent and metabolite ie benzidiazepines, also th ink of activity.

1stpass after Po through liver. Most biotransformation occurs in the cells microsomes smooth ER lisosomes,

mitochondria & change lipids to aq in the microsomes.

FIG 12

Oxidation is via an independent family of enzymes called cytochromeP450 CP450, which exists in all cells mostly in


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liver, and they are responsible for Ph 1 biotransformation.and also for upregulation & downregulation.

These induce ph 1 -- CYP3A & CYP2B- liver, 60% relevent drugs , genes to them exist

Drug metabolism lipid to keep lipid soluable.

Toxicity usually less with metabolism though exceptions do exist ie: tylenol undergoes ph 1 toxic

Metaboliteph 2(glutathione conjugation)detoxified

If there is too much toxins , there may not be enough enzyme or GSH to get rid of the toxins, & since liver is so involvedand has so much CP450 th eliver can become toxic ie tylenol OD.

Gluco upregulates CYP3A and dec enzymes activity for ph 1 biotransformation for metabolites

Side effects every thing causes side effects. o2 oxidizes protein and water intox can cause death reaking havoc with

lytes etc, so everything is toxic toxicity is dose dependent ie water a lot is required to be lethal, and botu lism a very

small amount is lethal. LD is lethal dose. Understand the distance between the ED & LD. Drugs with a wide TI are safest.

Know TI

Toxicity lethal, carcinogenic, tetragenic, mutogenic, so its not so much death but the other variables.

Next time follow drawing HA through organ s

Drug A not metabolizedby liver, is freely filtered by kidneys, is a weak acid, pKa of 6.5, if urine ph is 5 what happens to

drug. Does it stay in tubulus, get reabsorbed, or get excreted.

Think about precursor of ASA GI why it gets ols where it does, is it metabilized, how is it destroyed and excreted.

Thes renal excretion other poreres.

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intro to pharmacology i - class notes

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