MPP Block 1

pharmacology

a branch of medicine concerned with the uses, effect, and modes of actions of drugs

pharmacodynamics

drug receptor interactions happen at the binding sites (biochemical and physiological)

pharmacokinetics

what our body does to the drug

What are some pharmacodynamic properties

binding methods

agonist vs antagonist

lock and key method

perfect fit

Active site binding

confirmation has to take place making the rxn and affinity stronger

Agonist

“on” - changes the activity of targets

Full - max effect

Partial - medium effect

Inverse - turned off

Antagonist

target inhibitors

non-competitive inhibitors

bind at different sites which reduces efficacy

competitive inhibitors

bind at the same site and reduce potency

List the differences between pharmacokinetics and pharmacodynamics

kinetics = what the body does to the drug (ADME)

dynamics = what the drug does to the body ( forces/agonist vs antagonists)

Pharmacokinetic properties

Absorption

Distribution

Metabolism

Elimination

absorption

permits entry of drug into the plasma

Kinds of absorption

passive

facilitated

active

endocytosis

Passive absorption

Moves from high to low conc.

Facilitated absorption

Relies on the transporter

Active absorption

Energy and transporter must be present

Endocytosis

the absorption of large molecules

What effects absorption

blood flow

surface area

contact time

expression of p-glycoprotein

route of absorption (IV, IM, enteral…)

Distribution

drug leaves bloodstream to distribute

Volume of distribution

Low Vd - bound tightly in the blood

High Vd - bound loosely in the body

Drug distribution

how readily a drug distributes

What effects drug distribution

cardiac output

tissue volume

degree of binding drug to plasma

Metabolism

biotransformation of the drug so it is ready to be eliminated, takes place in the liver

Enteral administration

most common

Oral administration

self administered and easy to correct overdose

complicated due to pathways and first pass

Sublingual

under the tongue

bypass harsh GI environments and avoids first pass

parenteral administration

directly into system circulation

slow absorption which is good for drugs unstable in GI tract

most bioavailability

Oral/Nasal

rapid delivery across a large surface area

Intrathecal

breaks down the blood brain barrier

Rectal

good for patients that are struggling with PO intake

topical

local use

transdermal

dependent upon body mass

Why is biotransformation necessary

many drugs are lipophilic and would not otherwise be able to be excreted

metabolic products - metabolites

Biotransformation can alter drugs through

active - inactive (most common)

active - active or toxic metabolite

inactive pro - active drug

unexcretable - excretable

two types of biotransformation

phase 1 - oxidation reduction

phase 2 - conjugation hydrolysis

Phase 1

make lipophilic drugs more polar

Enzymes in phase 1

P450 reductase

CYP

Steps of phase 1

1. oxidized P450 combines with a drug substrate to form a binary complex

2. NADPH donates an electron to P450 reductase

3. A second electron is introduced to the same P450 reductase ( forms and activated oxygen complex)

4. this complex transfers activated oxygen to the drug substrate to make the oxidized product

P450 family

important for metabolism of steroids, lipids, and xenobiotics

P450 inducers - increased drug metabolism

1. decreased plasma drug conc

2. decreased drug activity if the metabolite is inactive

3. increased drug activity if the metabolite is active

4. decreased therapeutic drug effect

Phase 2

this consists of conjugation because many phase 1 metabolites are still too lipophilic to be excreted, so they are then excreted by the kidneys

Phase 2 qualifications

Drugs with an -OH, -NH2, -COOH group may enter directly into phase 2

Major body fluid compartments

body water is 55-60%

2/3 - ICF

1/3 - ECF

ICF components

K and Mg

ECF components

Na, Cl, Ca, and HCO3

Plasma Membrane structure

Phospholipids, cholesterol, glycolipids, integral and peripheral proteins

Phospholipid bilary

polar hydrophilic heads

nonpolar hydrophobic tails

Cholesterol binding

Binds with the heads to regulate membrane fluidity

• double bonds are stronger and increase membrane fluidity

Structural proteins

anchor to the cytoskeleton

Enzymes

catalyze rxns

Receptors

bind

Transport proteins

movement

Channels

provide movement

Carriers

bind to move across membrane

Pumps

Use energy to bind ions that need help

Passive

channels are present to move down conc gradient

Primary

Uses a pump to move against conc gradient

Secondary

the gradient is already established and uses energy of another solute typically Na

Open channels

no gates, free flowing

Leak ion channels

3 Na pumped out for every 2 K

• primary active transport

Selectivity filter

determines which ions can pass through the channel

Gated ion channels

more specific and controlled

• filter determines what can come through and a gate controls whether it is opened or closed

Stimuli that regulates channels

Voltage - change in membrane potential

Ligand - binding of a chemical signal

Mechanical - deformation

Carrier protein

specific binding site for a solute

facilitated diffusion

passive movement of a solute through a carrier protein

• no ATP required

Ca 2 - ATPase

PMCA uses ATP to pump Ca2 out of the cell

mitotoxicity hypothesis

harsh drugs given to stop all cell growth

EGF Receptor Antagonists

competes with ATP for binding to the cytoplasmic tyrosine kinase domain of EGFR

• gefitinib and erlotinib

Cancer expression of EGFR antagonists

irregularly high EGFR expression

Trastuzumab

antibody directed against ErbB2

cetuximab

antibody that binds EGFR ErbB1

Imatinib

a potent inhibitor of ABL kinases

dasatinib

a second class tyrosine kinase inhibitor

RAS/MAP kinase pathway

oncogenic mutuation is most common for malignancy

FTI’s

make way through membrane to stop RAS farnesylation

Sorafenib

works as a C-RAF inhibitor

PI3K signaling cascade

1. stimulation of growth receptors leads to activation

2. generation of PIP3

• negatively regulated by PTEN

mTOR inhibitors

serine-threonine kinase that regulates cellular functions

rapamycin

binds to FKBP12

JAK2 inhibitors

causes growth to be inhibited and undergo apoptosis

proteasome

trashcan of the cell

bortezomib

induces growth inhibition and apoptosis of tumor cells with few toxic effects on the rest

endocrine signaling

bloodstream to a far away target

paracrine signaling

close or nearby target

autocrine signaling

self talking signaling

cell to cell signaling

plasma membrane proteins

synaptic signaling

action potential and neurotransmitters

4 receptors that initiate intracellular signaling

1. ligand gated channels

2. G protein - coupled receptors

3. Catalytic receptors

4. nuclear receptors

ligand gated channel receptor example

nicotinic ACh receptor

GPCRs example

andrenergic receptors

catalytic receptor example

insulin receptors

nuclear receptor example

steroid receptor

step one fo the GPCR mechanism

activation: ligand binding changes conformation which causes release of GDP

step two of GPCR mechanism

GTP binds to G-alpha activating the g protein

step three of the GPCR mechanism

subunit dissociation: G - alpha GTP dissociates from G beta/gamma complex

step four of GPCR mechanism

effector activation: G alpha GTP regulates effector proteins, AC and PLC

step five of GPCR mechanism

GTP hydrolysis: G alpha hydrolyzes GTP-GDP through intrinsic GTPase activity

step six of GPCR mechanism

reassociation: G alpha - GDP then reassociates with the G beta/gamma to return to inactive state