Mechanisms of Drug Action Exam 1

principles of pharmacokinetics

absorption, distribution, biotransformation, and excretion

where does absorption typically occur

near the site of administration

absorption

describes the rate at which a drug leaves the site of administration and the extent to which this occurs (how well its taken from the site of administration)

bioavailability

the extent to which a drug reaches the site of action; how much of the drug compared to the original amount administrated is available for the receptor site

why do drugs sometimes get lost within the blood?

the blood is typically an aqueous environment but does contain solutes, like proteins, which the drug could potentially bind and then is no longer available for the intended receptor

what are factors that modify absorption and bioavailability?

drug solubility in aqueous solutions, pH, drug concentration, circulation at the site of absorption, area of contact b/w the drug and site of absorption, route of administration, molecular size and shape of the drugand the presence of food or other drugs.

what is the main barrier that drugs have to cross to gain access to drug targets?

some sort of cell membrane

what is a characteristic of drugs that pass through the membrane through simple diffusion?

They are typically small and lipophilic.

facilitated diffusion

allows for ions that wouldn’t normally pass through the hydrophobic inner membrane via a protein complex, goes with the concentration gradient

active transport

drugs bind to receptors on the protein to allow it to open and pass through, can facilitate movement against the concentration gradient per needs of the cell, energy dependent

saturability

the amount of drug that can bind to a target site until there won’t be any effect because there are no more sites available

in what form do weak acids and bases diffuse across the membrane?

non-ionized/neutral forms

weak acids dissociate into?

negatively charged ions

weak bases dissociate into?

positively charged ions

what does weak acid/base passage through the membrane depend on?

pH differences across the membrane, if charged in the blood going to stay in the blood

henderson hasselbalch equation

pH = pKa + log(A-/HA)

what are the most common routes of administration?

IV, subcutaneous, IM, oral

IV utilities and precautions

valuable for emergency use and can be titrated, increased risk of adverse effects

subcutaneous utilities and precautions

suitable for some insoluble suspensions, no large volumes, possible pain or necrosis

IM utilities and precautions

suitable for moderate volumes, precluded during anticoagulant meds

oral utilities and precautions

most convenient and economical, requires patient cooperation

intraarterial

injection straight into an artery

intrathecal

injection directly into the spinal cavity

goal of biotransformation and excretion

to produce inactive metabolites that are more polar so that they can be readily excreted from the body

where does metabolism typically occur?

liver

its typical for drugs to experience what reactions during metabolism

phase 1 reactions and then excretion, if they arent excreted they get converted into a substrate for a phase 2 reaction

what are phase 1 reactions?

mostly oxidation, reduction, hydrolysis

the oxidation reactions within phase 1 reactions are carried out where? by what enzymes?

in the liver by cyctochrome P450s

what are phase 2 reactions?

conjugations w glucuronic acid, sulfate, glutathione, amino acids, or acetate

where is cyctochrome P450 located?

it is membrane bound within the smooth ER

hemoprotein

iron-coordinated protein; iron is reduced and oxidized between Fe2+ and Fe3+, can only bind to oxygen in Fe2+ state (reduced)

what reduces cyctochrome P450 to Fe2+ state?

NADPH cyctochrome P450 reductase

most drugs are metabolized by which cyctochrome P450?

CYP3A

pharmacodynamics

the study of biochemical and physiological effects of drugs and their mechanisms of action

receptor

any component of the cell that can bind to a drug, which then modulates some activity of the cell

physiological receptors

proteins that normally bind endogenous regulatory ligands (naturally contained within the body)

agonists

drugs that bind to physiological receptors and mimic the effects of their endogenous counterparts, effect of the drug is similar to what naturally occurs

antagonists

drugs that have no intrinsic regulatory actvity but cause effects by inhibiting the action of the agonist

what is the extracellular side of the cell/receptor called?

ligand binding domain

what is the intracellular side of the cell/receptor called?

effector domain

what are steroid hormones?

lipophilic, nonpolar chemical messengers

what is the mechanism for steriod hormone receptors?

steroid hormones diffuse through the membrane, bind receptor, dimerize with another receptor, travel to the nucleus, bind to HRE, activate mRNA transcription

cytokines

involved in the immune response and the JAK/STAT pathway

what is the mechanism for the JAK/STAT pathway?

cytokines are released, bind to cytokine recepetors, receptors dimerize, JAKs bind to the recepetors and phosphorylate the tyrosine domain, STATs bind, JAKs phosphorylate STATs, STATs activate and travel to nucleus

what can happen when JAK/STAT are nonfunctional?

cancers, autoimmune diseases, constant delivery of growth signals to cells

what is the mechanism for RTKs?

ligand binds receptor, oligomerization, cross phosphorylation, SH2 domain binding, triggering of signaling pathways, activation of transcription factor that travels to the nucleus

what is the mechanism for nicotinic cholinergic receptors?

ligand binds, conformational change occurs, Na/Ca ions from through causing the membrane to depolarize

what are the endogenous and exogenous agonists of nicotinic cholinergic receptors?

acetylcholine and nicotine

Gs regulates what enzyme acitivity? this enzyme goes on to signal? in what way?

adenylyl cyclase, cAMP, stimulating

what do Gq proteins activate? which then hydrolyzes what?

PKC, PIP2

Gi proteins do what?

inhibits cAMP levels and therefore PKA

LY294002 - targets? action? pathway?

PI3K, antagonist, RTK

H-89 - targets? action? pathway?

PKA, antagonist, GPCR

forskolin - targets? action? pathway?

adenylyl cyclase, agonsit, GPCR

isoproterenol - targets? action? pathway?

B1 and B2 adrenergic receptors, agonist, GPCR

Db-cAMP - targets? action? pathway?

PKA, agonist, GPCR

BAPTA/EDTA - targets? action? pathway?

Ca, chelator, GPCR

autocoids

local hormones, synthesized near the site of action

why are autocoids different from true hormones?

autocoids usually act at the site near where they are synthesized, closeted from circulation

what tissues contain large numbers of mast cells and therefore histamines?

skin, bronchial, and intestinal mucosa

what enzyme transforms histadine to histamine?

histadine decarboxylase

mast cells are filled with what?

intracellular vesicles that contain histamine

cyctolytic histamine release

occurs when the cell membrane is physically damaged and the vesicles burst

non-cytolytic histamine release mechanism

some sort of antigen binds to cell-surface IgE antibodies and dimerize, the IgE complex can then interact with its receptor on the mast cell membrane, follows through the Gq pathway

what role does Ca play within non-cytolytic release of histamines?

acts as a key component in vesicle docking inside the plasma membrane, once docked it can fuse and release the contents of the cell

dimenhydrinate

first generation

diphenhydramine

first generation

hydroxyzine

first generation

meclizine

first generation

promethazine

first generation

chlorpheniramine

first generation

fexofenadine

second generation

loratadine

second generation

desloratadine

second generation

cetirizine

second generation

levocitirizine

second generation

what is the dfference between first and second generation antihistamines?

first generation antihistamines typically have sleepiness and anti-nauseous effects due to crossing of the brain barrier that affects H1 receptors in the brain

what is the mechanism for H1 receptors (for example in the bronchial smooth muscle cells)

histamine binds H1 receptor, H1 is couple with Gq causing calcium efflux, Ca binds calmodulin which associates MLCK, MLC phosphorylated and facilities muscle contraction

why aren’t H1 receptor antagonists used as treatments for asthma?

there are multiple causes of asthma, treatment tends to focus on relaxing the muscles

B2 adrenergic receptor agonists for asthma

typically end in -ol, albuterol

what is the mechanism for B2 adrenergic receptors to treat asthma?

albuterol binds receptor, stimulates Gs leading to activation of PKA, can either phosphporylate MLCK (relaxation) or phosphorylate CREB which causes increased transcription of B2-ARs

glucocorticoids and agonists for asthma treatment

steroid hormone receptors, some end in -one, prednisone

what is the mechanism for glucocorticoids to treat asthma?

prednisone binds, receptors dimerize, enter the nucleus, complex binds the GCRE, upregulates B2 adrenergic receptor transcription

what effect do glucocorticoids have on macrophages?

combines with them in hetero units which stops them from being able to enter the cell and signal the release of inflammatory cytokines

XOLAIR - new asthma drug

blocks IgE (in mast cells), reduces the release of histamine

fluticasone (GC) and salmeterol (B2) - new asthma drug

converts solids into inhalable smoke to get both benefits of GCs and B2s

Dupilumab - new asthma drug

monoclonal antibody blocking interleukin 4 and 13

what is rheumatoid arthritis?

overly active immune system that attacks joint tissues specifically, leads to bone loss and inflammation of joint tissues that lead to development of nodules

what plays a role in rheumatoid arthritis?

prostaglandins, play enough of a role to be targeted within therapy

why aren’t prostaglandin antagonists used? what is targeted instead?

there are no antagonists for clinical use, the synthesis of prostaglandins is inhibited

prostaglandins come from what? and are synthesized from what enzyme?

arachidonic acid, cyclooxygenase

what are cyclooxygenase antagonists?

NSAIDS (non-steroidal anti-inflammatory drugs)

COX-1

constantly expressed in most tissues

COX-2

expression induced during the inflammatory response

what is the difference between nonselective and selective COX inhbitors?

nonselective inhibits both COX1/2, selective only inhibits 2

aspirin

salicylate non-selective COX1 and COX2 inhibitor

methyl salicylate

salicylate non-selective COX1 and COX2 inhibitor

diflunsial

salicylate non-selective COX1 and COX2 inhibitor

salsalate

salicylate non-selective COX1 and COX2 inhibitor

olsalazine

salicylate non-selective COX1 and COX2 inhibitor