Pharmacodynamics (copy)

What 3 things are drug categorization based on?

* Safety Concern
* Abuse Potential
* Ability of patients to understand and execute directions for use

What does the scheduling of drugs/products dictate

* How drug is obtained by the patient
* How drug is prescribed by physician for dispensing from. a pharmacy

Regarding drug schedules what is NAPRA I

Perscription needed for sale by Pharmacist: includes Prescription drugs (Pr) found in the PDL,

Narcotics(N),

Controlled substances (C1, C2, C3), and

Targeted substances (TS) eg. fentanyl patch

Regarding drug schedules what is NAPRA II

Prescription is not required, but must be dispensed by a pharmacist

* drugs are kept behind the counter eg. insulin

Regarding drug schedules what is NAPRA III

Patient may obtain at pharmacy without need of pharmacist eg. Zantac

Regarding drug schedules what is Unscheduled

Patient may obtain at retail stores (gas station) and/or pharmacy eg. Aleve

What is a drug

* An substance that brings about change in biological function through chemical actions

What is another word for drug

* ligand

Pharmacodynamics

* The action of drugs on the body

Pharmacokinetics

* The action of the body on drugs

Biophase

* The target site of a drug

What properties must a useful drug enable

transport from site of administration to the target site

To avoid duration of action concern what must a useful drug be

inactivated and excreted from the body at a reasonable rate

At what temperature are most drugs solid

Room temperature

What kind of molecules are most drugs

Small organic molecules

How do drugs produce effects

by intereacting with macromolecular components of the organism called receptors

Whats the most important type of receptor for drugs

Protein

Types of drug receptors (4)

* some enzymes
* enzymes for metabolic pathways
* transporters
* structural proteins

How do most drugs exert their effects

By binding to a regulatory protein in the plasma membrane of cells (i.e. physiological receptors)

What do physiological receptors normally respond to

endogenous regulatory ligands

Signal Transduction Pathway

* Aka, the receptor-effector coupling mechanism
* Is the receptor, its cellular target, and any intermediary molecules

What kind of drugs don’t act on receptors (2)

* Antacids- they directly neutralize HCI in the stomach
* Osmotic diuretics

Primary Structure

* Proteins consisting of a sequence of aa’s determined by DNA code

Secondary Structure

* aa’s begin to interact with other nearby aa’s on the same protein
* Hydrogen bonds mainly
* ⍺-helix, β-barrel, and β-pleated sheets

Tertiary Structure

* Results from interaction of more distant aa’s along the protein molecule
* Hydrogen, ionic and covalent (disulfide) bonds

Quaternary Structure

* multiple polypeptides can interact to form more complex structures

Affinity

Favourability of a drug-receptor binding interaction

What do drugs need to possess to interact selectively with receptor-binding sites (4)

* Adequate size (100-1000 Da)
* Charge
* Shape
* Composition

Lower Limit

* 100Da
* Minimum size needed to impart specificity of action and allow binding to select receptors

Upper Limit

* 1000 Da
* Size limit allowing reasonable movement in the body to sites of action

Drugs and receptors interact by

means of chemical forces or bonds

Interaction strength (greatest to least)

* Covalent (irreversible thus cells must synthesize new receptors)
* Ionic
* Hydrogen
* Van der Waals

Are drugs that bind through multiple weak bonds to their receptors

a. more selective for the receptors

b. less selective for the receptors

more selective for the receptors

Intermolecular Interactions

Sum total of forces communicate high affinity of the drug for receptor

What does Imatinib do

prevent phsophorylation of the TK enzyme

Enantiomers

* optical isomers
* mirror images
* can exist for drugs with chiral center
* one is usually more powerful at producing effects-reflects better fit with receptor

The more restricted the cell-type distribution of the receptor targeted by a drug…

The more selective the drug is likely to be

What are 2 major functions of physiological receptor

* Ligand binding by ligand binding receptors
* Message propagation by effector domain

Drugs that can modify cellular function after binding to receptors can…(4)

* intiate
* enhance
* diminish
* terminate (block)

What are the main types of drug receptors? (4)

* Transmembrne Ion channels
* Transmembrane G-protein coupled
* Transmembrane Enzymatic Cutosolic Domain Coupled
* Intracellular

Ion Channels have key roles in… (4)

* Neurotransmission
* Cardiac conduction
* Smooth and skeletal muscle contraction
* Secretion

What can ion channels be classified based on? (3)

* Architecture ie. subunits
* Ion conducted thru the channel
* Mechanism of activation

Which activated channels are major drug targets regarding ion channels

Ligand and Voltage activated channels

Where are major ligand gated channels found?

In the CNS

What can major ligand gated channels act on

* Excitatory NTs (Ash or gluatmate)
* Inhibitor NTs (glycine or GABA)

The nicotinic acetylcholine receptor is a ________________ channel

ligand gated

Where are isoforms found?

Skeletal muscle and neurons

How many subunits consist of nicotinic acetylcholine receptor?

* 5 subunits
* 2-⍺, β, ɣ, δ

What causes activation of a nicotinic acetylcholine receptor channel?

The binding of 2 molecules of ACh to the ⍺ subunit and a confirmational change

What is the major electrolyte to pass

Na+

What are the voltage-activated channels (4)

* Na+
* K+
* Ca2+
* Cl-

What is the most abundant class of receptor in the body

G-Protein coupled receptors (GPCRs)

Over half of human GPCR are dedicated to

sensory perception (Sight, taste, smell)

Which drug receptor is the target of most drugs

GCPR

What do GPCRS bind to

A family of intracellular heterotrimeric GTP binding regulatory proteins(G-Proteins)

What is a major role for G-Protein

* To activate effector molecules that produce second messengers

What are the 5 major G proteins?

* G-stimulatory (Gs)
* G-inhibitory (Gi)
* Go
* Gq
* G12/13

Actions of G-stimulatory

* Activates Ca2+ channels, activates adenylyl cyclase

Actions of G-inhibitory

* Activates K+ channels, inhibits adenylyl cyclase

Actions of Go

* inhibits Ca2+ channels

Actions of Gq

* Activates phospholipase C

Actions of G12/13

* Diverse ion transporter interactions

Catecholamines ( ______ and ______ ) are _______ ligands

* epinephrine and norepinephrine
* endogenous

What do catecholamines do?

* stimulates the production of second messenger cAMP and cellular effects based on tissue localization

What are some important roles of the intracellular linked enzymatic domain? (3)

* growth and differentiation
* consist of a single membrane spanning protein
* activity nof these receptors includes adding/removing phosphate groups from specific aa’s - phosphorylation of a protein can dramatically alter is energy and shape

What are the 2 important transmembrane receptors with enzymatic cytosolic domain

A. Receptor Tyrosine Kinases

C. Tyrosine Kinase-Associated Receptors

What are receptor tyrosine kinases?

* largest group of this receptor class
* Endrogenous ligands: insulin, PDGF, VEGF
* Effectors include SH2 domains on other signalling molecules like Grb2
* Drugs: Imatinab (Gleevec®)-TK inhibitor
* Anticancer agent: targets BCR-Abl TK; \n underlies chronic myelogenous leukemia

What are tyrosine kinase-associated receptors?

* Includes cytokine receptors such as γ-interferon
* Hormones: growth hormone and prolactin
* Receptors have no intrinsic enzymatic activity

- Dimerization allows for binding of an intracellular tyrosine kinase ie. Janus Kinase (JAK)

- JAKs phosphorylate other proteins (STAT), which translocate to the nucleus

Another kind of intracellular receptor is

* nuclear hormone receptor

In nuclear hormone receptors circulating steroid hormones are

* lipophilic diffising thru the plasma membrane to bind transcription factors → modify nuclear events
* Receptors possess a ligand binding domain and a DNA binding domain

What do nuclear events depend on

which co-activator or co-repressors of gene transcription are recruited

In nuclear hormone receptor, is gene transcription fast or slow

* slow (min to hours), but usually long lasting
* lag on (slow onset of cellular effects)
* lag off (slow offset of cellular effects)
* eg. Glucocorticoids (dexamethasone)

Another kind of intracellular receptor is

* NO synthase and soluble guanylyl cyclase

Where is NO synthase most known

* Cardiovascular system

Why do NO synthase vascular smooth muscle effect cGMP

* Mainly due to cGMP acting on PKG
* Vasodilation from reduced intracellular calcium levels, eg. nitrovasodilators and angina pectoris

Some drugs receptors exist outside of the plasma membrane serving roles such as _________

communication

* vasoconstriction: ACE inhibitors eg. enalapril for hypertension
* Neurotransmitters: Acetylcholinesterase inhibitors eg. tacrine for treatment of Alzheimer’s disease

Some drug receptors provide a cell …

surface adhesion function

* allows cell-cell interaction for various functions eg. Inflammation, coagulation

Some drug receptors provide a

structural role for the cell

* Antineoplastics: Microtuble inhibitors

How do cells integrate multiple signals to produce a coherent cellular response?

* Signalling convergence by second messengers can generate coordinated net cellular effects

What is signal amplification?

The magnitude of a cellular response to a ligand is generally greater than the initiating stimulus

Cells have the ability to amplify the effects of receptor binding by

ligands

What is cellular regulation of receptors

* Drug induced activation or inhibition of a receptor can have a long lasting effect on subsequent responsiveness to drug binding
* prevent overstimulation of the pathway and cellular damage

the affinity of a drug is most influenced by

* changes in the “off” rate

K off/K on is:

* the Kd or dissociation rate constant;
* Kd is a constant for each drug-receptor combination

* R: proportion of free (unoccupied or unbound) receptors
* Kon: forward or association rate of equation
* LR: proportion of ligand (L) bound receptors (R)
* Koff: reverse or dissociation rate of the equation

Ka

* association rate constant; also equal to 1/Kd

The relationship between free (unoccupied) and bound receptors can be described as:

\-fractional occupation thery

maximum ligand receptor binding occurs when

\[LR\] = \[Ro\] or \[LR\]/Ro = 1.0

Kd corresponds to ligand concentration \[L\] where

50% of receptors are bound (occupied) by ligand

When KdA (Drug A) < KdB (Drug B)

* lower Kd indicates a tighter ligand receptor binding or greater affinity

Dose-Response. For many drugs, the response effect is proportional to

the concentration of receptors bound by drug

* D-R is closely related to drug-receptor binding

What are the 2 major types of D-R relationships

* Graded; D-R of an individual
* Quantal; D-R of a population of individuals

What is efficacy (Emax)?

the maximal response produced by the drug at that receptor

What is potency (EC50)?

The drug concentration which elicits 50% of the maximal response (max); functions of affinity and efficacy

What does quantal D-R plot?

the population that responsds to a given dose of drug as a function of the drug dose

What is the theapeutic index (TD50/ED50)

it gives an estimate of relative safety margin of drug

What are agonist?

drugs that bind a receptor and stabilize it in a particular conformation; usually the active conformation

Equation providing quantitative descripton of potency and efficacy (2)

* more potent drugs have greater affinity (lower Kd) for their receptors


* more efficacious drugs (larger Emax) usually cause a greater proportion of their receptors to be activated

What is a full agonist?

Capable of eliciting maximal responses at a given receptor

What is a partical agonist

not able to achieve the same maximal response art a given receptor; even with increasing agonist

* may show greater potency than a full agonist at a given receptor