Pharmacodynamics Flashcards
Drugs are categorized (scheduled) based on…..
-Safety concerns
-Abuse potential
-Ability of patients to understand and execute directions for their use
Scheduling of drugs/products dictates………
-How drug is obtained by the patient
-How drug is prescribed by physician for dispensing from a pharmacy
NAPRA I
Prescription needed for sale by Pharmacist; includes prescription drugs (Pr) ie found on the PDL, also narcotics (N), Controlled substances (C1, C2, C3) and targeted substances (TS) eg. Fentanyl patch
NAPRA II
Prescription not required; must be
dispensed by pharmacist ie. behind
the counter eg. insulin
NAPRA III
Client may obtain at pharmacy
without need of pharmacist eg.
ranitidine (ZantacⓇ )
Unscheduled
Client may obtain at retail stores
as well as pharmacy eg. naproxen
(Aleve Ⓡ )
The actions of drugs on the body are termed
Pharmacodynamics
The actions of the body on drugs is termed
Pharmacokinetics
At room temperature, most drugs are
Solid (e.g. aspirin)
Useful drugs must
-Have properties enabling transport from the site of administration to the target site (aka biophase)
-Be inactivated and excreted from the body at a reasonable rate to avoid duration of action concerns
Macromolecular components of the organism are called
Receptors
Most drugs are
Small organic molecules that produce effects by reacting with receptor
Proteins represent the most important type of receptor for drugs (4 examples)
- some hormones eg. insulin, growth factors, neurotransmitters
- enzymes for metabolic pathways
- transporters eg. Na+ , K+ -ATPase
- structural proteins eg. tubulin and nucleic acids
Physiological receptors
Regulatory proteins in the plasma
membrane of cells
Signal transduction pathway
The receptor, its cellular target and any intermediary molecules
Drugs that do not act on receptors
-Antacids directly neutralize HCl in the stomach
-Osmotic diuretics eg. mannitol promote increased urine formation by osmotic forces in the lumen of renal tubules
Proteins consist of a sequence of aa’s determined by DNA code called
Primary structure
Protein aa’s interact with other nearby aa’s on the same protein (is called..)
Secondary structure
Tertiary structure results from
Interaction of more distant aa’s along the protein molecule (
Hydrogen, ionic and covalent (disulfide) bonds)
Multiple polypeptides can interact to form more complex structures called
Quaternary structure
Favorability of a drug-receptor binding interaction is called
Affinity
In order for drugs to interact selectively with receptor binding
sites, they need to possess adequate
-size
-shape
-charge and atomic composition
Size (Lower limit)
minimum size needed to impart specificity of action and allow binding to select receptors
Size (Upper limit)
size limit allowing reasonable movement in the body to sites of action
Size (Lower limit)
size limit allowing reasonable movement in the body to sites of action
Where must very large drugs (eg. Protein therapeutics) often be administered?
directly into compartments where they have effects
Drugs and receptors interact by means of
Chemical forces or bonds
Drugs that bind thru multiple weak bonds to their receptors require
More precise fit (are more selective)
Bond strength order
Covalent > ionic > hydrogen >
van der waals
Covalent bonds are usually
Irreversible (few drugs rely on these receptors, must synthesize new receptors)
Intermolecular Interactions
Sum total of forces imparts high
affinity of the drug for receptor
Enantiomers
S (left-handed) and R (right-handed;) nomenclature based on organization of the atoms attached to the chiral center
Ranitidine (what is it and what does it do)
H2 (histamine receptor) antagonist or blocker
-Used to treat gastroduodenal ulcers by reducing HCl production
Lidocaine
Na+ channel blocker
-Highly expressed in several tissues
-Widespread adverse effects possible in CNS and heart if drug reaches the systemic circulation
2 major functions of physiological receptors
- ligand binding via ligand-binding domain
- message propagation via effector domain
Drugs modify cellular function after binding to receptors
-initiate
-enhance
-diminish
-terminate (block)
4 major types of drug receptors
-Transmembrane
Ion Channels
-Transmembrane
G-protein Coupled
-Transmembrane
Enzymatic Cytosolic Domain Coupled
-Intracellular
Polar (charged) anions and cations have key roles in
-Neurotransmission
-Cardiac conduction
-Smooth and Skeletal Muscle contraction
-Secretion
Ion channels can be classified based on: (3)
- Architecture ie. subunits
- Ions conducted thru the channel
- Mechanism of activation
- Ligand and Voltage activated channels
are major drug targets
Major ligand gated channels are found in the _______ and list 2 examples
CNS,
2 excitatory NTs
ACh or glutamate
2 Inhibitor NTs
glycine or GABA
One ligand gated channel
nicotinic acetylcholine receptor
nicotinic acetylcholine receptor in the closed state
Channel pore is occluded by bulky amino acid side chains
Full opening (activation) of the nicotinic acetylcholine receptor channel occurs with
Binding of 2 molecules of ACh to the α subunits and
a conformational change = pore opening
Electrolytes passed in nicotinic acetylcholine receptor channel
Na+ is the major electrolyte passed; K+ can also pass
How can refractory period be prolonged
Local anesthetics eg. lidocaine
bind to the channel
Sulfonylurea receptor (SUR1)
- Regulates the ATP-dependent K+ channel in pancreatic β-cells
- Sulfonylurea class oral hypoglycemics eg. Glipizide facilitate closure of the channel and secretion of insulin by binding to the
SUR1 receptor
Most abundant
class of receptors in the body
G-protein coupled receptors (GPCRs)
How many GPCRs do humans express and what are majority dedicated to
Humans express over 800 GPCRs
* Over half dedicated to sensory perception (sight, taste, smell)
(Remainder dedicated to regulating nerve activity, tension in smooth
muscle, metabolism, force and rate of cardiac contraction, and
secretion of most glands)
G proteins
intracellular heterotrimeric GTP-binding regulatory proteins termed G proteins
Signals from G proteins are usually terminated by
hydrolysis of GTP to GDP by inherent GTP-ase activity of the α subunit
One major role for G proteins is to activate ________ _______ that produce _______ _______
Effector molecules, second messengers
Well characterized effector molecules
adenylyl cyclase, guanylyl cyclase, phospholipase C, various ion channels
One important receptor class in the G protein receptor family is
the
β-adrenergic receptor group
Catecholamines (epinephrine and norepinephrine) are ____________ and what do they do
endogenous ligands
-Stimulate the production of second messenger cAMP and cellular effects based on tissue localization
Key G protein mediated second messengers (4)
-cGMP
-IP3
-cAMP
-DAG
Transmembrane
Receptors with Enzymatic Cytosolic Domains role
play important roles in cell metabolism, growth
and differentiation……tonic activation can cause tumors
A difference between Transmembrane
Receptors with Enzymatic Cytosolic Domains and G proteins
Consist of single membrane spanning proteins compared to the
seven membrane spanning G protein receptors
Many transmembrane
Receptors with Enzymatic Cytosolic Domains form ______ or ________ _______ to transmit their signals
dimers, multisubunit complexes
Transmembrane
Receptors with Enzymatic Cytosolic Domains activity inclues
adding/removing phosphate
groups from specific aa’s
2 examples of Transmembrane Receptors with Enzymatic Cytosolic Domains
-Receptor tyrosine kinases
-Tyrosine kinase-associated receptors
Receptor tyrosine kinases RTKs) include
SH2 domains on other signaling molecules (such as Grb2)
Receptor tyrosine kinases include endogenous ligands such as
Insulin, PDGF, VEGF
Tyrosine Kinase-Associated Receptors include ______ receptors
cytokine
Tyrosine Kinase-Associated Receptors hormones
growth hormone and prolactin
Do Tyrosine Kinase-Associated Receptors have enzymatic activity
No
JAK/STAT pathway simplified
- Dimerization allows for binding of an intracellular
tyrosine kinase ie. Janus Kinase (JAK) - JAKs phosphorylate other proteins (STAT) which translocate to the nucleus
Two types of intracellular receptors
-nuclear hormone receptors
-NO synthase and soluble guanylyl cyclase
Nuclear hormone receptors
Circulating steroid hormones are lipophilic diffusing thru the plasma
membrane to bind transcription factors = modify nuclear events
Nuclear hormone receptors possess
a ligand binding domain and a DNA binding domain
(Nuclear hormone receptors) nuclear events depend on
which co-activators or co-repressors of gene transcription are recruited
Nuclear hormone receptors gene transcription duration
- Gene transcription is slow (min to hrs) but usually long-lasting
- Lag on (slow onset of cellular effects)
- Lag off (slow offset of cellular effects)
- eg. Glucocorticoids (dexamethasone)
Isoforms of NO and where is it produced
-Endothelial (eNOS)
-Inducible (iNOS)
-Neuronal (nNOS)
What does NO bind to and what does it do
NO binds to the N-terminal domain of soluble GC (guanylyl cyclase) and enhances (200-
400X) its activation of cGMP
Vascular smooth muscle effects of cGMP and what are they due to
- Mainly due to cGMP acting on PKG
- Vasodilation from reduced
intracellular calcium levels
eg. nitrovasodilators and
angina pectoris
Drug receptors outside of PM for communication
- Vasoconstriction: ACE inhibitors eg.enalapril for hypertension
- Neurotransmitters: Acetylcholinesterase inhibitors eg. tacrine
for treatment of Alzheimer’s disease
Drug receptors that provide a cell surface adhesion function
- Allows cell-cell interaction for various functions eg. inflammation,
coagulation (eptifibatide an antagonist of the platelet GPIIb-IIIa receptor)
Drug receptor providing structural role for cell
Antineoplastics: Microtubule inhibitors eg. paclitaxel for cancer therapy
How do cells integrate multiple signals to produce a coherent cellular response?
Signaling convergence by second messengers can generate coordinated net cellular effects
The magnitude of a cellular response to a ligand is generally ________ than the initiating stimulus
greater
Small influx of Ca2+ thru
voltage gated Ca2+ channels triggers the release of _________
amounts from intracellular stores
large
