MODULE 1 Flashcards
the body of knowledge concerned with the action of chemicals on biologic systems.
PHARMACOLOGY
The study of substances that interact with living systems through chemical processes, especially by binding to regulatory molecules and activating or inhibiting normal body processes.
PHARMACOLOGY
The science of substances used to prevent, diagnose, and treat disease.
MEDICAL PHARMACOLOGY
The branch of pharmacology that deals with the undesirable effects of chemicals on living systems, from individual cells to humans to complex ecosystem.
TOXICOLOGY
- the science of medical use of drugs
- was developed as the precursor to pharmacology
THE MATERIA MEDICA
developed the methods of experimental physiology and pharmacology
FRANCOIS MAGENDIE
CLAUDE BERNARD
the use of drugs in the treatment of disease, which is a development from the ancient practice of “____” and spirits in attending to sick
SHAMANS
The latest development was on
PHARMACOGENOMICS
It is the relation of the individual’s genetic makeup to his or her response to specific drugs.
PHARMACOGENOMICS
Short nucleotide chains called ____, were synthesized to be complementary to natural RNA or DNA
ANTISENSE OLIGONUCLEOTIDES (ANOs)
It may be defined as any substance that brings about a change in biologic function through its chemical actions
DRUG
DRUG MAY INTERACT AS AN:
activator of a specific molecule
AGONIST
DRUG MAY INTERACT AS AN:
inhibitor of a specific molecule
ANTAGONIST
DRUG MAY INTERACT AS AN:
“the target molecule” for drug
INTERACTS WITH THE RECEPTOR
A drug may be synthesized within the body
HORMONES, ENDOGENOUS
A drug may be chemicals not synthesized in the body
XENOBIOTICS “ STRANGER”, EXOGENOUS
refers to a drug that have almost exclusively harmful effects.
POISON
The ____ of the drug makes the poison (Paracelsus)
DOSE
Another similar term for poison which refers to poison of biologic origin and is usually synthesized by plants or animals
TOXIN
To achieve selective binding, the drug molecule should be at least ____ units in size.
100 MW
Drugs with MW greater than 1000 ____ between compartments, so must be administered directly into the compartment where they have their effect.
DO NOT DIFFUSE READILY
MAJOR TYPES OF DRUG-RECEPTOR CHEMICAL FORCES/BONDS
- very strong; not reversible.
- Example: Aspirin (acetyl group) and cyclooxygenase
COVALENT
MAJOR TYPES OF DRUG-RECEPTOR CHEMICAL FORCES/BONDS
- weaker than covalent
- vary from relatively strong linkages between permanently charged ionic molecules to weaker hydrogen bonds and very weak induced dipole forces
ELECTROSTATIC
MAJOR TYPES OF DRUG-RECEPTOR CHEMICAL FORCES/BONDS
usually quite weak; it is the interaction of highly lipid-soluble drugs with the lipids of the cell membrane
HYDROPHOBIC
MAJOR TYPES OF DRUG-RECEPTOR CHEMICAL FORCES/BONDS
HYDROPHOBIC:
* Certain drugs exhibit chirality (stereoisomerism) such as ____
* Its (S)(-) isomer is a potent beta blocker while the (R)(+) isomer is a hundred-fold weaker at the beta receptor.
CARVEDILOL
MAJOR TYPES OF DRUG-RECEPTOR CHEMICAL FORCES/BONDS
HYDROPHOBIC:
Carvedilol (S)(-) isomer
POTENT BETA BLOCKER
MAJOR TYPES OF DRUG-RECEPTOR CHEMICAL FORCES/BONDS
HYDROPHOBIC:
Carvedilol (R)(+) isomer
hundred-fold weaker at the beta receptor
MAJOR TYPES OF DRUG-RECEPTOR CHEMICAL FORCES/BONDS
The (+) enantiomer of ____ is more potent and is less toxic than the (-) enantiomer
KETAMINE
TWON DIVISIONS OF PHARMACOLOGY
- Is the study of how the body absorbs, distributes, metabolizes, and excretes drugs (ADME)
- What the body does to the drug
PHARMACOKINETICS
K - katawan
TWON DIVISIONS OF PHARMACOLOGY
- Describes the action of drugs
- It includes the measurement of responses to drugs and how response relates to drug dose or concentration
- What the drug does to the body
PHARMACODYNAMICS
D - drug
DISCIPLINES RELATED TO PHARMACOLOGY
- the study of the use of drugs to treat diseases.
- The use of drug treatment is to:
- Cure a disease
- Delay disease progression
- Alleviate the signs and/or symptoms of the disease
- Facilitate nonpharmacologic therapeutic intervention
PHARMACOTHERAPEUTICS (PHARMACOTHERAPY)
DISCIPLINES RELATED TO PHARMACOLOGY
is the study of the relationship of genetic factors to variations in drug response
PHARMACOGENETICS
DISCIPLINES RELATED TO PHARMACOLOGY
is the study of the cost effectiveness of drug treatments
PHARMACOECONOMICS
DISCIPLINES RELATED TO PHARMACOLOGY
is the study of the effect of drugs on population
PHARMACOEPIDEMIOLOGY
study of drug’s adverse effects
TOXICOLOGY
is the study of a poison, usually one produced by or occurring in a plant or microorganism
TOXINOLOGY
study of doses
POSOLOGY
study of drug’s manufacture, preparation and dispensing of drugs
PHARMACY
is the study of preparing and dispensing drugs
PHARMACEUTICS
is the study of the identification and preparation of crude drugs from natural sources
PHARMACOGNOSY
the science of drug preparation and the medical use of drugs
MATERIA MEDICA
is the application of all principles in pharmacy to humankind
CLINICAL PHARMACY
refers to what the body does to a drug. Four properties determine the onset, intensity, and the duration of drug action
PHARMACOKINETICS
PHARMACOKINETICS
____ from the site of administration permits entry of the drug (either directly or indirectly) into plasma
ABSORPTION
PHARMACOKINETICS
the drug may then reversibly leave the blood-stream and distribute into the interstitial and intracellular fluids.
DISTRIBUTION
PHARMACOKINETICS
he drug may be biotransformed by ____ by the liver or other tissues.
METABOLISM
PHARMACOKINETICS
the drug and its metabolites are eliminated from the body in urine, bile, or feces.
ELIMINATION
The pre-requisite to drugs’ access to the biologic system is the
ROUTE OF ADMINISTRATION
Drugs administered via ____ route, gets into the system rapidly and more efficiently than those given via extravascular route.
INTRAVASCULAR
Drugs given IV need not undergo ____ since it is administered directly into the systemic circulation.
ABSORPTION
A hundred percent (100%) bioavailability is expected once the drug is administered ____
INTRAVENOUSLY
For drugs given via extravascular route (oral, peroral, rectal, etc.) need to undergo ____ process (depending on the dosage form used) prior to absorption
LIBERATION
Drugs that undergo absorption especially via the GI tract need to be in
SOLUTION
The ____ characteristics of the drugs influences its absorption
PHYSICOCHEMICAL
For rapid and efficient absorption, the drug must be in
SOLUTION
____, ____, ____ drug molecules cross the biologic membrane more rapidly and efficiently than the ionized, more polar moiety
SMALL, NONIONIC, LIPOPHILIC
LUNA
Once the drug becomes available in the plasma, ____ follows
DISPOSITION
is the process by which drug leaves the systemic circulation and enters the various compartments (tissue compartments)
DISPOSITION
The term ____ includes distribution to different organs such as the site of action (e.g. CNS, heart, etc.), liver (for metabolism and excretion) and kidneys (for excretion)
DISPOSITION
process that terminates the action of the drug by promoting its clearance
DRUG ELIMINATION (metabolism & excretion)
Important Pharmacokinetic Principles
____ properties of drugs are partly responsible for their actions.
PHARMACOKINETIC
The ____ characteristics of the drug influences the rate and extent of drug input (liberation and absorption) and output (distribution, metabolism and excretion) processes.
PHYSICOCHEMICAL
provides the fundamental concept of the PK characteristics of drugs based on the degree of ionization as influenced by pH.
HENDERSON-HASSELBALCH
- At low pH (acid environment) these are in their unionized form.
- The unionized form is more lipophilic, thus can cross the membrane rapidly and efficiently through passive diffusion.
- remain unionized in the acid region of the GIT (stomach), thus optimum absorption occurs in this area.
- At high pH (basic environment) these become ionized, thus more polar in character.
- Excretion is favorable when the drug is in its ionized form.
WEAK ACIDS
environment in which WEAK ACIDS are in their unionized form
low ph
acidic environment
environment in which WEAK ACIDS are in their ionized form
high pH
basic environment
the unionized form of weak acids are more ____
lipophilic
weak acids in their unionized form can cross the membrane rapidly and efficiently through
LIPOPHILIC
PASSIVE DIFFUSION
optimum absorption of weak acids occurs in what area
STOMACH
Excretion is favorable when the drug is in its ____ form
IONIZED
- are best absorbed in the alkaline region of the GIT (small intestines) because they are in their unionized form.
- As mentioned earlier, unionized moiety is nonpolar and lipophilic, so can cross the membranes more efficiently.
- To promote the excretion of ____, an acid environment (low pH) is desired since it could make alkaline drugs to become more ionized.
- More ionized form of the drug is polar and less lipophilic (hydrophilic), thus are excretable.
WEAK BASES
Weak bases are best absorbed in what area
SMALL INTESTINES
To promote the excretion of weak bases, an ____ environment (____) is desired since it could make alkaline drugs to become more ionized.
acidic, low pH
an important PK principle that determines the ability of the drug to reach the circulation and be distributed to various organs and reach its site of action.
PERMEATION across the membrane
MECHANISMS OF DRUG PERMEATION
The most commonly mechanism involved in drug permeation is
(either through intercellular junctions or through the cell membrane)
PASSIVE DIFFUSION
MECHANISMS OF DRUG PERMEATION
Drug permeation is governed by ____ which describes the passive flux of molecules down a concentration gradient (from a region of higher concentration to a region of lower concentration)
FICK’S LAW / FICK’S FIRST LAW OF DIFFUSION
MECHANISMS OF DRUG PERMEATION
Some permeation mechanism utilized a ____ system
CARRIER-MEDIATED
MECHANISMS OF DRUG PERMEATION
CARRIER-MEDIATED SYSTEM:
The transport system may be an ____ (against the concentration gradient) or ____ (along the concentration gradient) process.
ACTIVE, PASSIVE
MECHANISMS OF DRUG PERMEATION
Both ____ and ____ (carrier-mediated) utilized a carrier or transporter to cross the membrane.
ACTIVE TRANSPORT & FACILITATED DIFFUSION
MECHANISMS OF DRUG PERMEATION
- a mechanism of drug permeation.
- This involves the engulfment of impermeant molecules by the vesicles in cell membrane via endocytosis (pinocytosis or phagocytosis), release into the cell, and expulsion of the material via membrane vesicles (exocytosis)
VESICULAR TRANSPORT
MECHANISMS OF DRUG PERMEATION
pinocytosis or phagocytosis
ENDOCYTOSIS
MECHANISMS OF DRUG PERMEATION
release into the cell, and expulsion of the material
EXOCYTOSIS
TRANSPORT MOLECULES IMPORTANT IN PHARMACOLOGY
target of cocaine and some tricyclic antidepressants
NET
TRANSPORT MOLECULES IMPORTANT IN PHARMACOLOGY
target of selective serotonin reuptake inhibitors and some tricyclic antidepressants
SERT
TRANSPORT MOLECULES IMPORTANT IN PHARMACOLOGY
target of reserpine
VMAT
TRANSPORT MOLECULES IMPORTANT IN PHARMACOLOGY
- increased expression confers resistance to certain anticancer drugs
- inhibition increases blood levels of digoxin
MDR1
TRANSPORT MOLECULES IMPORTANT IN PHARMACOLOGY
confers resistance to certain anticancer and antifungal drugs
MRP1
TRANSPORT MOLECULES IMPORTANT IN PHARMACOLOGY
NET physiologic function
norepinephrine reuptake from synapse
TRANSPORT MOLECULES IMPORTANT IN PHARMACOLOGY
SERT physiologic funtion
serotonin reuptake from synapse
TRANSPORT MOLECULES IMPORTANT IN PHARMACOLOGY
VMAT physiologic function
transport of dopamine and norepinephrine into adrenergic vesicles in nerve endings
TRANSPORT MOLECULES IMPORTANT IN PHARMACOLOGY
MDR1 physiologic function
transport of many xenobiotics out of cells
TRANSPORT MOLECULES IMPORTANT IN PHARMACOLOGY
MRP1 physiologic function
leukotriene secretion
describes the actions of a drug on the body and the influence of drug concentrations on the magnitude of the response.
PHARMACODYNAMICS
Most drugs exert their effects, both beneficial and harmful, by ____ (that is, specialized target macromolecules) present on the cell surface or within the cell
INTERACTING WITH RECEPTORS
The drug–receptor complex initiates alterations in biochemical and/or molecular activity of a cell by a process called
SIGNAL TRANSDUCTION
is the division of Pharmacology that describes the action of drugs. It includes the **measurement of responses **to drugs and how response relates to drug dose or concentration.
PHARMACODYNAMICS
TYPE OF ACTION PRODUCED BY THE DRUG
- drugs may increase or enhance the function of an organ or a system.
- Example: Caffeine increases the activity of the CNS that makes us awake or stimulated (energized)
STIMULATION
TYPE OF ACTION PRODUCED BY THE DRUG
- Drugs inhibit or decrease the function of an organ or the system.
- Alcohol is an example, it decreases the activity of the CNS leading to drowsiness, decrease concentration, affect balance and equilibrium and even decrease memory and learning functions.
DEPRESSION
TYPE OF ACTION PRODUCED BY THE DRUG
- This is an action attributed to local effects of the drug to a tissue or cell.
- An example of drug that gives this type of action are the stimulant cathartics. Some laxatives promote peristaltic movement by irritating the wall of the GIT causing increase motility and evacuation.
IRRITATION
TYPE OF ACTION PRODUCED BY THE DRUG
action of vitamins, minerals, or other supplements
REPLACING DEFICIENCY OF AN ESSENTIAL CHEMICAL
TYPE OF ACTION PRODUCED BY THE DRUG
action of anti-infectives and antineoplastics
Killing/Weakening invading microorganism/rapidly proliferating cells
Based on the action produced by the drug on a particular system
intended; it is usually the desired effect that leads to its therapeutic use
PRIMARY
Based on the action produced by the drug on a particular system
unintended; commonly leading to undesired effects (side effects, adverse drug reactions)
SECONDARY
MAJOR MECHANISMS OF DRUG ACTION (MOA)
- Alter the cell environment by physical or chemical processes
- Example:
Ø action of antacid - alters the pH of the stomach
Ø action of antidotes, e.g., activated charcoal - adsorbs the toxins
STRUCTURAL NONSPECIFIC
MAJOR MECHANISMS OF DRUG ACTION (MOA)
- Alter cell function by **drug-receptor interactions **
- Majority of drugs’ action is through this mechanism
- To understand this mechanism, it is important to know the different targets into which drugs are capable of interacting with.
STRUCTURAL SPECIFIC
targets for drug action are either ____ or ____
PROTEIN OR NON-PROTEIN
Majority of drugs interact with ____ targets such as receptors, ion-channel, enzymes and carrier molecules
PROTEIN
DIFFERENT LEVELS OF DRUG ACTION
- Interaction with drug’s molecular target
- The drug target (receptor, ion channel, enzyme, carrier molecule)
MOLECULAR
DIFFERENT LEVELS OF DRUG ACTION
- Transduction
- The biochemicals linked to drug target (ion channel, enzyme G protein)
CELLULAR
DIFFERENT LEVELS OF DRUG ACTION
- An effect on tissue function
- Electrogenesis, contraction secretion, metabolic activity, proliferation
TISSUE
DIFFERENT LEVELS OF DRUG ACTION
- An effect on system function
- Integrated systems including linked systems (e.g., NS, CVS)
SYSTEM
For a drug to produce an action, it must first interact with a ____ within the molecule
SPECIFIC TARGET
For a drug to produce an action, it must first interact with a specific target within the molecule. This interaction will be followed by a ____ wherein a cellular response is produced.
TRANSDUCTION MECHANISM
- Any target molecule with which a drug molecule has to combine in order to elicit its specific effect
- It is the component of a cell or organism that interacts with a drug and initiates the chain of events leading to the drug’s observed effects.
DRUG RECEPTOR
is the capacity of a drug to form the complex with its receptor (DR complex), e.g., the key entering the hole of the lock has got an affinity to its levers
AFFINITY
it is the ability of a drug to trigger the pharmacological response after making the drug receptor complex
INTRINSIC ACTIVITY / EFFICACY
refers to any molecule which attaches selectively to particular receptors or sites
LIGAND
- refers to an agent which activates a receptor to produce an effect similar to that of the physiologic signal molecule.
- It has both high affinity as well as high intrinsic activity, therefore can trigger the maximal biological response
AGONIST
- an agent which prevents the action of an agonist on a receptor but doesn’t have any effect of its own.
- it has only affinity but no intrinsic activity. this drug binds to the receptor and blocks the binding of an endogenous agonist.
ANTAGONIST
- an agent which** activates a receptor** to produce a sub maximal effect but antagonizes the actions of full agonist.
- it has full affinity but with low intrinsic activity and hence are only partly as effective as agonist.
PARTIAL AGONIST
- Agent which activates a receptor produce an effect in the opposite direction to that of the agonist
- Have full affinity but intrinsic activity ranges between 0 to -1
INVERSE (NEGATIVE ANTAGONIST)
largely determine the quantitative relations between dose or concentration of drug and pharmacologic effects
RECEPTORS
are responsible for selectivity of drug action
RECEPTORS
mediate the actions of pharmacologic agonists and antagonists
RECEPTORS
NATURE OF DRUG RECEPTORS
so-called because their ligands are presently unknown, which may prove to be useful targets for the development of new drugs
ORPHAN RECEPTOR
NATURE OF DRUG RECEPTORS
- the best characterized receptors;
- modify the actions of endogenous chemical signals (neurotransmitters, autacoids, hormones)
REGULATORY PROTEINS
Other proteins identified as drug receptors
- may be inhibited (or less commonly activated) by binding a drug.
- Example: dihydrofolate reductase - receptor for methotrexate
ENZYMES
receptor for methotrexate
DIHYDROFOLATE REDUCTASE
Other proteins identified as drug receptors
Example: Na+, K+ ATPase – receptor for digoxin
TRASNPORT PROTEINS
Other proteins identified as drug receptors
Example is Tubulin – the receptor for colchicine
STRUCTURAL PROTEINS
recepor for colchicine
TUBULIN
Aspects of Drug-receptor Functions
Receptors as determinants of the quantitative relation between the ____ of a drug and the ____
concentration of a drug & pharmacologic response
Aspects of Drug-receptor Functions
Receptors as ____ and ____ that provide targets for important drugs
REGULATORY PROTEINS
COMPONENTS OF CHEMICAL SIGNALING MECHANISMS
inhibits depolarization = relaxants
1) Class I Anti-arrhythmic
2) Local Anesthetics: Ester: 1 “i” * Amide: 2 “i
3) Some anticonvulsants: Carbamazepine, Phenytoin
Na channel blockers
Aspects of Drug-receptor Functions
Receptors as key determinants of the ____ and ____ effects of drugs in patients
THERAPEUTIC
TOXIC
Five basic mechanisms of transmembrane signaling
A ____ that can be induced to open or close by the binding of a ligand
LIGAND-GATED TRANSMEMBRANE ION CHANNEL
Five basic mechanisms of transmembrane signaling
A ____ whose intracellular enzymatic activity is allosterically regulated by a ligand that binds to a site on the protein’s extracellular domain
TRANSMEMBRANE RECEPTOR PROTEIN
Five basic mechanisms of transmembrane signaling
A ____ that crosses the membrane and acts on an intracellular receptor;
LIPID-SOLUBLE LIGAND
Five basic mechanisms of transmembrane signaling
A transmembrane receptor that binds and stimulates a protein ____
TYROSINE KINASE
TYPES OF RECEPTORS
- Receptor-Operated Channel (ROC)
- Voltage-Operated Channels (VOC)
TYPE 1: ION CHANNEL TYPES
Five basic mechanisms of transmembrane signaling
A transmembrane receptor protein that stimulates a ____ (G protein), which in turn modulates production of an intracellular second messenger.
GTP-BINDING SIGNAL TRANSDUCER PROTEIN
TYPES OF RECEPTORS | TYPE 1: ION CHANNEL TYPES
- Also known as ligand gated ion channels, or transmitter operated channels
-
Directly linked to a receptor, and opens only when the receptor is activated
Ø Na+ ion channel: Nicotinic receptor + acetylcholine -
Heart (VOC), Muscles (ROC) -
Sodium inside the cell > depolarization of the membrane or increase of conduction of the impulse of the membrane > Contraction of muscles
Ø Cl- ion channel: GABAA Receptor
Ø Glycine receptor, 5HT3 receptor
RECEPTOR-OPERATED CHANNEL
- most abundant receptor
- Are sometimes called metabotropic receptors, 7 transmembrane serpentine receptor
- Are receptors for many hormones and slow transmitters
- e.g. muscarinic Ach receptor, adrenergic receptors and neuropeptide receptors
- Are membrane receptors which are coupled to intracellular effector systems via G-protein
TYPE 2: G-PROTEIN COUPLED RECEPTORS
TYPES OF RECEPTORS | TYPE 1: ION CHANNEL TYPES
ROC BEHAVIOR 3 RECOGNIZED STATES:
open
ACTIVATED
TYPES OF RECEPTORS | TYPE 1: ION CHANNEL TYPES
Receptor-Operated Channel is also known as
ligand gated ion channel
transmitter operated channel
TYPES OF RECEPTORS | TYPE 1: ION CHANNEL TYPES
ROC BEHAVIOR 3 RECOGNIZED STATES:
Closed, but openable in response to an appropriate stimulus
RESTED (NON-CONDUCTING)
EXCITATORY
VGIC opening
Na⁺, Ca⁺²
C
ROC BEHAVIOR 3 RECOGNIZED STATES:
Closed, and unable to open in response to an appropriate stimulus for a rested state channel
INACTIVATED
molecular mechanism of action that involves modulation of the transition of the ROC between states
GATING
TYPES OF RECEPTORS | TYPE 1: ION CHANNEL TYPES
VOLTAGE-OPERATED:
5 types of Ca channels
L T N P Q
TYPES OF RECEPTORS | TYPE 1: ION CHANNEL TYPES
VOLTAGE-OPERATED (Na channel):
opens and closes slowly (in 10’s of millisecond)
SLOW GATE
TYPES OF RECEPTORS | TYPE 1: ION CHANNEL TYPES
- The behavior is modulated endogenously by membrane potential (voltage)
- Examples:
Ø Na channel (cardiac)- contains two voltage operated
gates
VOLTAGE-OPERATED CHANNEL
TYPES OF RECEPTORS | TYPE 1: ION CHANNEL TYPES
VOLTAGE-OPERATED:
* opening of channels result in generation of outgoing currents
* more than 10 types in the heart
K channels
TYPES OF RECEPTORS | TYPE 1: ION CHANNEL TYPES
VOLTAGE-OPERATED (Na channel):
opens and closes quickly (in milliseconds)
FAST GATE
TYPES OF RECEPTORS | TYPE 1: ION CHANNEL TYPES
VOLTAGE-OPERATED:
* found in heart & smooth muscles
* opens during depolarization and then activates by voltage depending gating
Ca channels
TYPES OF RECEPTORS | TYPE 1: ION CHANNEL TYPES
VOLTAGE-OPERATED:
most important type in Ca channel
L
TYPES OF RECEPTORS | TYPE 1: ION CHANNEL TYPES
VOLTAGE-OPERATED:
* channels in the CNS and in the peripheral
Cl channels
- Acts as an on-off switches for cell signaling
- Stimulation or inhibition results in the modulation of the enzyme system responsible for producing the following transduction components;
- Cyclic nucleotides – cAMP
- Diacylglycerol
- Inositol phosphates (IP3)
G-PROTEIN
EXCITATORY
cell change
+
INHIBITORY
cell change
-
EXCITATORY
state
depolarization
EXCITATORY
response
stimulation
contraction
inhibit hyperpolarization = stimulants
1) Insulin secretagogues
K channel blocker
INHIBITORY
VGIC opening
K⁺, Cl⁻
INHIBITORY
response
depression
relaxation
dilation
INHIBITORY
state
hyperpolarization
cAMP SYSTEM
lungs
β2
stimulant hyperpolarization = relaxants
* Minoxidil - arteriolar vasodilator
* Diazoxide - arteriolar vasodilator
K channel stimulants
cAMP SYSTEM
general effect
CONTRACTION
cAMP SYSTEM
metabolize cAMP
decrease cAMP levels
inhibit contraction
PDE3
TYPE 2: G-PROTEIN COUPLED RECEPTORS
are also known
METABOTROPIC RECEPTORS
cAMP SYSTEM
heart
β1
G-Protein Coupled Effector Systems
- The adenylate cyclase/cAMP system
- The phospholipase C/Inositol phosphate system
- The regulation of ion channel
cAMP SYSTEM
for stimulation
Gs
cAMP SYSTEM
decrease cAMP
GI
cAMP SYSTEM
responsible for production of cAMP
AC SYSTEM
G-Protein Coupled Effector Systems
involves GQ
PHOSPHOLIPASE C / INOSITOL PHOSPHATE SYSTEM
PHOSPHOLIPASE C / INOSITOL PHOSPHATE SYSTEM
Phospholipase C produces ____ and ____
secondary messengers produced in phospholipase C
DAG & IP₃
PHOSPHOLIPASE C / INOSITOL PHOSPHATE SYSTEM
secondary messenger that activates protein kinase
DAG
PHOSPHOLIPASE C / INOSITOL PHOSPHATE SYSTEM
DAG activates ____
protein kinase
PHOSPHOLIPASE C / INOSITOL PHOSPHATE SYSTEM
secondary messenger that increases calcium ions
IP3
PHOSPHOLIPASE C / INOSITOL PHOSPHATE SYSTEM
IP3 increases ____
calcium ions
PHOSPHOLIPASE C / INOSITOL PHOSPHATE SYSTEM
- responsible for contraction
- important for the heart
calcium ions
- Activation of hormone-sensitive lipase
- Inactivation of glycogen synthase
-
Activation of phosphorylase kinase
- Increased lipolysis
- Reduced glycogen synthesis and increased glycogen breakdown
-
Activation of L-type calcium channels and sarcoplasmic reticulum in cardiac cells
- Increased calcium currents and release
PHOSPHORYLATION
- Modulation of the release of endocrine hormones and neurotransmitters
- Smooth muscle contraction
- Inflammation
- Ion transport
- Tumor promotion
PROTEIN-KINASE LINKED TRANSDUCTION
- Smooth muscle contraction
- Increased rate of contraction and relaxation of cardiac myocytes
- Secretion of transmitter molecules of glandular secretions
- Hormone release
- Cytotoxicity
- Activation of certain enzymes
Ca⁺²-linked transduction
G-protein couple receptors can control ion channel function by mechanism that do not involve
secondary messengers
G-protein interacts ____ with the channel
directly
an opioid receptor that open K+ channel thus enhance K+ permeability
MUSCARINIC ACH
SECONDARY MESSENGERS
- mediates hormonal responses:
- mobilization of stored energy
- conservation of water by the kidney
- Ca2+ homeostasis
- increased rate and contractile force of heart muscle
- It also regulates the production of adrenal and sex steroids
- relaxation of smooth muscle
- other endocrine and neural processes
CYLIC ADENOSINE MONOPHOSPHATE (cAMP)
SECONDARY MESSENGERS | cAMP
the breakdown of carbohydrates in liver or triglycerides in fat cells stimulated by b-adrenomimetic catecholamines
mobilization of stored energy
SECONDARY MESSENGERS | cAMP
- conservation of water by the kidney is mediated by ____
- it is an anti-diuretic hormone ADH
vasopressin
SECONDARY MESSENGERS | cAMP
Ca⁺² homeostasis is regulated by ____
parathyroid hormone
SECONDARY MESSENGERS | cAMP
DAG when phosphorylated yields ____
phosphatidic acid
SECONDARY MESSENGERS | cAMP
- Confined to the membrane, where it activates a phospholipid- and calcium sensitive protein kinase called protein kinase C
- Terminated by either phosphorylation to yield phosphatidic acid, which is then converted back into phospholipids, or it is deacylated to yield arachidonic acid
diacylglycerol (DAG)
SECONDARY MESSENGERS | cAMP
DAG when deacylated yield ____
arachidonic acid
SECONDARY MESSENGERS | cGMP
a blood-borne peptide hormone
ATRIAL NATRIURETIC PEPTIDE
SECONDARY MESSENGERS | cAMP
- responsible for the increase of Ca
- Diffuses through the cytoplasm to trigger release of Ca2+
- Elevated cytoplasmic Ca2+ concentration promotes the binding of Ca2+ to the calcium-binding protein calmodulin
- Inactivated by dephosphorylation
- Ca2+ is actively removed from the cytoplasm by Ca2+ pumps
INOSITOL TRIPHOSPHATE (IP3)
SECONDARY MESSENGERS | cGMP
- enhance production of IP3, and DAG → increase Ca = Contraction
- by Gq
PHOSPHOLIPASE C (PLC) SSYSTEM
SECONDARY MESSENGERS
- Produced by membrane-bound guanylyl cyclase
- Acts by stimulating a cGMP-dependent protein kinase
- Terminated by enzymatic degradation of the cyclic nucleotide and by dephosphorylation of kinase substrates
- Increased concentration causes relaxation of vascular smooth muscle
CYCLIC GUANOSINE MONOPHOSPHATE (cGMP)
SECONDARY MESSENGERS | cGMP
-
Activation - by Gs
→ increase concentration of 2°messenger: cAMP -
Inhibition - by Gi
→ reduce concentration of 2°messenger: cAMP
ADENYLYL CYCLASE (AC) SYSTEM
SECONDARY MESSENGERS | cGMP
binds to and activates a cytoplasmic guanylyl cyclase
vasodilation
NITRIC OXIDE
TYPE 3: KINASE-LINKED RECEPTORS
an intracellular protein kinase domain that they incorporate within their structure
tyrosine kinase
TYPES OF RECEPTORS
- These are membrane receptors which incorporate an intracellular protein kinase domain (tyrosine kinase) within their structure
- Examples are insulin receptors and receptors for various cytokines and growth factors
- Transduction mechanisms are mainly involved in events controlling cell growth and differentiation, and act directly by regulating gene transcription
TYPE 3: KINASE-LINKED RECEPTORS
TYPE 3: KINASE-LINKED RECEPTORS
mechanisms that are mainly involved in events controlling cell growth and differentiation
transduction
TYPE OF RECEPTORS
- Also known as nuclear receptors
- Intracellular receptors
- Include receptors for steroid hormones, thyroid hormones, Vitamin D and retinoic acid
- Effects are produced as a result of altered protein synthesis, and thus slow in onset
TYPE 4: RECEPTORS THAT REGULATE GENE TRANSCRIPTION
TYPE 4: RECEPTORS THAT REGULATE GENE TRANSCRIPTION
are also known as
NUCLEAR RECEPTORS
TYPE 4: RECEPTORS THAT REGULATE GENE TRANSCRIPTION
effects are produced as a result of
altered protein synthesis
TYPE 4: RECEPTORS THAT REGULATE GENE TRANSCRIPTION
onset
slow
ion channel in GABA receptor
CHLORIDE ION
interaction leads to reduced level causing peripheral neuritis
ISONIAZID & PYRIDOXAL PHOSPHATE
stimulate dopa decarboxylase leading to nullification of L -Dopa’s action
PYRIDOXAL PHOSPHATE
inhibits xanthine oxidase prevents conversion to uric acid
ALLOPURINOL
tx for acute gout
colchicine
tx for chronic gout
allopurinol
- Facilitate passage of ions or molecules across cell membranes by altering their conformation from a rested state to an activated state
- Classes: Uniporters, Symporters, Antiporters
ENERGY-INDEPENDENT
- Translocate its passenger through altered conformation where proteins are converted into an enzyme that normally hydrolyzes ATP (energy dependence)
- e.g. Na+/K+ - ATPase
ENERGY-DEPENDENT
usual movement of K⁺ when activated
exit
effect of partial agonist + full agonist
antagonism effect
1 intrisic activity
full agonist
more than 0, less than 1 IA
partial agonist
less than 0 IA
inverse agonist
The relative concentration required to produce a given magnitude of effect is ____ and depends on affinity and efficacy
potency
has high efficacy (full activation)
full agonist
Types of Drug Antagonism
- also known as physiologic antagonism
- 2 ligands acting on different targets producing opposite effects
Example: Norepinephrine and Acetylcholine - NE target B1—> tachycardia (increased heart rate)
- ACh target M2 —> bradycardia (heart rate slower than normal)
FUNCTIONAL ANTAGONISM
has intermediate efficacy (less activation)
partial agonist
Types of Drug Antagonism
Functional antagonism is also known as
physiologic antagonism
Types of Drug Antagonism
- Pharmacologic antagonism
- 2 ligands acting on the same target producing opposite effects
Example: Norepinephrine + Propranolol - NE activate B1—> tachycardia
- Propranolol inhibit B1 —> bradycardia
RECEPTOR ANTAGONISM
Types of Drug Antagonism
Receptor antagonism is also known as
PHARMACOLOGIC ANTAGONISM
Types of Drug Antagonism
Neutralization, chelation
CHEMICAL ANTAGONISM
involves metal
chelation
antidote for Heparin
Protamine sulfate
Fe poisoning
Deferoxamine
Cu poisoning
Penicillamine
Classification of antagonism based on duration of action
- fast noncovalent interaction;
- within 24 hours - safer
reversible
Classification of antagonism based on duration of action
- slow covalent interaction;
- days to weeks - toxic
irreversibleq
Classification based on surmountability
- Surmountable
- Increase the dose of the agonist
- reversible; safe
competitive
Classification based on surmountability
- Non surmountable;
- no effect even with increasing the dose of agonist
- irreversible; toxic
noncompetitive
Types of Drug Interaction
the response elicited by combined drugs is equal to the combined responses of the individual drugs (1 + 1 = 2)
alcohol, sedative
addition
Types of Drug Interaction
the response elicited by combined drugs is greater than the combined responses of the individual drugs (1 + 1 = 3)
SYNERGISM
Types of Drug Interaction
a drug which has no effect on the system enhances the effect of the other (0 + 1 = 2)
levodopa & carbidopa, amoxicillin & clavulanic acid
POTENTIATION
Types of Drug Interaction
Drug inhibits the effect of another due to opposite pharmacological actions (1 + 1 = 0)
ANTAGONISM
Special pharmacological responses
the effect of the drug gradually diminishes when given continuously or repeatedly
DESENSITIZATION & TACHYPHYLAXIS
Special pharmacological responses
- describes a more gradual decrease in responsiveness to a drug
- administration of low doses in long periods
TOLERANCE
Special pharmacological responses
used to describe the loss of effectiveness of antimicrobial or antitumor drugs
DRUG RESISTANCE
Special pharmacological responses
beneficial therapeutic response that arises from psychological factors
PLACEBO
POTENCY
Lesser dose
greater potency
maximum response
EFFICACY
It is characterized by the magnitude of resistance increasing continuously with greater concentration of unbound drug at the receptor site
GRADED RESPONSE
dose required to achieve 50% of efficacy
POTENCY
more common type of graph in graded response
sigmoidal
Smallest dose which produces efficacy
ceiling dose
POTENCY
Greater dose
lesser potency
- Degree of changes in response with a change in the dose of the drug administered
- Slanting assess safety
slope
is the concentration of drug yielding 50% occupancy of the receptor and is dependent on the affinity of a drug for its receptor
MAXIMAL BINDING Kd
Kd
Drugs with high binding affinity
LOW Kd
- are the proportion of receptors not needed for the production of the maximal response.
- It exists if the maximal drug response is obtained at less than maximal occupation of the receptor. Determination is usually made by comparing the concentration for 50% of maximal effect (EC50) with the concentration for 50% of maximal binding (KD)
spare receptors
Kd
Drugs with low binding affinity
HIGH Kd
- Graphically plots the percent of the population that responds to a drug versus the drug dose
QUANTAL DOSE RESPONSE RELATIONSHIP
the observable response can be described only in terms of an all or none event.
QUANTAL RESPONSE
- Indicates potential variability of responsiveness among individuals
- May be used to generate information regarding margin of safety
QUANTAL DOSE RESPONSE CURVE
QUANTAL DOSE CURVE
the dose at which 50% of the individual exhibit the specified quantal effect
MEDIAN EFFECTIVE DOSE (ED50)
QUANTAL DOSE CURVE
the dose required to produce a particular toxic effect in 50% of humans
MEDIAN TOXIC DOSE (TD50)
QUANTAL DOSE CURVE
the dose with which the toxic effect is death to 50% of the animals
MEDIAN LETHAL DOSE (LD50)
- Also called Margin of Safety
- The ratio of the lethal doses to 50% of the population over the median effective dose
- The higher the TI, the safer the drug; the lower the TI, the greater the possibility of toxicity
- Example: TI for barbiturates as a class is 10; for cardiac glycosides 3.0.
THERAPEUTIC INDEX
Therapeutic index is also called
MARGIN OF SAFETY
formula for Therapeutic index
LD50 or TD50 / ED50
