MODULE 1 Flashcards
1
Q
the body of knowledge concerned with the action of chemicals on biologic systems.
A
PHARMACOLOGY
1
Q
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.
A
PHARMACOLOGY
2
Q
The science of substances used to prevent, diagnose, and treat disease.
A
MEDICAL PHARMACOLOGY
3
Q
The branch of pharmacology that deals with the undesirable effects of chemicals on living systems, from individual cells to humans to complex ecosystem.
A
TOXICOLOGY
4
Q
- the science of medical use of drugs
- was developed as the precursor to pharmacology
A
THE MATERIA MEDICA
5
Q
developed the methods of experimental physiology and pharmacology
A
FRANCOIS MAGENDIE
CLAUDE BERNARD
5
Q
the use of drugs in the treatment of disease, which is a development from the ancient practice of “____” and spirits in attending to sick
A
SHAMANS
6
Q
The latest development was on
A
PHARMACOGENOMICS
7
Q
It is the relation of the individual’s genetic makeup to his or her response to specific drugs.
A
PHARMACOGENOMICS
8
Q
Short nucleotide chains called ____, were synthesized to be complementary to natural RNA or DNA
A
ANTISENSE OLIGONUCLEOTIDES (ANOs)
9
Q
It may be defined as any substance that brings about a change in biologic function through its chemical actions
A
DRUG
10
Q
DRUG MAY INTERACT AS AN:
activator of a specific molecule
A
AGONIST
11
Q
DRUG MAY INTERACT AS AN:
inhibitor of a specific molecule
A
ANTAGONIST
12
Q
DRUG MAY INTERACT AS AN:
“the target molecule” for drug
A
INTERACTS WITH THE RECEPTOR
13
Q
A drug may be synthesized within the body
A
HORMONES, ENDOGENOUS
14
Q
A drug may be chemicals not synthesized in the body
A
XENOBIOTICS “ STRANGER”, EXOGENOUS
15
Q
refers to a drug that have almost exclusively harmful effects.
A
POISON
16
Q
The ____ of the drug makes the poison (Paracelsus)
A
DOSE
17
Q
Another similar term for poison which refers to poison of biologic origin and is usually synthesized by plants or animals
A
TOXIN
18
Q
To achieve selective binding, the drug molecule should be at least ____ units in size.
A
100 MW
19
Q
Drugs with MW greater than 1000 ____ between compartments, so must be administered directly into the compartment where they have their effect.
A
DO NOT DIFFUSE READILY
20
Q
MAJOR TYPES OF DRUG-RECEPTOR CHEMICAL FORCES/BONDS
- very strong; not reversible.
- Example: Aspirin (acetyl group) and cyclooxygenase
A
COVALENT
21
Q
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
A
ELECTROSTATIC
22
Q
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
A
HYDROPHOBIC
23
# **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
24
# **MAJOR TYPES OF DRUG-RECEPTOR CHEMICAL FORCES/BONDS**
HYDROPHOBIC:
Carvedilol **(S)(-)** isomer
POTENT BETA BLOCKER
25
# **MAJOR TYPES OF DRUG-RECEPTOR CHEMICAL FORCES/BONDS**
HYDROPHOBIC:
Carvedilol **(R)(+)** isomer
hundred-fold weaker at the beta receptor
26
# **MAJOR TYPES OF DRUG-RECEPTOR CHEMICAL FORCES/BONDS**
The **(+) enantiomer** of ____ is **more potent** and is **less toxic** than the **(-) enantiomer**
KETAMINE
27
# **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
PHARMACO**K**INETICS
| K - katawan
28
# **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
PHARMACO**D**YNAMICS
| D - drug
29
# **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)
30
# **DISCIPLINES RELATED TO PHARMACOLOGY**
is the study of the **relationship** of **genetic factors** to variations in **drug response**
PHARMACOGENETICS
31
# **DISCIPLINES RELATED TO PHARMACOLOGY**
is the study of the **cost effectivenes**s of drug treatments
PHARMACOECONOMICS
32
# **DISCIPLINES RELATED TO PHARMACOLOGY**
is the study of the **effect of drugs** on **population**
PHARMACOEPIDEMIOLOGY
33
study of drug’s **adverse effects**
TOXICOLOGY
34
is the study of a **poison**, usually **one produced by** or **occurring** in a **plant** or **microorganism**
TOXINOLOGY
35
study of **doses**
POSOLOGY
36
study of drug’s **manufacture**, **preparation** and **dispensing** of drugs
PHARMACY
37
is the study of **preparing** and **dispensing** drugs
PHARMACEUTICS
38
is the study of the **identification** and **preparation** of **crude drugs** from **natural sources**
PHARMACOGNOSY
39
the science of drug **preparation** and the **medical use** of drugs
MATERIA MEDICA
40
is the **application of all principles** in pharmacy to **humankind**
CLINICAL PHARMACY
41
refers to what the **body** does to a drug. Four properties determine the **onset**, **intensity**, and the **duration** of drug action
PHARMACOKINETICS
42
# **PHARMACOKINETICS**
____ from the **site of administration** permits **entry** of the drug (either directly or indirectly) **into plasma**
ABSORPTION
43
# **PHARMACOKINETICS**
the drug may then **reversibly leave the blood-stream** and **distribute** into the **interstitial** and **intracellular fluids**.
DISTRIBUTION
44
# **PHARMACOKINETICS**
he drug may be **biotransformed** by ____ by the **liver** or other tissues.
METABOLISM
45
# **PHARMACOKINETICS**
the drug and its metabolites are **eliminated** from the body in **urine**, **bile**, or **feces**.
ELIMINATION
46
The **pre-requisite** to **drugs' access** to the **biologic system** is the
ROUTE OF ADMINISTRATION
47
Drugs administered via ____ route, gets into the system **rapidly** and **more efficiently** than those given via **extravascular** route.
INTRAVASCULAR
48
Drugs given **IV** need **not undergo** ____ since it is **administered directly** into the systemic circulation.
ABSORPTION
49
A **hundred percent (100%) bioavailability** is expected once the drug is administered ____
INTRAVENOUSLY
50
For drugs given via **extravascular** route (*oral*, *peroral*, *rectal*, etc.) **need to undergo** ____ process (depending on the dosage form used) **prior to absorption**
LIBERATION
51
Drugs that **undergo absorption** especially via the **GI tract** need to be in
SOLUTION
52
The ____ characteristics of the drugs **influences** its **absorption**
PHYSICOCHEMICAL
53
For **rapid** and **efficient absorption**, the drug must be in
SOLUTION
54
____, ____, ____ drug molecules **cross the biologic membrane more rapidly** and efficiently **than** the **ionized**, **more polar moiety**
SMALL, NONIONIC, LIPOPHILIC
| LUNA
55
Once the drug becomes **available in the plasma**, ____ follows
DISPOSITION
56
is the process by which drug **leaves the systemic circulation** and **enters** the **various compartments** (**tissue compartments**)
DISPOSITION
57
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
58
process that **terminates** the **action of the drug** by **promoting** its **clearance**
DRUG ELIMINATION (metabolism & excretion)
59
# **Important Pharmacokinetic Principles**
____ properties of drugs are **partly responsible** for their **actions**.
PHARMACOKINETIC
60
The ____ characteristics of the drug **influences** the **rate** and **extent** of **drug input** (**liberation** and **absorption**) and **output** (**distribution**, **metabolism** and **excretion**) processes.
PHYSICOCHEMICAL
61
provides the **fundamental concept** of the **PK characteristics** of drugs based on the **degree of ionization** as **influenced by pH**.
HENDERSON-HASSELBALCH
62
* 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
63
**environment** in which **WEAK ACIDS** are in their **unionized form**
low ph
acidic environment
64
**environment** in which **WEAK ACIDS** are in their **ionized form**
high pH
basic environment
65
the **unionized** form of **weak acids** are more ____
lipophilic
66
**weak acids** in their **unionized** form can **cross the membrane** rapidly and efficiently through
| LIPOPHILIC
PASSIVE DIFFUSION
67
**optimum absorption** of **weak acids** occurs in what area
STOMACH
68
**Excretion** is **favorable** when the drug is in its ____ form
IONIZED
69
* 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
70
**Weak bases** are **best absorbed** in what area
SMALL INTESTINES
71
To **promote the excretion** of **weak bases**, an ____ **environment** (____) is **desired** since it could **make alkaline drugs to become more ionized**.
acidic, low pH
72
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
73
# **MECHANISMS OF DRUG PERMEATION**
The **most commonly mechanism involved** in drug permeation is
| (either through intercellular junctions or through the cell membrane)
PASSIVE DIFFUSION
74
# **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
75
# **MECHANISMS OF DRUG PERMEATION**
**Some** permeation mechanism utilized a ____ system
CARRIER-MEDIATED
76
# **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
77
# **MECHANISMS OF DRUG PERMEATION**
Both ____ and ____ (carrier-mediated) utilized a **carrier** or **transporter** to **cross the membrane.**
ACTIVE TRANSPORT & FACILITATED DIFFUSION
78
# **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
79
# **MECHANISMS OF DRUG PERMEATION**
pinocytosis or phagocytosis
**ENDO**CYTOSIS
80
# **MECHANISMS OF DRUG PERMEATION**
**release** into the cell, and **expulsion** of the material
**EXO**CYTOSIS
81
# **TRANSPORT MOLECULES IMPORTANT IN PHARMACOLOGY**
target of **cocaine** and some **tricyclic antidepressants**
NET
82
# **TRANSPORT MOLECULES IMPORTANT IN PHARMACOLOGY**
target of **selective serotonin reuptake inhibitors** and some **tricyclic antidepressants**
SERT
83
# **TRANSPORT MOLECULES IMPORTANT IN PHARMACOLOGY**
target of **reserpine**
VMAT
84
# **TRANSPORT MOLECULES IMPORTANT IN PHARMACOLOGY**
* **increased expression confers resistance** to certain **anticancer drugs**
* **inhibition increases blood levels** of **digoxin**
MDR1
85
# **TRANSPORT MOLECULES IMPORTANT IN PHARMACOLOGY**
confers **resistance** to certain **anticancer** and **antifungal** drugs
MRP1
86
# **TRANSPORT MOLECULES IMPORTANT IN PHARMACOLOGY**
**NET** physiologic function
**norepinephrine** reuptake from synapse
87
# **TRANSPORT MOLECULES IMPORTANT IN PHARMACOLOGY**
**SERT** physiologic funtion
**serotonin** reuptake from synapse
88
# **TRANSPORT MOLECULES IMPORTANT IN PHARMACOLOGY**
**VMAT** physiologic function
**transport** of **dopamine** and **norepinephrine** into adrenergic vesicles in nerve endings
89
# **TRANSPORT MOLECULES IMPORTANT IN PHARMACOLOGY**
**MDR1** physiologic function
transport of many **xenobiotics** out of cells
90
# **TRANSPORT MOLECULES IMPORTANT IN PHARMACOLOGY**
**MRP1** physiologic function
**leukotriene** secretion
91
describes the **actions of a drug on the body** and the **influence of drug concentrations** on the magnitude of the response.
PHARMACODYNAMICS
92
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
93
The **drug–receptor complex** initiates **alterations** in **biochemical** and/or **molecular activity** of a cell by a process called
SIGNAL TRANSDUCTION
94
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
95
# **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
96
# **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
97
# **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
98
# **TYPE OF ACTION PRODUCED BY THE DRUG**
action of **vitamins**, **minerals**, or other **supplements**
REPLACING DEFICIENCY OF AN ESSENTIAL CHEMICAL
99
# **TYPE OF ACTION PRODUCED BY THE DRUG**
action of anti-**infectives** and **antineoplastics**
**Killing**/**Weakening** invading microorganism/rapidly proliferating cells
100
# **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
101
# **Based on the action produced by the drug on a particular system**
**unintended**; commonly leading to **undesired** effects (**side effects**, **adverse drug reactions**)
SECONDARY
102
# **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
103
# **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
104
**targets** for drug action are either ____ or ____
PROTEIN OR NON-PROTEIN
105
**Majority** of drugs **interact with** ____ targets such as **receptors**, **ion-channel**, **enzymes** and **carrier** molecules
PROTEIN
106
# **DIFFERENT LEVELS OF DRUG ACTION**
* **Interaction** with **drug’s molecular target**
* The drug target (**receptor**, **ion channel**, **enzyme**, **carrier** molecule)
MOLECULAR
106
# **DIFFERENT LEVELS OF DRUG ACTION**
* **Transduction**
* The **biochemicals** linked to drug target (**ion channel**, enzyme **G protein**)
CELLULAR
107
# **DIFFERENT LEVELS OF DRUG ACTION**
* An effect on **tissue** function
* **Electrogenesis**, **contraction secretion**, **metabolic** activity, **proliferation**
TISSUE
108
# **DIFFERENT LEVELS OF DRUG ACTION**
* An effect on **system** function
* **Integrated systems** including linked systems (e.g., **NS**, **CVS**)
SYSTEM
109
For a drug to **produce an action**, it must **first interact with** a ____ **within** the molecule
SPECIFIC TARGET
110
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
111
* **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
112
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
113
it is the ability of a drug to **trigger** the **pharmacological response** after making the **drug receptor complex**
INTRINSIC ACTIVITY / EFFICACY
114
refers to any molecule **which attaches selectively** to **particular receptors** or **sites**
LIGAND
115
* 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
116
* 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
117
* 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
118
* 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)
119
largely determine the **quantitative relations** between **dose** or **concentration** of drug and **pharmacologic effects**
RECEPTORS
120
are responsible for **selectivity of drug action**
RECEPTORS
121
**mediate** the **actions** of **pharmacologic agonists** and **antagonists**
RECEPTORS
122
# **NATURE OF DRUG RECEPTORS**
so-called because their **ligands** are p**resently unknown**, which may prove to be **useful targets** for the **development of new drugs**
ORPHAN RECEPTOR
123
# **NATURE OF DRUG RECEPTORS**
* the **best characterized receptors**;
* **modify** the **actions** of **endogenous** chemical signals (**neurotransmitters**, **autacoids**, **hormones**)
REGULATORY PROTEINS
124
# **Other proteins identified as drug receptors**
* may be **inhibited** (or less commonly activated) by **binding a drug**.
* Example: **dihydrofolate reductase** - receptor for **methotrexate**
ENZYMES
125
receptor for **methotrexate**
DIHYDROFOLATE REDUCTASE
126
# **Other proteins identified as drug receptors**
Example: **Na+**, **K+ ATPase** – receptor for **digoxin**
TRASNPORT PROTEINS
127
# **Other proteins identified as drug receptors**
Example is **Tubulin** – the receptor for **colchicine**
STRUCTURAL PROTEINS
128
recepor for **colchicine**
TUBULIN
129
# **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
130
# **Aspects of Drug-receptor Functions**
Receptors as ____ and ____ that **provide targets** for important drugs
REGULATORY PROTEINS
COMPONENTS OF CHEMICAL SIGNALING MECHANISMS
130
**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
130
# **Aspects of Drug-receptor Functions**
Receptors as **key determinants** of the ____ and ____ **effects** of drugs in patients
THERAPEUTIC
TOXIC
130
# **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
131
# **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
131
# **Five basic mechanisms of transmembrane signaling**
A ____ that crosses the membrane and **acts on an intracellular receptor**;
LIPID-SOLUBLE LIGAND
131
# **Five basic mechanisms of transmembrane signaling**
A **transmembrane receptor** that **binds** and **stimulates** a **protein** ____
TYROSINE KINASE
132
# **TYPES OF RECEPTORS**
1. **Receptor**-Operated Channel (ROC)
2. **Voltage**-Operated Channels (VOC)
TYPE 1: ION CHANNEL TYPES
132
# **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
132
# **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
132
* **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
133
# **TYPES OF RECEPTORS | TYPE 1: ION CHANNEL TYPES**
**ROC** BEHAVIOR 3 RECOGNIZED STATES:
**open**
ACTIVATED
133
# **TYPES OF RECEPTORS | TYPE 1: ION CHANNEL TYPES**
**Receptor**-Operated Channel is also known as
ligand gated ion channel
transmitter operated channel
133
# **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)
133
# **EXCITATORY**
VGIC opening
Na⁺, Ca⁺²
134
# C
ROC BEHAVIOR 3 RECOGNIZED STATES:
**Closed**, and **unable to open** in response to an appropriate stimulus for a rested state channel
INACTIVATED
134
molecular mechanism of action that involves **modulation of the transition** of the **ROC between states**
GATING
134
# **TYPES OF RECEPTORS | TYPE 1: ION CHANNEL TYPES**
VOLTAGE-OPERATED:
5 types of **Ca channels**
L T N P Q
134
# **TYPES OF RECEPTORS | TYPE 1: ION CHANNEL TYPES**
VOLTAGE-OPERATED (Na channel):
**opens** and **closes slowly** (in **10’s of millisecond**)
SLOW GATE
134
# **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
134
# **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
135
# **TYPES OF RECEPTORS | TYPE 1: ION CHANNEL TYPES**
VOLTAGE-OPERATED (Na channel):
**opens** and **closes quickly** (in **milliseconds**)
FAST GATE
135
# **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
135
# **TYPES OF RECEPTORS | TYPE 1: ION CHANNEL TYPES**
VOLTAGE-OPERATED:
**most important type** in **Ca channel**
L
136
# **TYPES OF RECEPTORS | TYPE 1: ION CHANNEL TYPES**
VOLTAGE-OPERATED:
* channels in the **CNS** and in the **peripheral**
Cl channels
136
* 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
136
# **EXCITATORY**
cell change
+
136
# **INHIBITORY**
cell change
-
136
# **EXCITATORY**
state
depolarization
136
# **EXCITATORY**
response
stimulation
contraction
137
**inhibit** hyperpolarization = **stimulants**
1) **Insulin secretagogues**
K channel blocker
137
# **INHIBITORY**
VGIC opening
K⁺, Cl⁻
137
# **INHIBITORY**
response
depression
relaxation
dilation
137
# **INHIBITORY**
state
hyperpolarization
137
# **cAMP SYSTEM**
lungs
β2
137
**stimulant** hyperpolarization = **relaxants**
* **Minoxidil** - arteriolar vasodilator
* **Diazoxide** - arteriolar vasodilator
K channel stimulants
137
# **cAMP SYSTEM**
general effect
CONTRACTION
137
# **cAMP SYSTEM**
**metabolize** cAMP
**decrease** cAMP levels
**inhibit** contraction
PDE3
137
# **TYPE 2: G-PROTEIN COUPLED RECEPTORS**
are also known
METABOTROPIC RECEPTORS
137
# **cAMP SYSTEM**
heart
β1
137
G-Protein Coupled **Effector** Systems
1. The adenylate cyclase/**cAMP** system
2. The **phospholipase C**/**Inositol phosphate** system
3. The regulation of ion channel
138
# **cAMP SYSTEM**
for stimulation
Gs
139
# **cAMP SYSTEM**
decrease cAMP
GI
140
# **cAMP SYSTEM**
responsible for **production** of cAMP
AC SYSTEM
141
# **G-Protein Coupled Effector Systems**
involves GQ
PHOSPHOLIPASE C / INOSITOL PHOSPHATE SYSTEM
142
# **PHOSPHOLIPASE C / INOSITOL PHOSPHATE SYSTEM**
**Phospholipase C** produces ____ and ____
| **secondary messengers** produced in phospholipase C
DAG & IP₃
143
# **PHOSPHOLIPASE C / INOSITOL PHOSPHATE SYSTEM**
secondary messenger that **activates protein kinase**
DAG
144
# **PHOSPHOLIPASE C / INOSITOL PHOSPHATE SYSTEM**
DAG activates ____
protein kinase
145
# **PHOSPHOLIPASE C / INOSITOL PHOSPHATE SYSTEM**
secondary messenger that **increases calcium ions**
IP3
146
# **PHOSPHOLIPASE C / INOSITOL PHOSPHATE SYSTEM**
**IP3** increases ____
calcium ions
147
# **PHOSPHOLIPASE C / INOSITOL PHOSPHATE SYSTEM**
* responsible for **contraction**
* important for the **heart**
calcium ions
148
* **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
149
* **Modulation** of the **release** of **endocrine hormones** and **neurotransmitters**
* **Smooth muscle** contraction
* **Inflammation**
* **Ion transport**
* **Tumor** promotion
PROTEIN-KINASE LINKED TRANSDUCTION
150
* **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
151
**G-protein couple receptors** can **control ion channel function** by mechanism that **do not involve**
secondary messengers
152
G-protein **interacts** ____ with the channel
directly
153
an **opioid receptor** that **open K+ channel** thus **enhance K+ permeability**
MUSCARINIC ACH
154
# **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)
155
# **SECONDARY MESSENGERS | cAMP**
the **breakdown** of **carbohydrates** in **liver** or **triglycerides** in fat cells **stimulated** by **b-adrenomimetic catecholamines**
mobilization of stored energy
156
# **SECONDARY MESSENGERS | cAMP**
* **conservation of water by the kidney** is mediated by ____
* it is an **anti-diuretic hormone** ADH
vasopressin
156
# **SECONDARY MESSENGERS | cAMP**
**Ca⁺² homeostasis** is regulated by ____
parathyroid hormone
156
# **SECONDARY MESSENGERS | cAMP**
DAG when **phosphorylated** yields ____
phosphatidic acid
156
# **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)
156
# **SECONDARY MESSENGERS | cAMP**
DAG when **deacylated** yield ____
arachidonic acid
156
# **SECONDARY MESSENGERS | cGMP**
a **blood-borne peptide** hormone
ATRIAL NATRIURETIC PEPTIDE
157
# **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)
157
# **SECONDARY MESSENGERS | cGMP**
* **enhance** production of IP3, and DAG → increase Ca = Contraction
* by **Gq**
PHOSPHOLIPASE C (PLC) SSYSTEM
157
# **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)
157
# **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
157
# **SECONDARY MESSENGERS | cGMP**
**binds to** and **activates** a **cytoplasmic guanylyl cyclase**
| vasodilation
NITRIC OXIDE
157
# **TYPE 3: KINASE-LINKED RECEPTORS**
an **intracellular protein kinase domain** that they **incorporate within their structure**
tyrosine kinase
157
# **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
157
# **TYPE 3: KINASE-LINKED RECEPTORS**
**mechanisms** that are **mainly involved** in events **controlling cell growth** and **differentiation**
transduction
158
# **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
159
# **TYPE 4: RECEPTORS THAT REGULATE GENE TRANSCRIPTION**
are also known as
NUCLEAR RECEPTORS
160
# **TYPE 4: RECEPTORS THAT REGULATE GENE TRANSCRIPTION**
**effects** are **produced** as a result of
altered protein synthesis
161
# **TYPE 4: RECEPTORS THAT REGULATE GENE TRANSCRIPTION**
onset
slow
162
163
**ion channel** in **GABA** receptor
CHLORIDE ION
164
**interaction** leads to **reduced level** causing **peripheral neuritis**
ISONIAZID & PYRIDOXAL PHOSPHATE
165
**stimulate dopa decarboxylase** leading to **nullification of L -Dopa’s action**
PYRIDOXAL PHOSPHATE
166
**inhibits** **xanthine oxidase** prevents conversion to **uric acid**
ALLOPURINOL
167
tx for **acute** gout
colchicine
168
tx for **chronic** gout
allopurinol
169
* 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
170
* **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
171
usual movement of **K⁺** when **activated**
exit
172
effect of **partial** agonist + **full** agonist
antagonism effect
173
**1** intrisic activity
full agonist
174
more than 0, less than 1 IA
partial agonist
175
less than 0 IA
inverse agonist
176
The **relative concentration** required to produce a given **magnitude of effect** is ____ and depends on **affinity** and **efficacy**
potency
177
has **high efficacy** (full activation)
full agonist
178
# **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
179
has **intermediate efficacy** (less activation)
partial agonist
180
# **Types of Drug Antagonism**
**Functional antagonism** is also known as
physiologic antagonism
181
# **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
182
# **Types of Drug Antagonism**
**Receptor** antagonism is also known as
PHARMACOLOGIC ANTAGONISM
183
# **Types of Drug Antagonism**
Neutralization, chelation
CHEMICAL ANTAGONISM
184
involves **metal**
chelation
185
antidote for **Heparin**
Protamine sulfate
186
**Fe** poisoning
Deferoxamine
187
**Cu** poisoning
Penicillamine
188
# **Classification of antagonism based on duration of action**
* **fast** **noncovalent** interaction;
* **within** 24 hours - **safer**
reversible
189
# **Classification of antagonism based on duration of action**
* **slow covalent** interaction;
* **days to weeks** - **toxic**
irreversibleq
190
# **Classification based on surmountability**
* **Surmountable**
* **Increase** the **dose** of the **agonist**
* **reversible**; **safe**
competitive
191
# **Classification based on surmountability**
* **Non** surmountable;
* **no effect** even with increasing the dose of agonist
* **irreversible**; **toxic**
noncompetitive
192
# **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
193
# **Types of Drug Interaction**
the response elicited by combined drugs is **greater than** the combined responses of the individual drugs (**1 + 1 = 3**)
SYNERGISM
194
# **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
195
# **Types of Drug Interaction**
Drug **inhibits** the **effect of another** due to **opposite pharmacological actions** (**1 + 1 = 0**)
ANTAGONISM
196
# **Special pharmacological responses**
the effect of the drug **gradually diminishes** when given **continuously** or **repeatedly**
DESENSITIZATION & TACHYPHYLAXIS
197
# **Special pharmacological responses**
* describes a **more gradual decrease** in **responsiveness** to a drug
* administration of **low doses** in **long periods**
TOLERANCE
198
# **Special pharmacological responses**
used to describe the **loss of effectiveness** of **antimicrobial** or **antitumor** drugs
DRUG RESISTANCE
199
# **Special pharmacological responses**
beneficial therapeutic response that arises from **psychological factors**
PLACEBO
200
# **POTENCY**
**Lesser** dose
greater potency
200
maximum **response**
EFFICACY
200
It is characterized by the **magnitude of resistance** increasing continuously with **greater concentration of unbound drug** at the receptor site
GRADED RESPONSE
200
**dose** required to achieve **50% of efficacy**
POTENCY
200
**more common type of graph** in graded response
sigmoidal
200
**Smallest dose** which **produces efficacy**
ceiling dose
200
# **POTENCY**
**Greater** dose
lesser potency
201
* **Degree of changes in response** with a **change in the dose** of the drug administered
* **Slanting assess safety**
slope
201
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
201
# **Kd**
Drugs with **high** binding affinity
LOW Kd
201
* 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
202
# **Kd**
Drugs with **low** binding affinity
HIGH Kd
203
* Graphically plots the **percent of the population** that **responds to a drug** versus the **drug dose**
QUANTAL DOSE RESPONSE RELATIONSHIP
204
the **observable response** can be described only in terms of an **all** or **none** event.
QUANTAL RESPONSE
205
* Indicates **potential variability** of **responsiveness** among individuals
* May be used to **generate information** regarding **margin of safety**
QUANTAL DOSE RESPONSE CURVE
206
# **QUANTAL DOSE CURVE**
the **dose** at which **50% of the individual** exhibit the **specified quantal effect**
MEDIAN EFFECTIVE DOSE (ED50)
207
# **QUANTAL DOSE CURVE**
the **dose** required to produce a **particular toxic effect** in 50% of **humans**
MEDIAN TOXIC DOSE (TD50)
208
# **QUANTAL DOSE CURVE**
the **dose** with which the **toxic effect** is **death** to 50% of the **animals**
MEDIAN LETHAL DOSE (LD50)
209
* 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
210
**Therapeutic index** is also called
MARGIN OF SAFETY
211
formula for **Therapeutic index**
LD50 or TD50 / ED50
