General Pharmacology

Outlines
Definition Sources of drugs Nomenclatures of drugs Classification of drugs Ideal ppties of drugs Routes of drug admn Basic principles
Pharmacokinetics Pharmacodynamics
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Definition

Pharmacology
The study of drugs and their interactions with living systems, The study of the physicochemical properties of drugs and their biochemical and physiologic effects, or Kdge of the history, sources and uses of drugs and their ADME.

Clinical pharmacology
The study of drugs in humans The study of drugs in patients and in healthy volunteers

 Therapeutics [Pharmacotherapeutics]
The use of drugs to diagnose, prevent, or treat disease or to alter physiology The medical use of drugs

Drug
Any chemical that can affect living processes.

General categorization of drugs

Medicinal Social Illegal

 Sources of drugs 1. Natural products

Higher plants Arthropodes Marine organisms Fermentation products of MOs
Antibiotics

2. Physiological transmitters 3. Synthetic cpds

Combinatorial chemistry

4. Existing drugs, etc

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 Nomenclature of drugs 1. Code No (code designation)

Used for a drug/chemical under investigation Given by research team Formed with the initial(s) of lab, chemist, or research team ffed by a no to represent a drug Doesnt identify the chemical nature of drug

2. Chemical name
Describes the drugs chemical structure Based on rules of nomenclature of chemistry Not suitable for routine use Long & complex- inappropriate for routine use E.g. acetyl salicylic acid, p-N-acetaminophenol

3. Proprietary (Brand) name

Trade name (mark) Patented name (15-20 yrs) The name selected & used by the manufacturer Must be approved by FDA Written with capitalization of first letter of each word of name A single drug can have multiple trade names
Create confusion Promote medication errors & miscommunication about drugs

E.g. Aspirin, Tylenol

Refers to the common name established by which a drug is known irrespective of manufacturer Chosen & given by official agencies- USANC, FDA, WHO, INN, Each drug has only one generic name E.g. aspirin, paracetamol
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4. Non-proprietary (Generic) name

 E.g., The three types of drug names

Type of Drug Name

Chemical Trade (proprietary) Generic

Name Examples
N-acetyl-para-aminophenol
Tylenol Acetaminophen

 Drug names are used for two purposes, especially generic ones: 1. For written and oral communication about medicines
For accurate communication

2. For labeling medication containers

Avoids double medication Promotion of safe and effective drug use

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Classification of drugs Pharmacological effect

Analgesics Antipsychotics Antihypertensives Antibiotics Anticancer Antiasthmatics Sedative Anticonvulsants Some have multiple effects
Barbiturates Opiates Pencillins Steroids All cpds of a certain chemical group have the same biological action Antihistamines Cholinergics Usually NT involved Enzymes Receptors DNA More specific classification of drugs
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2.

Chemical structure

3.

Target system

4.

Site of action

Properties of an ideal(good) drug

1. 2. 3. 4. 5. 6.
7. 8. 9. 10.

Effectiveness Safety Selectivity Reversible action Predictability Ease of admn- convenience, adherence & decrease admn errors Freedom from drug interactions Low cost Chemical stability Possession of a simple generic name
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In reality, there's no such thing as a perfect drug

 Because No Drug Is Ideal

Available medications are not ideal. No drug is safe. All drugs produce side effects. Drug responses may be difficult to predict and may be altered by drug interactions. Drugs may be expensive, unstable, and hard to administer. Because medications are not ideal, all members of the healthcare team must exercise care to promote therapeutic effects and minimize drug-induced harm.

Medicines can act as poisons

Poisons can act as medicines

The objective of drug therapy is to provide maximum benefit with minimum harm

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Routes of Drug Administrations

Affects the bioavailability of the drug Affect the onset and duration of the pharmacologic effect Most commonly two major groups
Enteral (via the GIT) Parenteral (outside the GIT)

A. Enteral routes
1. 2. 3. 4. Oral/PO Buccal Sublingual Rectal
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A. Enteral routes

1. Per Os (PO) Two barriers to cross:

The layer of epithelial cells that lines the GIT The capillary wall

P-glycoprotein Transcellular rather than paracellular transport Highly variable absorption

Factors that can influence absorption include 1. Solubility and stability of the drug 2. Gastric and intestinal pH 3. Gastric emptying time 4. Food in the gut 5. Co-administration of other drugs 6. Special coatings on the drug preparation

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 Advantages

Common Easy Convenient Inexpensive Reversible (Safe) Ideal for self-medication

Slow & variability Inactivation First pass effect Patient requirements
Conscious, cooperative patient
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Disadvantages

Local irritation

2. Sublingual routes
Oral mucosal delivery Under tongue E.g- sublingual tablets-nitroglycerin, isopreternol, erythrityl tetranitrate, isosorbide dinitrate Require sweetening agent Rapidly dissolved Potent Faster absorption than PO and skin Shorter duration of action

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3. Buccal route
B/n cheek and gum The drug released rapidly/slowly Sorbitrate sublingual tablet Sorbitrate chewable tablet Sorbitrate oral tablet For angina pectoris Devoid of first pass effect & gastric destruction

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4. Rectal admn
As solid or liquid dosage forms For local or systemic drug delivery For drugs not tolerated orally- children & elders Suppository Aspirin, paracetamol, theophylline, barbiturates

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B. Parenteral Routes 1. Intravenous, IV No barriers to absorption

Both instantaneous and complete absorption

Advantages
Most rapid onset- for emergencies Precise drug level control in blood Use of large fluid volumes Use of irritant drugs

Disadvantages
Expensive Difficulty Inconvenience Irreversibility Inject slowly[1 min]- to minimize risk & CNS toxicity
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 Fluid overload Risk of infection Risk of Embolism [blood vessel blockade]

Damage of venous wall by needle/clot Destruction of RBCs by hypo/hypertonic fluids-debris Particles of undissolved drugs

Drug must be water soluble

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2. Intramuscular, IM
Barriers to absorption
Capillary wall Large spaces between the cells No significant barrier to absorption

Absorption pattern
The rate of absorption is determined by two factors: 1. Water solubility of the drug
Rapid with water-soluble drugs Slow with poorly soluble drugs

2. Blood flow to the site of injection

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 Site of injection
1. 2. 3. 4. Dorsogluteal Ventrogluteal Anterolateral thigh-area Deltoidarea

Advantages
Permits use of poorly soluble drugs Permits use of depot preparations

Disadvantages
Possible discomfort Inconvenient Painful Potential for injury
Local tissue injury Nerve damage

Risk of bleeding
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3. Subcutaneous, SQ
The pharmacokinetics of SQ administration are nearly identical to those of IM administration These routes have similar absorption patterns, advantages and similar drawbacks to IM.

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4. Intravaginal
For mostly local delivery E.g. Antifungal agents

5. Intranasal
For local and systemic effects As an alternative to injection Must be nonirritant and well tolerated e.g. Nasal vasoconstrictors

6. Inhalation
Bronchodilators Corticosteroids As aerosols and inhalation solutions
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7. Optic
Mainly for local effects Sterile aqueous solutions Barrier for absorption is cornea

8. Otic

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9. Topical
For local or systemic action For systemic delivery- percutaneous or transdermal Barrier of absorption- superficial layer of epidermis, stratum corneum

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Parenteral vs enteral Because of ease, convenience, and relative safety, oral administration is generally preferred to parenteral administration. However, there are situations in which parenteral administration may be superior. These are
Emergencies that require rapid onset of drug action. Situations in which plasma drug levels must be tightly controlled. Treatment with drugs that would be destroyed by gastric acidity, digestive enzymes, or hepatic enzymes if given orally Treatment with drugs that would cause severe local injury if administered by mouth
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 Treating a systemic disorder with drugs that cannot cross membranes Treating conditions for which the prolonged effects of a depot preparation might be desirable. Treating patients who cannot or will not take drugs orally.

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A. Pharmacokinetics (PK) From two Greek words

Pharmakon (drug or poison) Kinesis (motion)

The study of drug movement throughout the body Four basic PK processes: absorption, distribution, metabolism, and excretion
All acting in concert, determine the concentration of a drug at its sites of action

The impact of the body on drug Examines the movement of a drug over time through the body
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 Fig. The four basic pharmacokinetic processes

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 The intensity of the response to a drug is directly related to the conc of the drug at its site of action
To maximize beneficial effects- achieve enough high conc to elicit desired responses To minimize harm- avoid conc that are too high Achieved by selecting the most appropriate route, dosage, and dosing schedule

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 Fig. Factors that determine the intensity of drug responses.

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a) Drug absorption
The process by which a drug moves from the site of administration to the blood. Requires passage across biological membranes The rate & extent of absorption determines the onset & intensity of drug action, respectively. Drug absorption can occur by the ffing processes: 1. Passive diffusion
Simple diffusion Facilitated diffusion Filtration

2. Active transport 3. Endocytosis

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 Passive diffusion
Most common means of drug absorption Rate of passive diffusion across biological membranes is dependent upon: 1. Conc. difference across membrane 2. Size (100-500) 3. Polarity 4. Ionization
Variable for drug Dependent upon envtal pH 1. Stomach: 1-3 2. Duodenum: 5-7 3. Rest of small intestine: 7-8
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 Effect of pH on absorption of acidic drugs

1. In a low pH (acid) envt (e.g. stomach) [H+] is high HA H+ + A [HA] increases Drug absorption increases 2. In a high pH (basic) envt (e.g. small intestine) [H+] is low HA H+ + A [A-] increases Drug absorption decreases
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 Effect of pH on absorption of basic drugs

1. In a low pH (acid) envt (e.g. stomach) [H+] is high H+ + B HB+ [BH+] increases Drug absorption decreases 2. In a high pH (basic) envt (e.g. small intestine) [H+] is low H+ + B HB+ [B] increases Drug absorption increases
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 Passive drug absorption in the small intestine

The vast majority of drug absorption occurs in the small intestine Particularly in duodenum where conc gradient is highest Applies to acidic and basic drugs Contributing factors
Extremely large surface area Extremely high perfusion

Active transport
Not common to drugs Require energy expenditure & specific transport proteins Saturable Effectively transport highly polar cpds Transport against a conc gradient
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 Factors affecting drug absorption I. Biological (intrinsic) factors

1. 2. 3. 4. 5. 6. Local pH of the gut Presence of food and other drugs in gut Surface area of the gut Motility of the gut Local circulation (blood flow) of the gut First pass metabolism

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II. Pharmaceutical factors

Physical state Particle size of drug Disintegration time Dissolution time
The amount of administered drug that reaches the systemic circulation following administration by any route IV= 100% Oral 100% Other routes 100% Must be factored in dose calculation 38

Bioavailability

 Major factors affecting drug bioavailability

1. First-pass metabolism 2. Efflux from enterocytes 3. Physicochemical properties of drug that affects absorption 4. Nature of drug formulation

IV administration circumvents these factors.

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Ion Trapping (pH Partitioning) Because the ionization of drugs is pH dependent, when the pH of the fluid on one side of a membrane differs from the pH of the fluid on the other side, drug molecules will tend to accumulate on the side where the pH most favors their ionization. Accordingly, since acidic drugs tend to ionize in basic media, and since basic drugs tend to ionize in acidic media, when there is a pH gradient between two sides of a membrane,
Acidic drugs will accumulate on the alkaline side. Basic drugs will accumulate on the acidic side.

The process whereby a drug accumulates on the side of a membrane where the pH most favors its ionization is referred to as ion trapping or pH partitionig
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Fig. Ion trapping of drugs.

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b) Drug distribution The process of reversible transfer of a drug to and

from the site of measurement (blood or plasma) & tissues It is a passive process
Conc gradient b/n plasma & tissue

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 It determines conc of drug at its site of action

Pharmacological action of a drug The onset, intensity, and duration of action.

Drugs transverse capillary membranes by

Hydrostatic pressure Passive diffusion

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 Factors affecting drug distribution: 1. Tissue permeability of the drug

Physiochemical properties of the drug
o o o Molecular size Ionization Lipophilicity

Physiological barriers to diffusion of drugs[capillary permeability]

o o o BBB BPB BTB

2. Blood flow 3. Binding of drugs to blood & tissue components

Plasma proteins[albumin, glycoprotein, globulin, LP]
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4. Miscellaneous factors
Age Pregnancy Obesity Diet Disease states Drug interactions, etc

Blood flow to tissues Drugs are carried by the blood to the tissues and organs of the body. Determines the rate of drug distribution Two pathologic conditions-abscesses & tumorslow regional blood flow can affect drug therapy.
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 Capillary permeability Drugs in the vascular system leave the blood at capillary beds. a) Typical Capillary Beds
Most capillary beds offer no resistance to the departure of drugs b/c of large gap junctions Fig. Drug movement at typical capillary beds

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b) The Blood-Brain Barrier & P-glycoprotein

The unique anatomy of capillaries in the CNS Tight junctions b/n the cells that compose the walls of most capillaries in the CNS. These junctions are so tight that they prevent drug passage. Fig. Drug movement across the blood-brain barrier

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c) Placental Drug Transfer

The membranes of the placenta separate the maternal circulation from the fetal circulation The membranes of the placenta do NOT constitute an absolute barrier to the passage of drugs. Factors that may influence placental drug transfer 1. Placental blood flow 2. Molecular size of drug 3. Lipid solubility of drug 4. pKa of drug

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d) Blood -Testis Barrier It has tight junctions b/n the neighboring cells of sertoli which restricts the passage of drugs to spermatocytes and spermatids.

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 Special considerations
Consequence of physicochemical properties of drug and unique physiological properties of organ/tissue: 1. Bones/teeth- TTC 2. Thyroid- iodine containing drugs 3. Brain- BBB excludes most drugs 4. Adipose tissue- accumulate large amounts of lipid soluble drugs 5. Placental transfer of drugs- can cause congenital anomalies (malformation of fetus) by crossing the placental barrier by simple diffusion

Volume of distribution
Measures the extent of drug distribution
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Protein Binding of Drugs

Drugs can form reversible bonds with various proteins in the body.

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Consequences of protein binding (protein bound drug): 1. It is pharmacologically inactive 2. It restricts its disposition 3. It can be a source of drug interaction
90% protein bound drug Low therapeutic index drugs Steeper dose-response curve

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c) Drug metabolism (biotransformation)

The irreversible enzymatic modification of drug structure in the body Reduces their lipid solubility & biological activity Making them progressively more water soluble and favours renal elimination

Sites of Drug Metabolism Major organ is liver

By the hepatic microsomal enzyme system or cytochrome P450 A group of 12 closely related enzyme families. 3 (CYP1, CYP2, and CYP3)- metabolize drugs Each has subfamily & specific groups The other metabolize endogenous compounds

Others
Intestines, plasma, kidneys, nasal mucosa, skin, placenta and lungs 54

 Objective
To make lipid soluble, un-ionized and less polar drugs more water soluble, ionized and more polar

It involves
1. Conversion of inactive drug into active drug 2. Conversion of active drug/agent into active metabolites 3. Conversion of active drug or active metabolite into inactive metabolite

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Phases of Drug Metabolism

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Metabolism to enhance excretion

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 Two phases of drug metabolism 1. Phase I

Functionalization rxns Non-synthetic rxns Preparatory rxns Involve unmasking or introduction of a small reactive polar FGs[-OH, -COOH, -SH, -O- or NH2] on the parent drug molecule Serve as substrates for phase II rxn Occur in ER (microsomes) of liver cells. The most important rxns- oxidation, reduction and hydrolysis Carried out by CYPs, FMOs, & EHs
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2. Phase II
Conjugation rxns Synthetic Rxns Covalently add large, polar endogenous molecules to parent drug or phase I metabolite Inactive and excretable (glucuronide, glutathione, sulfate, acetate, amino acids etc) Involves high energy intermediates & specific transfer enzyme Glucuronidation, sulfation, glutathione conjugation, Nacetylation, methylation. All these rxns occur in cytoplasm except GU.
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Factors affecting drug metabolism

1. Age
At extreme ages- Neonates & elderly Women metabolize certain drugs more slowly than men Alcohol use Smoking

2. Sex 3. Social habits

4. Concomitant drug use, DDI

Certain drugs as enzyme inducers Other drugs as enzyme inhibitors
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5. Food
Grapefruit juice- furano-coumarins Vegetables- cabbage Charcoal broiled meats

6. Genetic variation (polymorphism)

N-acetyltransferases Pseudocholinesterase Drug metabolizing enzyme d/ce both qt &/or ql

7. Pathological factors
Liver Ds Heart failure

8. Nutritional status & envtal factors

Cofactors derived from food
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d) Drug Excretion The irreversible removal of drugs from the body.

Primarily via kidney and bile

Routes of Drug Excretion 1. Renal Drug Excretion It is the net effect of three distinct mzms within the kidneys: 1. Passive glomerular filtration 2. Active tubular secretion and 3. Passive tubular reabsorption
Functional unit of the kidney is nephron Nonvolatile, water soluble, low MW, or slowly biotransformed drugs are excreted via kidney.
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Factors altering renal drug excretion Renal drug clearance is lower [reduce dose] in: 1. Age-at extreme ages 2. Disease-Kidney and heart disease 3. Competition for active tubular transport 4. pH-dependent ionization- to manipulate poison & medication overdose

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2. Non-renal routes of drug excretion 1. Fecal excretion

1. Biliary excretion- large, ionized molecules/conjugates/ 2. Direct intestinal excretion- non-oral absorbable drugs

 Enterohepatic recirculation
A cpd is conjugated in the liver, excreted in the bile, deconjugated in the intestine and is reabsorbed into the circulation. This phenomenon prolongs the duration of action of a drug Therapeutic significance 1. Bile acids are conjugated in the liver to taurine and gycine and excreted in the intestine where they are deconjugated 95% of bile salts are reabsorbed and are used in cholesterol synthesis If we give bile acid binding resin, we interrupt the enterohepatic recycling of bile acids and reduce cholesterol synthesis. 2. Oral contraceptive failure when an antibiotic is taken 67 Rifampin-reduce OC effectiveness

2. Pulmonary excretion
For gaseous & volatile liquids In exhaled air Rate of loss determined by:
1. 2. 3. Rate of respiration Pulmonary blood flow Solubility of the agent in blood

3. Salivary excretion
Dependent on pH partition and protein binding

4. Breast/mammary/ milk
Dependent on Lipophilicity, protein binding, degree of ionization, Secretion of basic and lipid-soluble compounds

5. Skin excretion 6. Others- hairs, nails, tears, etc

Plasma Drug Levels

In most cases, the time course of drug action bears a direct relationship to the concentration of a drug in the blood. For most drugs, there is a direct correlation between therapeutic and toxic responses and the amount of drug present in plasma

Fig. Single-dose time course

Fig. Drug accumulation with repeated administration.

Two plasma drug levels are of special importance:

1. The minimum effective concentration, MEC 2. The toxic concentration, MTC

Therapeutic range (window)

A range of plasma drug levels falling b/n MEC & MTC. The objective of drug dosing is to maintain plasma drug levels within the therapeutic range. Wide/narrow TR safety

B. Pharmacodynamics
The study of the biochemical and physiologic effects of drugs and the molecular mechanisms by which those effects are produced. The study of what drugs do to the body and how they do it. What the drug does to the body.

Why be concerned about how drugs work? 1. Aids evaluation of medical literature 2. Aids in pt-therapist r/ship 3. Peace of mind 4. Aids in understandings of drug interactions adverse effects and contraindications.
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How do drugs act/ work 1. A few drugs act by simple mzms

Related to their physicochemical ppties E.g., chelators, antacids, mannitol, adsorbents, etc Called receptorless drugs drugs

2. Most drugs act by binding to cells

To produce a biological response drug molecules must exert some chemical influence on one or more constituents of the cell Drug molecules must get very close to constituent cellular molecules for their function to be altered.

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 What are these binding sites?

1. Mainly proteins 2. Nucleic acids- DNA 3. Lipids

Protein targets for drug binding

1. Enzymes
By acting as substrate analogues Competitively inhibits enzyme by reversibly or irreversibly

2. Ion channels [voltage gated & ligand gated] 3. Carrier molecules 4. Receptors
Recognition sites for drugs

5. Structural proteins

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Signal transduction pathways Drug-receptor interactions

Produces a response The events involved in this response are called signal transduction Common responses in the body: 1. Transient increase in intracellular free calcium levelsmuscle contraction 2. Activation of enzymes for various biochemical reactions 3. Neurotransmission 4. Secretion of neurotransmitters and hormones

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 The general equation for the interaction between drugs and their receptors: D+ R D - R ComplexResponse
A reversible binding A receptor has two configurations
ON & OFF

A receptor must be in the ON configuration (activated state) to influence cellular function.

Functions of receptors
1. Determine the quantitative r/ship b/n drug dose & pharmacologic effect 2. Responsible for the selectivity of drug action 3. Mediate the actions of both pharmacologic agonists and antagonists
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 Fig. Interaction of drugs with receptors for norepinephrine

Drugs, which can either:

Mimic the actions of endogenous NE ( COP) or Block the actions of endogenous NE ( COP).

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 Receptor families
The body has many different receptors 4 fundamental mzms or types: 1. Cell membraneembedded enzymes 2. Ligand-gated ion channels 3. G proteincoupled receptor systems 4. Nuclear receptors

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 Receptors and Selectivity of Drug Action The more selective a drug is, the fewer side effects it will produce Selective (limited) drug effect
One receptor subtype with one physiological functions

Widespread (varied) drug effect

One receptor subtype regulates several physiological functions Different receptor subtypes

To bind with its receptor, a drug must have a appropriate shape, size, charge & physical ppties.
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Theories of Drug-Receptor Interaction Two theories of drug-receptor interaction: 1. Simple Occupancy Theory
The intensity of the response to a drug is proportional to the number of receptors occupied by that drug A maximal response will occur when all available receptors have been occupied

Shortcoming
Not explain Potency Efficacy

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2. Modified Occupancy Theory Ascribes two qualities to drugs: 1. Affinity

The strength of the attraction b/n a drug and its receptor. Reflects drug potency Drugs with high affinity are very potent

2. Intrinsic activity
The ability of a drug to activate a receptor upon binding Reflects drug maximal efficacy Two drugs can occupy the same number of receptors but produce effects of different intensity; the drug with greater intrinsic activity will produce the more intense response.
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Dose-Response Relationships The relationship between the size of an administered dose and the intensity of the response produced It determines:
1. The minimum amount of drug we can use 2. The maximum response a drug can elicit, 3. How much we need to increase the dosage in order to produce the desired increase in response

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 Fig. Basic components of the dose-response curve

DRR has three phases: Phase 1 occurs at low doses

Flat curve b/c too low dose to elicit a measurable response

Phase 2 increase dose elicits increase in response

Graded response produced

Phase 3 at higher dose, unable to elicit a further increase in response

Flat curve
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 Two types of responses 1. Graded (individual) responses

As the dosage increases, the response becomes progressively larger Responses are often described as a percentage of maximal response Therapeutic effects can be adjusted to fit the needs of each patient Adjust the dosage until the desired response is achieved Essential for successful drug therapy

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1. Quantal/All-or-none/ responses
Drugs produce only one intensity of response No adjustment means to better or suit response to the pt For too strong or too weak response E.g., analgesia for headache, digitalis to stop heart, sleep or lethal dose for anesthesia. Responses are represented as cumulative percentage of subjects exhibiting a defined effect Can be defined for both toxic and therapeutic effects This allows the calculation of therapeutic index The Therapeutic Index A measure of a drug's safety. Determined using laboratory animals The ratio of a drug's LD50 to its ED50
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Relatively safe drug

Not very safe drug

 Two important terms of dose-response curve:

Efficacy Potency

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 Potency The amount of drug we must give to elicit an effect An index of how much drug must be administered to elicit a desired response Usually not an important quality in a drug Indicated by the relative position of the dose-response curve along the x (dose) axis A potent drug is one that produces its effects at low doses The potency of a drug implies nothing about its maximal efficacy Efficacy The largest effect that a drug can produce. Indicated by the height (plateau) of the dose-response curve An index of the maximal response a drug can produce An important quality in a drug
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Agonists, Antagonists, and Partial Agonists Full agonists

Drugs that mimic the body's own regulatory molecules Produce maximal response Have both affinity & high intrinsic activity

Partial agonists
Mimic the actions of endogenous regulatory molecules Produce lower/submaximal/intermediate/ responses Have affinity but only moderate intrinsic activity

Antagonists
Drugs that block the actions of endogenous & exogenous agonists No response 88 Have affinity but with no intrinsic activity

 Types of antagonism 1. Chemical

Interaction of two drugs in solution such that the effect of active drug is lost E.g. metal chelators and toxic metals

2. Physiological
Interaction of two drugs with opposing physiological actions Histamine vs. epinephrine on BP

3. Pharmacological
Blockage of the action of a drug-receptor interaction by another cpd Bind to receptors but do not activate signal transduction mzms Cimetidine vs. histamine 89

 Two major types of pharmacological antagonists: 1. Competitive antagonists

Reversible binding Reduce potency Surmountable Commonly used therapeutically Irreversible binding Reduce maximal response Insurmountable Rarely used clinically Effect is subside in a few days
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2. Noncompetitive antagonists

 Fig. Dose-response curves in the presence of competitive and noncompetitive antagonists

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THANK YOU

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