Basic Pharmacology.

Basic Pharmacology

What is a drug? What is pharmacology ? any chemical agent which
effects any biological process What is pharmacology ? the study of how drugs effect biological systems

Lange Katzung

Pharmacology - Study of substances that interact with living systems through chemical processes

Pharmacology - Especially by binding to regulatory molecules and activating (turning on) or inhibiting (turning off) normal body processes

Pharmacology - Pharmcology is NOT the memorizing of long lists of medications or drug companies’ latest products

Pharmacology This course intends to teach you about how medications are used to treat and prevent illness It also reveals the complexity of living regulatory systems

Medical Pharmacology - Medical Pharmacology is the science of substances used to prevent, diagnose and treat diseases.

Toxicology - Toxicology is the branch of pharmacology that studies the harmful effects of chemicals on living systems

Drug - A drug is ANY substance that interacts with a molecule or protein that plays a regulatory role in living systems

What is 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.

What is a drug? - may be defined as any substances that brings about a change in biologic function through its chemical actions

The drug molecule interacts as an agonist (activator) or antagonist (inhibitor) with a specific molecule in the biologic system that plays a regulatory role. This target molecule is called a receptor.

Drug (D) + receptor-effector (R) = drug-receptor-effector complex – effect
D + R = drug-receptor complex = effector molecule = effect D + R = drug-receptor complex – activation of coupling molecule = effector molecule = effect Inhibition of metabolism of endogenous activator = increased activator action on an effector molecule = increased effect

Drug affinity – the tendency of two substances to form strong or weak chemical bonds forming molecules or complexes

A. Physical Nature of Drugs
Solid drugs -> oral route aspirin or atropine Liquid drugs -> oral route, IM, SC nicotine or ethanol Gaseous drugs -> inhalation nitrous oxide, halothane, amylnitrite Many drugs are weak acids or bases pH differences in the body may alter the degree of ionization of drug

Pharmacokinetics Pharmacodynamics Pharmacotherapeutics Pharmacocognosy
What is Pharmacology ? Pharmacokinetics Pharmacodynamics What the body does to drug What the drug does to body Pharmacology Pharmacotherapeutics Pharmacocognosy The study of the use of drugs Identifying crude materials as drugs Toxicology

Pharmacokinetics What the body does to the drug - Absorption
- Distribution - Metabolism (Biotransformation) - Excretion Half-life (t1/2) - the time required for the plasma concentration of a drug to be reduced by 50 %

Pharmacodynamics What the drug does to the body - Drug receptors
- Effects of drug - Responses to drugs - Toxicity and adverse effects of drugs

Sources of Drugs Pharmacocognosy
Animals Plants Minerals Synthetic Microbes

Many of these old sources are still in use today
Foxglove plant Meadow flower Colchicum autumnale Beef or pork pancreas Digitalis comes from the foxglove plant and is used in the treatment of CHF Colchicine is the drug of choice for treatment of gout Insulin is used today to treat diabetes and is derived from the pancreas of beef or pork or may be synthetically produced as well.

Drugs Derived from Plants
Ephedrine is present in the leaves of a bushy shrub (species name Ephedra), which, when burned were used by the ancient Chinese to treat respiratory ailments. Today, it is a bronchodilator. Many estrogen hormone replacement therapy drugs are derived from yams. The belladonna plant – source of atropine, which is still used to dilate the pupils.

Endogenous Exogenous Hormones Xenobiotics Toxins Receptor

Agonist Competitive antagonist Noncompetitive antagonist Chemical antagonist Physiologic antagonist – any drug or chemical that has an opposite effect but through completely different physiologic pathways Specificity – whether agonist or antagonist, drugs must be a specific size and shape to interact with a given receptor

Agonist – is any drug that binds to a receptor and activates the receptor
Competitive antagonist – is any pharmacologic antagonist that “competes” with the binding of agonist at the binding site Noncompetitive antagonist – is any pharmacologic antagonist that binds to a site on the receptor other than the agonist binding site Chemical antagonist – any drug that binds directly to an agonist and deactivates the agonist

Histamine and Epinephrine
Anaphylaxis is a severe systemic allergy reaction. Excess histamine released by the body is part of the problem. Epinephrine is given to counteract the effects of histamine

Drug-Receptor Interactions
Agonists activates or enhances cellular activity. triggers a series of biochemical events alteration in function second messengers: biochemicals that initiate these changes Antagonists do not initiate a change in cellular function. prevent the binding and the action of agonists “blockers”

Drug-Receptor Interactions
Factors Governing Drug Action 1. Affinity: measure of the tightness that a drug binds to the receptor 2. Intrinsic activity: measure of the ability of a drug to generate an effect, producing a change in cellular activity

Binding of a drug drug must interact with complementary surfaces on the receptor.

Antagonist exhibit affinity for the receptor
do not have intrinsic activity at the receptor competitive antagonist: binds to the receptor in a reversible mass-action manner -agonists given in high concentrations  can displace the antagonist from the receptor -agonist can then produce its effect

Drugs must have specificity
- Whether agonist or antagonist, drugs must be of a specific size, charge, and shape to interact with a given receptor

Drugs must be absorbed - A drug must be able to be absorbed by the body. A drug must have delivery - a drug must be able to be delivered to site of action

Drugs must have elimination
drugs must be eliminated at a reasonable rate

Most drugs are weak acids or bases
Weak vs strong NaCl example pH pKa – is the pH at which the molecule or drug is completely balanced between the uncharged (lipid soluble) and the charged (water soluble) form

Stronger means more complete dissociation not how much it burns
NaCl Na+ Cl- NaCl is not a strong acid or a strong base this is just a concept for explanation

HCl H+ Cl- NaOH Na+ OH-

Neutralize H+ plus OH- results in H2O Adding base to acid neutralizes them

Weak means incomplete dissociation in water
Weak acid like aspirin = C8H7O2COOH = white powder If you placed it in water (H2O) R-COOH R-COO-H+ (uncharged aspirin) (ionic aspirin) (lipophilic/fat soluble) (hydrophilic/water soluble)

Saturated Instead of dissolving… Mass Action pushes the equation to the left NaCl Na+ Cl- In Mass Action:

pH pH is a measure of acidity (<7) pH is a measure of alkalinty (>7)

Acidity pH < 7 Acidity means the solution has excess H+ This “mass action” of H+ can push the equation toward the protonated form of the drug

If you placed it in acid R-COOH R-COO-H+ (uncharged aspirin) (ionic aspirin) (lipophilic/fat soluble) (hydrophilic/water-soluble) Because of mass action (too much H+) Shifts to the fat-soluble part of the drug

Alkalinity pH >7 Alkalinity means the solution is able to remove any H+ from the solution This “mass action” of H+ can pull the equation toward the unprotonated form of the drug

If you placed it in a basic solution
R-COOH R-COO- (uncharged aspirin) (ionic aspirin) (lipophilic/fat soluble) (hydrophilic/water-soluble) Basic solution has OH-

Most drugs are weak acids or weak bases because only small changes in pH are required to shift between: Lipid soluble (easily passes cell membranes) Water soluble (does not pass without transport)

In cases of Tricyclic Antidepressant overdose, we “alkalinize” the blood with sodium bicarbonate to change the drugs effect on the body

DRUG CLASSIFICATION - Based on the main effect (e.g. analgesics).
Based on the chemical structure - Based on the main effect (e.g. analgesics). - Based on the therapeutic use (e.g. antipsychotic). Based on mechanism of action (e.g. serotonin agonist).

Henderson Hasselbach equation:
Log [RH]/[R] = pKa-pH Protonated over the unpronated form

Physiologic pH – 7.35 - slightly alkaline

Drugs interact with receptors by means of chemical forces or bonds – covalent, electrostatic, lipophilic, Van der Waals – sub-atomic forces

Ex. Aspirin, covently bonding to platelets
Covalent – very strong, usually not reversible Ex. Aspirin, covently bonding to platelets

Ionic groups (+ and – attract)
Electrostatic – pretty strong Ionic groups (+ and – attract) Hydrogen bonds – H attracted to Oxygen or Nitrogen

Lipophilic – fat-loving - weak bonds
Hydrophobic – water-hating, Lipophilic – fat-loving - weak bonds

Affinity – how tightly the receptor binds to the drug

Pharmacodynamics - Propanolol is a beta adrenergic antagonist – meaning lowering blood pressure and heart rate by antagonizing beta receptors preventing the agonist from activating it

Pharmacokinetics Propanolol is metabolized and eliminated by the liver and kidneys

The terms pharmacodynamics and pharmacokinetics are commonly used interchangeably among medical personnel

Drug Receptors – are responsible for selectivity of drug action
Locks are responsible for what the key does

Drug Receptors – are responsible for selectivity of drug action
Locks are responsible what the key does

Drug Receptor – is a specific molecule, usually a protein, that interacts with a specific chemical that then causes a change in the specific molecule, causing a change in the regulatory function

Natural Curves – the interaction between a drug or ligand and its receptor can be described by a curve

- because drugs effect natural regulatory processes, their effect follows a natural curve

Concentration and Response
Response usually increases in response to dose As dose increases, response increment diminishes At some dose there is no further increase in response

Logarithm – instead of the axis being linear we can make them logarithmic

Potency vs Efficacy

Efficacy – refers to the effect of a drug
Efficacy – refers to the effect of a drug. The more effect, the more efficacious the drug

Potency – refers to the concentration of a drug needed for the effect
Potency – refers to the concentration of a drug needed for the effect. The less the concentration required, the more potent the drug.

Potency and Efficacy - are used interchangeably by medical personnel

Quantal Dose Effect Curves
- implies a binary or on/off response to a drug -either the effect is achieved or not Like a drug used to stop seizure Either no effect (zero effect) Or seizure stopped (max effect)

like a drug used to stop ventricular fibrillation (VF or Vfib) – heart attack
Either no effect (zero effect) Or Vfib stopped (max effect)

Pharmacology – is NOT the memorizing of long lists of medications or drug companies’ latest products
- This course should let you know the beauty and complexity of creation and some life lessons

EC 50 – concentration of drug required to achieve half of the maximum expected response

ED 50 – dose of drug required to achieve half of the expected response

TD 50 – dose of the drug required to achieve toxicity in half of the subjects given the drug

LD 50 – dose of the drug required to be lethal to half of the subjects given the drug

Bioavailability – describes the concentration of drug in systemic blood in relation to the amount of drug given

How the drug is administered effects bioavailability

Tissue bioavailability – describes the concentration of drug in target tissue in relation to the amount of drug given

PO – by mouth Blood from the GI tract goes directly to the liver first The liver metabolizes many drugs before they enter the systemic blood supply This takes time

PO Bioavailability of PO medications is rarely 100% Bioavailability of PO medication range from 10% to 50% usually

IV – intravenous Drug goes directly into the bloodstream Bioavailability is 100%

Many medications can either be given PO or IV
Is the IV dose always going to equal PO dose?

IM – intramuscular Into muscle To out of muscle depot to blood

SC – subcutaneously Under skin Out of subcutaneous fat depot to blood

PR – by rectum - To liver via GIT blood

Inhalation – directly to lungs
- Then to bloodstream

Transdermal – applied to skin, crosses skin to systemic blood supply
- e.g. nicotine patch

Topical – applied to skin, action intended locally at the site of administration

Intranasal – into and across nasal mucosa
To bloodstream To base of brain (pituitary)

Intrathecal – into the cerebrospinal fluid
Foramen magnum – hole skull/spine To brain via CSF

Epidural – outside of the spinal dura – hard layer of the spinal cord
- Anesthesia

Intraarticular – into the joint space
- Steroid injection into knee

Prodrug – many drugs are administered into their INACTIVE forms
- When drugs make their first pass through the liver, they are converted into their active forms

Protonsil – the first sulfonamide antibiotic, had excellent antibacterial properties when administered to humans (in vivo). Had no antibacterial properties when placed in the petri dish or test tube with bacteria (in vitro).

Permeation – penetration of drug into the tissue

Mechanisms of Permeation
Aqueous diffusion Lipid diffusion Special carriers for molecules large enough for aqueous or lipid diffusion Endocytosis and exocytosis

Transformation – chemical changing of the drug by the body
Liver transformation Peripheral transformation GI transformation

Phase I reactions Oxidation Phase I involves conversion to water soluble metabolite CYP Cytochrome P450

Phase II reaction Conjugation If not polar enough they will undergo Phase II reaction which they are conjugated to highly polar groups

Phase II reaction Conjugation - In reality many substances can undergo either transformation in any order

Elimination – removal of drug from the body

Renal and Hepatic Elimination
Urination – elimination by kidney Defecation – hepatic elimination via bile - Most drugs require both

Volume of Distribution – amount of drug in body relative to concentration of drug in blood

Small volume of distribution – if a drug is given and the drug stays exclusively in the bloodstream, the drug will have a small volume of distribution

Large volume of distribution – if a drug is given and the drug is distributed to the entire body, the drug will have a large volume of distribution

Clearance – rate of elimination in relation to the drug concentration
CL = Rate of elimination/concentration

Drug Accumulation – whenever drug doses are repeated, the drug will accumulate until dosing stops
If the dosing interval is shorter than 4 half-lives accumulation will occur We consider 5 half-lives as complete elimination of the drug

if a drug has a half-life of 1 hour, and we give the drug on the 6th hour, drug accumulation will not occur

Loading Dose – Vd x TC

Maintenance Dose Dosing Rate = Clearance x Target Concentration

First Pass Effect All drugs absorbed by GI tract enter the portal blood supply and go directly The liver metabolizes many drugs before they enter the systemic blood supply

- Chemical name - *Generic name - Trade name
Drug Nomenclature - Chemical name - *Generic name - Trade name Chemical Name: 2-(4-isobutylphenyl)-propionic acid Generic Name: ibuprofen Trade Names: Advil, Aches-N-Pain, Brufen, Emodin, Haltran, Medipren, Midol 200, Motrin, Nuprin, Rufen, Trendar, Wal-Profen *preclinical nomenclature = company abbrev (e.g. WAY , MK-869)

Routes of Administration
Critical to efficacy Rapidity of onset Duration of effects Magnitude of effects Systemic administration Drug into circulatory system via ... Enteral routes Parenteral routes Drug effects throughout body ~

Routes of Drug Administration
Enteral within or by way of the GI tract Oral (PO), rectal, sublingual Parenteral Not within the alimentary canal Inhalation, IM, SC, IP, topical Central Into the brain or spinal cord Intrathecal, ICV

Routes of Drug Administration common abbreviations…
PO = per os = oral IV = intravenous = into the vein IM = intramuscular = into the muscle SC = subcutaneous = between the skin and muscle IP = intraperitoneal = within the peritoneal cavity icv = intracerebroventricular = directly into the ventricle of the brain

Oral Per Os (PO) Cooperation required Can recall ~
by mouth absorption across membrane in GI most common most variable 1st pass metabolism Cooperation required Can recall ~

Oral Sublingual Chewing Absorption: e.g., nitroglycerin, buprenorphine
mucous membrane salivary glands e.g., nitroglycerin, buprenorphine Chewing absorbed across lining of mouth ~

Injection Intravenous (iv) Location important directly into vein
rapid onset of effects Fastest ~ Intramuscular (im) Location important Deltoid - rapid Thigh - moderate Buttocks - slowest Difference in blood supply & distance

Routes of Drug Administration and Absorption.
Injecting (Intravenous): Puts drugs directly into a vein Put drugs into muscles or under skin

Injection Subcutaneous (sc) Disadvantages under skin
slow, steady absorption Disadvantages Variable absorption limited volume skin irritations ~

Injection Intrathecal Mostly as local anesthesia
under sheath of nerve fibers, spinal cord, or brain Mostly as local anesthesia little importance for most psychoactive drugs ~

Inhalation Smoking Lungs Fast absorption gases or vapors
densely lined with capillaries large surface area Fast absorption Similar to iv ~

Routes of Drug Administration and Absorption.
Inhaling: Allows the vaporized drug to enter the lungs, the heart and then the brain in about 7-10 seconds (Most rapid) (Pictures) Marijuana inhaling tent used by the Scythians, c. 500 B.C. Man in India smokes ganja (marijuana) in a “chillum” pipe.

Other routes Transdermal patches Suppositories - rectal or vaginal
absorbed by skin slow continuous release also liposomes: via injection Suppositories - rectal or vaginal absorption incomplete & unpredictable Pellets - Norplant Microcatheter & pump ~

Routes of Drug Administration and Absorption
Contact or Transdermal Absorption Absorption through the skin is the slowest method of drug use. It often takes 1–2 days for effects to begin and the absorption can continue for about 7 days. Nicotine, fentanyl, and heart medications can also be absorbed this way Skin creams & ointments absorbed through skin

Toxicity Toxicity is the ability of a chemical to damage an organ system, to disrupt a biochemical process, or to disturb an enzyme system.

Drug Formulation Dosage = the amount of drug to be administered
usually based on weight Example: mg/kg Concentration = how the drug is formulated Example: mg/ml Injection Volume = a liquid measurement based on weight Example: ml/kg

Factors Affecting Response to Drugs
Dosage Route of Administration IV IH subling IM, SC IP PO topical Rate of Absorption Rate of Elimination Physiochemical properties of the drug age, sex, species, metabolism, etc…

Volume of Distribution – tells us how extremely how a drug is distributed to the rest of the body compared to the plasma

Here is any volume of water, measured in liters:
Dose/volume We now have a concentration of drug in solution measured in dose/volume

Here is any volume of water measured in liters we can call it a “compartment”
We can think of this compartment as the “total body” So when we put drug into a single compartment We can easily surmise amount of drug in “total body”

Plasma Rest of Body

Major Compartments Water compartments Total body water (0.6 L/kg)
Extracellular fluid (0.2L/kg) Blood (0.08L/kg) Plasma (0.04L/kg)

Volume of Water Compartments
70kg – total body = 42 liters plasma = 3 liters It would be simple if the drug was distributed evenly, as if a single compartment. But rarely is a drug distributed evenly.

Plasma Rest of Body

Some drugs remain mostly in plasma
Some drugs are extensively distributed to other parts of the body.

Volume of distribution – tells us how extensively drug is distributed to the rest of the body compared to the plasma. Is defined by the ratio of the amount of drug in total body to the concentration of drug in plasma

Volume of distribution = Amount of drug in body
Plasma concentration V = A/C

So if a dose of 50 mg of Drug A results in plasma concentration of 0
So if a dose of 50 mg of Drug A results in plasma concentration of 0.1 mg per liter. V = 50mg/0.1 mg/liter Volume of Distribution for Drug A is 500 liters. The units cancel resulting in liters How is it that the volume of distribution of Drug A is far greater than any actual compartment volume?

Drug A is extensively distributed to other parts of the body
Plasma Rest of Body

In this situation it is due to extensive tissue binding of Drug A in the rest of the body
Imagine activated charcoal that absorbs Drug A in the “rest of body compartment” If we add 50mg of Drug A, resulting in plasma concentration of 0.1mg/liter.

Conceptually, this would be the same as adding 50mg of Drug A to a lone plasma concentration of 500 liters.

Volume of Distribution
Abstractly describes this in terms of the plasma as a single lone compartment It is NOT an actual volume, so it may be much higher than any real body volume Because it is based on easily measured parameters, volume of distribution is an essential component of pharmacotherapeutic equations

Volume of Distribution – is the amount of drug in body relative to concentration of drug in systemic blood - If a drug is given, and this drug is absorbed and completely distributed to every single cell in the body…this would be a large volume of distribution

- if a drug is given, and this drug is absorbed and remains exclusively in the blood, going nowhere else…this would be a small volume of distribution

Major Components – Water, Fat, Bone
Total Body Water – 0.6L/kg Extracellular Fluid – 0.2L/kg Blood – 0.08L/kg Plasma – 0.04L/kg

Fat Brain Adipose Tissues Cell Membranes – Lipid Bilayer

Protein Binding There are many types of proteins in the blood plasma Albumin These proteins will bind many drugs Drugs that are “protein bound” are not able to activate receptors until they are “free”

- These proteins act like a sponge on many drugs, not freeing the drugs until the proteins are saturated - Stopping or starting a drug that binds to plasma protein changes the levels of other protein bound drugs

Causing a seizure by stopping a blood thinner
A person was admitted to the hospital for surgery. The person took Coumadin as a blood thinner, and Dilantin as an anticonvulsant Both Warfarin or Coumadin and Dilantin are highly plasma protein binding drugs

Three days before surgery the Coumadin (blood thinner) was stopped.
Because Coumadin is protein bound, and stopped, this left protein binding sites available for Dilantin These extra binding sites absorbed the Dilantin, remember only “free” drug is effective

The Dilantin going from free to protein bound, caused less Dilantin to be available to prevent seizure

Biotransformation – everything you eat that is absorbed by the blood is sent to the liver first for processing Detoxify Transform nutrients Make lipophilic substances water soluble Water solubility – renal elimination

Xenobiotics – the human body is constantly exposed to a wide variety of foreign substances
- Many substances have no effect (physiologically inert), but some may provoke a physiologic response (drug).

CYP family Cytochrome P450 Enzymes metabolize thousands of endogenous and exogenous compounds Most CYP enzymes can metabolize many different chemicals or substrates This acounts for their central importance in metabolizing the extremely large number of endogenous and exogenous molecules.

Aromatic Ring Very stiff shape They are everywhere Things that are stiff are excellent for making keys

L-Tyrosine

Why is drug biotransformation necessary?

Most drugs are lipophilic and/or strongly bound to plasma proteins and thus are not readily filtered by the kidney Polycyclic Aromatic Rings – toxins Why is biotransformation important?

- Most drugs would have a prolonged duration of action if elimination depended solely on renal excretion

Polycyclic Aromatic Rings – toxins; very fat soluble

Phase I reactions Oxidation Phase 1 involves conversion to water soluble metabolite CYP Cytochrome P450

Phase II Conjugation Phase II reactions are when substances are conjugated or connected to highly polar groups - glucose, glutathione, glucuronic acid

CYP Family Cytochrome P450 CYP enzymes metabolize thousands of endogenous and exogenous compounds Most CYP enzymes can metabolize multiple substrates Many can catalyze multiple reactions This accounts for their central importance in metabolizing large number of endogenous and exogenous molecules

Metabolic machine

Enzyme Induction -some drugs induce cytochrome P450 by causing an increased amount of cytochrome P450 enzymes Enzyme inhibition – results in decreased P450 enzymes and increased pharmacologic activity of the drug

Enzyme inhibition List is exhaustive but includes cimetidine, ketoconazole, erythromycin, ethinyl estradiol Enzyme inhibition – drug decreases enzyme synthesis

Enzyme induction -some drugs induce cytochrome P450 by causing an increased amount of cytochrome P450 enzymes -results in increased metabolism and decreased pharmacological action of the drug Examples: cigarette smoke, charcoal broiled meat, phenobarbital

Enzyme Induction – drug increases enzyme production
“Everybody is different in how they metabolize drugs”

Basic Pharmacology.

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