Pedanius Dioscorides - Described over 600 medicinal plant - first pharmacopeia

• Pharmacopeia (drug making)- a book containing an official list of medicinal drugs together
with articles on their preparation and use

John Newport Langley - Discovery of how a signal is transmitted from one nerve to another via synapse

• Chemicals react on receptive substances - credited with discovery of drug receptors

Thomas Elliott - Propose concept of chemical neurotransmission (Adrenalin secreted by sympathetic

nerves)

Paul Ehrlich - Discovered arsphenamine first drug treatment for syphilis

• Toxins and nutritive substances bind selectively to specific receptor molecules (side chain theory)
• Initiated concept of chemotherapy - Chemicals used for treatment and called
them chemoreceptors
• Won 1908 Nobel Prize for work on immunity
Otto Loewi - Showed vagus nerve of one heart when stimulated releases “vagus-stoff” which slowed the
rate of the heart

• Showed stimulation of the sympathetic nerve released a different chemical (accelerans-

stoff) which increased the heart rate (Ach and epinephrine which have opposite effect)

Henry Dale - Coined terms adrenergic and cholinergic

• 1936 Nobel Prize to Otto and Dale for discoveries relating to chemical transmission of
nerve impulses

Discovery of insulin in 1921-22 by Canadian Scientists - Federick Banting- physician, Charles Best- grad
student, JJR Macleod- prof, JB Collip- biochemist

• Insulin  Type I diabetes: lack of insulin

• 1923 Nobel prize in physiology – Banting & Macleod
Alexander Fleming - Discovered penicillin.

Howard Florey and Ernst Chain showed penicillin can cure infections - 1945 Nobel Prize

Sir John Vane - Aspirin relieves pain and reduces inflammation via inhibition of prostaglandin synthesis -
Nobel prize in 1982

Sir James Black - Discovered netherlide, first beta blocker (later propranolol) - Nobel Prize in 1988

• Also developed cimetidine a histamine H2 blocker, for inhibiting stomach acid secretion and
the treatment of peptic ulcer
• Developed the concept of “receptor selective drugs”. He followed the method of
modelling drugs based on receptor structure.

Nitrates used for angina - NO signaling mediator in endothelial cells, neurons, phagocytes, and other cell
types from L-arginine
 • Smooth muscle relaxing antiplatelet effect, helps fight infections
• Viagra

Robert Furchgott - Isolated aortic strips, Endothelial cells produce substance that relaxes blood vessels

• Sandwich experiment
• Discovered NO as endothelium derived relaxing factor - Nobel Prize 1998

Pharmacology: the study of the changes produced in living animals by chemical substances, especially
the actions of drugs, used to treat disease

• A branch of medicine that deals with the interaction of drugs with the systems and processes
of living animals, in particular, the mechanisms of drug action as well as the therapeutic and
other uses of the drug
• derived from the Greek word pharmakon, meaning a magic charm for treating disease
Drug: broadly defined as any chemical agent that affects living processes

• a drug is a chemical substance that affects the processes of the mind or body.
o any chemical compound used in the diagnosis, treatment, or prevention of disease
or other abnormal condition.
o a substance used recreationally for its effects on the central nervous system, such as
a narcotic
Drug name: Can be referred to in 1 of 4 ways

• One or more proprietary (brand) names, a non-proprietary (generic) name (worth

remembering) pre-market manufacturer code and a chemical name.

Pharmacokinetics: Absorption, distribution, metabolism, excretion

• What the body does to the drug. Drug produces changes in the body, side effects (beneficial
or harmful), adverse effects due to interactions or unknown mechanisms
• Iatrogenic effect (illness caused by medical treatment/examination by physician)
Pharmacodynamics: Drug-receptor interaction, signal transduction, and responses (effects)

• What the drug does to the body. Absorption into systemic circulation, extraction from
systemic circulation or after metabolism, metabolism (biotransformation from systemic
circulation), distribution to site of action receptors or tissue reservoir

Dose of drug (kinetics) resulting drug concentration in body over time  mechanism and magnitude
of drug effect (dynamics)

Routes of administration: Enteral – Oral, Sublingual (under the tongue), Rectal. Parenteral (non
digestive tract) – Intravenous, Intramuscular, Subcutaneous, Intrathecal (subarachnoid space),
Intraperitoneal

Drug absorption: passage of drug from the site of administration into the general circulation (except for
directly applied drugs)
 • A drug that is injected intravenously is thus immediately and completely (100%) absorbed

Factors affecting drug absorption: Better absorbed - Non-ionized, Small molecules, Lipid soluble. Poorly
absorbed – Ionized, Large molecules

• Factors that affect drug absorption and distribution are active at sites where there is a barrier
created by uninterrupted cell layers (GI tract epithelium, capillary beds in most organs
including the brain)
• Two important organs: Capillary beds in the kidney glomerulus and the liver. Gaps between
endothelia cells or fenestrations (pores) which allow even polar molecules, large molecules
and lipophobic molecules to pass through easily and enter organ
o Help liver and kidney in their function to deal with most molecules in the blood and
body and metabolize or excrete them

Uninterrupted cell layer barrier: Brain capillaries, Small non-polar lipid soluble molecules can enter

Capillary barrier with gaps between endothelial cell (fenestrations): Liver sinusoids, kidney glomerulus
capillaries, All molecules except very large proteins can pass

Filtration: of most molecules from glomerular capillary into tubule (nephron) lumen occurs freely

• Not limited by charge or size or lipid solubility, Except large proteins, Gaps between
endothelial cells

Reabsorption: Of molecules from tubule lumen into peritubular capillary. Regulated by charge or size or
lipid solubility of molecules. ONLY lipid soluble molecules are reabsorbed. No gaps

Poorly absorbed drugs: oral absorption - Destroyed by stomach acid or digestive enzymes. Penicillin G,
insulin

• Chelated to components of food to form insoluble complexes. Tetracyclines

• So polar they won’t cross membrane. Aminoglycoside antibiotics: streptomycin, gentamycin
• Undergo extensive metabolism. Nitroglycerin, adrenaline, dopamine

Ionization: effect of pH on drug absorption

• Absorption of weak acids and bases. most drugs are weak acids or bases
o Weak acidic drugs: Phenobarbital, naproxen, aspirin, phenytoin, warfarin
o Weak basic drugs: Amphetamine, ephedrine, quinidine, propranolol, diazepam
• pKa of drug is defined as the pH at which half of the drug is ionized
o pH of the medium will determine how much of the drug is ionized, number of
protons will depend on the pH of the medium, more acidic more protons, alkaline
(basic) less
• An acid is a proton donor HA = H+ + A-
o Protonated form is uncharged and better absorbed
• A base is a proton acceptor B + H+ = HB+
o Protonated form is charged and not well absorbed

Clinical relevance of weak acids, weak bases and the effect of pH on their ionization
 • Ion trapping: At steady state an acidic drug would accumulate on the more basic side of
a membrane, and a basic drug on the more acidic side
o Mother’s plasma 7.4  Fetal plasma / breast milk 7.0-7.2. Fetal plasma slightly more
acidic
o Basic drugs taken by mother can accumulate in fetal circulation and breast milk,
harmful effects can ensue
▪ Non-ionized basic drug would cross cell membrane
▪ Ionized basic drug would accumulate on the acidic side (doesn’t cross)
o At alkaline pH: Non-ionized fraction is greater
o At acidic pH: Ionized fraction is greater
• Poisoning
o Acidification or alkalinisation of urine can accelerate the excretion of basic or
acidic drugs that have reached toxic conc in the body
▪ To increase excretion of acidic drugs (phenobarbital and salicylates) intravenous
sodium bicarbonate is given
▪ To increase excretion of basic drugs (amphetamine), ammonium chloride
or ascorbic acid may be given
• Renal clearance of salicylic acid- effect of urinary pH
o Given an infusion of sodium bicarbonate significant reduction of plasma half-life and
fall in plasma salicylate

First pass effect (first pass metabolism): Metabolizing enzymes in the intestinal wall and/or liver can
result in very little or no drug reaching the general circulation

• Clinical Significance: some drugs are ineffective orally

• Bioavailability: Fraction of orally given drug that reaches the circulation. Between 0 and 1
o Bioavailability = quantity of drug reaching systemic circulation / quantity of
drug administered
• Clinical relevance: Cheese-wine reaction - Tyramine is a sympathomimetic amine found in foods
such as cheese and wine. Normally metabolized by monoamine oxidase enzymes in GI wall and
liver
o When a patient is taking a MAO inhibiter, tyramine will be absorbed and
reach circulation and nerve terminals where it releases norepinephrine (NE)
o NE will stimulate adrenergic receptors causing tachycardia and high blood

pressure Some Drugs bind to plasma proteins: Acidic drugs  albumin. Basic drugs  a1-acid

glycoprotein
• Drugs compete for binding sites which are saturable
Drug distribution: After absorption drug is distributed to various body compartment

• Factors affecting distribution from general circulation to tissue compartments are: Ionization,
Capillary permeability (increased inflammation in injury, larger wound, more permeable, inc
infection risk), Blood flow (less blood flow, longer it takes drug to reach), Plasma protein
binding (only free drugs reach – some proteins stuck in blood)
Capillary Permeability: In liver, kidney and spleen, capillaries are very leaky – cell gaps for passage (even
ionized can pass)

• Drugs leave the capillaries regardless of whether they are poorly lipid soluble, charged, or polar
• In other tissues, selective capillary permeability varies somewhere between the above
two extremes

Blood-Brain Barrier: Brain capillaries have tight junctions, more than 1 cell layer to pass

• Glucose and amino acids have specific carrier-mediated transport systems

• Only lipophilic drugs diffuse across brain capillaries (unless actively transported)
• clinical implications: the degree to which drugs penetrate the brain should be known to
treat diseases of the nervous system properly
o Aminoglycoside antibiotics penetrate brain tissue poorly due to polar structure, so
must be administered intrathecal or intraventricular injection (inject in CSF)
o Inflammation increases capillary permeability, drugs can pass and
reach infection/inflammation site

Blood flow: Tissue that receives more blood flow receives more drug b/c drugs reach majority of
tissues via general circulation

• Rate at which drugs distribute from bloodstream into various tissues, depends on the
relative blood flow to the various tissues
o Brain, liver, kidneys > skeletal muscle > fat (huge storage organ – lipid soluble drugs), skin

Body fluid compartments and volume of distribution (Vd) - When we administer a drug, it
distributes into many compartment - volume of distribution. NOT always uniformly distributed

• Volume of distribution: theoretical (or apparent) volume in which the total amount
of administered drug should be uniformly distributed to account for its plasma or
blood concentration
• Vd= Dose administered / plasma concentration (plasma conc. Indicates how much in organs)
o If the concentration in the plasma is less (e.g. lipid soluble drug in fat stores) Vd will
be very high
▪ A high Vd indicates that most of the drug is in the extravascular compartment
o If the concentration in plasma is high (due to plasma protein binding) its Vd will be
low
▪ Low Vd indicates that most of the drug is in the vascular compartment (a
drug highly bound to plasma protein)

Total body water (TBW) 60% of body weight. 2/3 of TBW in intracellular fluid space. 1/3 of TBW in
extracellular fluid space. 1/3 of ECF in intravascular (plasma)

Adult blood volume: 5L

Biotransformation (Drug Metabolism): Chemical modification of drugs by enzymes, to make them more
polar (less lipid soluble), and therefore readily excretable by the kidneys

• Drug metabolizing enzymes are present in: Liver, GI wall, Lungs, Kidneys, Skin, Blood, Brain
Two-phase biotransformation:

• Phase I (functionalization): Enzymes are oxidases. Oxidation, reduction, hydrolytic reactions

(makes the drug more polar, but not necessarily inactive). Many drugs become inactive
after phasometabolism. Can produce active metabolites
• Phase II (conjugation): Conjugation to polar groups: glucuronidation, sulfonation,
acetylation (most of these result in drug inactivation). Becomes highly polar and therefore
inactive

Phase I enzymes: Microsomal cytochrome P450 (major group of enzymes – over 100) monooxygenase
family of enzymes which mainly oxidize drugs (10-12 isoforms which metabolize drugs)

• These enzymes act on structurally unrelated drugs (i.e. not very substrate specific)
o Located in ER of the cell. Require oxygen. Metabolize the widest range of drugs. In
most cases these reactions inactivate a drug
• CYP  CYP1 (family)  CYP1A (sub-family)  CYP1A1 (isoform- gene number)
• Over 90% of drug oxidation by cytochrome enzymes can be attributed to 6 main CYPs:
o CYP1A2 CYP2C19 CYP2E1 CYP2C9 CYP2D6 CYP3A4
▪ CYP3A4 is the primary enzyme for metabolism of about half of all drugs and
is inhibited or induced by many drugs. Can lead to drug-drug interactions
(DDIs)

Affecting drug biotransformation: Enzyme induction and inhibition: drugs (including herbals) and other
substance (food) can stimulate or inhibit the expression of metabolizing enzymes (esp. cytochrome P450
enzymes)

• can cause DDI when two or more drugs are metabolized by the same enzyme

Induction of enzyme and drug interactions:

• Inducers (faster): Cause expression of more CYP enzymes and faster elimination of
substrate drugs. Lower than expected drug levels can cause treatment failure
o i.e. rifampin (antibiotic), barbiturates, St. John’s Wort (herbal antidepressant)
• Inhibitors: Inhibit the activity of CYP enzymes and reduce elimination of substrate drugs
o Higher than expected drug levels can cause drug toxicity
o i.e. grapefruit juice (strong inhibitor of CYP enzyme, elderly drink for health reasons),
climetidine (stomach acid inhibitor) (was over the counter DDI high risk),
erythromycin (antibiotic), itraconazole (antifungal)

CYP polymorphism - genetic variations in the population. Mutations are found in some drug
metabolizing enzymes in some people (sometimes increases, usually decreases) – reduced activity =
dysfunctional enzyme

• Most common P450 polymorphism in Caucasians is CYP2D6 expression. 7-10% of Caucasians

and 2-5% of Africans lack expression of this enzyme
• Codeine is almost ineffective as an analgesic in these patients. It must be metabolized by
CYP2D6 to morphine for analgesic effect (opioid, should be metabolized into morphine, with
mutation morphine NOT produced) – addiction risk
Phase II reactions: conjugation reactions (binding cofactor and substrate). Chemical group such as
glucuronic acid, sulfate, glutathione, amino acids, or acetate is added to drug
 • Conjugated drug is highly polar, in most cases inactive, Conjugated drug is rapidly excreted
• Enzymes for phase II reactions are mostly located in the cell cytosol
• Autosomal variations
o 50% of Americans and 60-70% of Europeans have reduced expression of
acetylating enzyme (N-acetyl transferase or NAT- slow acetylators) - can suffer
from toxicity improperly working enzyme causes drug to work slow
o They slowly metabolize drugs such as isoniazid (antituberculosis drug)
procainamide (anti-arrythmic drug) and caffeine
• Not typically involved in DDI
Factors affecting drug metabolism: Lipid solubility of drug (reach enzyme in every site in the body), First
or zero order rate of metabolism, Blood flow to liver (important in elderly b/c it decrease, drug dose
reduction for drugs highly metabolized in the liver), Maturation of metabolizing enzymes (important in
neonates and infants – not able to metabolize drugs, typically drug kills premature, not condition),
Diseases of liver and kidney (lab report gives indirect info of liver and kidney condition)

Drug Metabolism- Prodrugs: Certain drugs do not reach their site of action because of pharmacokinetic
obstacles. Drug can be destroyed by digestive enzymes

• a prodrug is an inactive precursor with favourable pharmacokinetics, which is metabolized

into the active drug in the body
• Prodrugs are inactive (ineffective) - until metabolised and converted into active form
o Ex. proton-pump inhibitors - omeprazole, lansoprazole are prodrugs (used to reduce
stomach acid secretion), levo-dopa is a prodrug - converted into the active
compound dopamine (used for Parkinson’s)
P-glycoprotein: an efflux pump, uses energy (ATP), removes compounds from inside to outside (pumps
outside cell to be effective), has broad substrate specificity for drugs - digoxin, quinidine, and others

• located at many sites (luminal surfaces): colon, small int, kidney tubules, brain, liver -
bile canaliculi, placenta, cancer tissue
• increased (induced) by some drugs (St. John’s Wort, rifampin)
• Inhibited by some drugs (Verapamil, quinidine, macrolide, antibiotics, antifungals), will
inhibit other parts of the body with p-glycoprotein – not just cancer
• P-glycoprotein in BBB protects the CNS from variety of structurally diverse compounds
through efflux mechanisms
• Plays a role in drug resistance to cancer chemotherapeutic agents
• Over-expressed in tumor cells after exposure to anticancer agents, and pumps out
anticancer drugs
• Drugs such as calcium channel blocker, phenothiazines and cyclosporin A, inhibit P-
glycoprotein and may be useful to reverse resistance

Enterohepatic recirculation: Entero (GI tract)  hepatic (liver) – prolongs the half life of drugs – longer
life if in plasma longer

• Compound is conjugated in liver, excreted in bile, deconjugated in intestine by intestinal

bacterial enzymes, and is reabsorbed into the circulation (physiologically causing reabsorption)
 o If the cycle has errors the drug becomes ineffective (prescribed antibody while on birth
control, the pill can fail b/c enterohepatic cycle is interrupted, antibiotic rifampin
induces CYP enzymes to metabolize contraceptive hormones – reduces effectiveness)
• Phenomenon prolongs duration of action (half-life) of drug
Enterohepatic recycling - Therapeutic significance: Bile acids are conjugated in liver to taurine and
glycine and excreted in the intestine where they are deconjugated (95% of bile salts are reabsorbed
and used in cholesterol synthesis). Hypercholesterolemia cuts the supply of bile salts and binds bile –
reducing cholesterol levels

• If we give a bile acid binding resin such as cholestyramine, we interrupt the

enterohepatic recycling of bile salts and reduce cholesterol synthesis and plasma levels

Factors affecting drug excretion: Lipid solubility (less soluble, more excreted), First or zero rate of
metabolism, Blood flow to kidney (GFR) (drug excretion), Maturation of metabolizing enzymes
(important in neonates and infants), Diseases of liver and kidney (infant vs adult vs elder), Competition
of transport system in renal tubules (organic bases and acids) (transports more than 1 type of drug),
pH of blood and urine (ion trapping) (degree of ionization – more ionization = more excretion), plasma
protein binding

Clearance: the volume of blood from which a drug is irreversibly removed per unit of time (Unit:
ml/min(/kg) – ml of plasma cleared of drug in 1 min) must know how much drug remains each day to
maintain the dose for multiple day drug treatment

• Clearance values useful to calculate maintenance dose of drug. Dose that will allow us
to maintain a steady-state of conc of a drug in plasm
• most drugs removed from the body by more than one organ (kidney is main)
• Rate of administration (maintenance dose) = rate of elimination
o Maintenance dose = Cp (steady state plasma concentration) x Cl (clearance)
• Whole body (systemic) clearance of a drug is the sum of clearance of that drug by all organs
Renal Clearance: Filtration is passive the kidney does not filter protein-bound drug. Only free drug is
filtered at glomerulus

• Some drugs i.e. strong acids (low pKa) and strong bases (high pKa) are secreted mainly in
the proximal tubes (active process with separate transporters for anions and cations)
• Unless the drug is very polar, some of it is going to be reabsorbed (sum of passive and
active processes)
o Net removal= filtered + secreted – reabsorbed

Drug Elimination Kinetics: Most drugs (used clinically) are eliminated according to a first-order rate

• A constant fraction of drug is eliminated per unit of time (Rate of elimination is proportional
to the plasma concentration). Blood concentration declines in an exponential fashion over
time

Zero-Order elimination: Metabolic mechanism for most drugs will be saturated only at very
high concentrations- doses not commonly used therapeutically
 • The metabolic capacity for very few drugs becomes saturated at [ ] with in the therapeutic
range (ex. Phenytoin, aspirin (acetylsalicylic acid ASA), carbamazepine, ethanol)
• constant amount of drug is eliminated per unit of time b/c that is the maximum rate
of elimination when the pathway for elimination is saturated
• toxicity occurs b/c no enzymes to metabolize (not enough enzyme) important to stay in
range [------------] therapeutic dose capacity – effective without toxicity
[--------------------------------] enzyme capacity 1st order – handles therapeutic dose
[--------------] enzyme capacity 0 order – less than therapeutic dose – toxicity risk
The drug will go through first order before entering zero order

Half-life: is the time required for the blood (or plasma) [ ] of a drug to be reduced by 50% - 1st order
ONLY

• Applies to drugs that are eliminated by the first order rate of elimination (time to steady-
state (constant [ ] of drug in plasma) or elimination is independent of dosage) – never reach
100% steady state
• If a fixed dose of a drug is given repeatedly at fixed intervals, it takes about 5 half-lives for
that drug to achieve steady-state [ ] in the plasma (about 97% of steady state)
o If half-life of drug is 20 hrs, then it will reach steady [ ] (where elimination rate equals the
administration rate) after 5x20 = 100 hrs
- For practical purposes, it takes about 5 half-lives for about 97% of a drug to be
effectively eliminated from the body (when administration is stopped) – long time for
full removal

Drug Interactions: A situation in which a substance affects the activity of a drug (too much reaching –
toxicity, OR not enough – ineffective) - Can be prevented in most cases

• Drug interactions cause up to 2.8% of hospital admissions

• People older than 65 use more drugs  open invitation for DDI
• Women take more drug s- psychoactive and arthritis drugs
• Drug use is greatest among the frail elderly, hospitalized patients, and nursing home residents
(7- 8 different drugs together)

Drug interactions: Interactions between 2 drugs (DDI) most common - Between two drugs
metabolized by same CYP isoform (e.g. rifampin and estrogen). Drug-food interactions - Drugs
metabolized by CYP enzymes and grapefruit juice. Between drug and herbs - St. John’s Wort (over
counter for depression). Other interactions: Blood electrolytes (Digoxin (for heart failure) and K+)

• Pharmacodynamic interaction: Two drugs affecting the same system (effect on the organism)
o Two sedative drugs will produce more sedation
• Pharmacokinetic interaction: One drug changes absorption, distribution, metabolism
or excretion (ADME) of another
o Absorption: Antacids reduce absorption of tetracycline (AB), Calcium
supplements reduce absorption of thyroxine (HRM)
o Distribution: Competition for plasma protein binding by non-steroidal anti-
inflammatory drugs (NSAIDS) and warfarin (A-COAG) (Impossible NOT to have
interaction of these drugs)
 o Excretion: Probenecid reduces excretion of penicillin by competition for the
kidney tubule transport system (beneficial DDI)
o Metabolism- one drug affecting the metabolism of another drug is the most common
reason for DDI - Two drugs metabolized by the same enzyme can compete for
enzyme (CYP3A4)

Liver and kidney health and drug effect/toxicity: Liver and kidney (major organs of metabolism and
excretion) affect metabolism and excretion and plasma levels of many drugs

• Important to consider health of these two organs when deciding dose – proper function?
• Doses of drugs with high hepatic extraction ratio have to be reduced in chronic liver disease
• Doses of many drugs may have to be reduced in chronic kidney disease
Drug metabolism interactions: When a patient is taking two or more drugs, the possibility of drug
interactions resulting from metabolism should be considered (ALWAYS ask if on drugs)

• When a patient is taking a single drug metabolized by the cytochrome P450 enzymes (the
most common enzyme class), interactions with food items or herbal medicines should be
considered
• In cases of drug toxicity or treatment failure genetic variation of metabolizing enzymes should
be considered

Pharmacodynamics: Drugs, receptors, and pharmacological response

• Most drugs produce their pharmacological effects by binding to specific receptors in target
tissues (receptor is a macromolecule whose biological function changes when a drug binds to
it)
o Most drugs act on receptors (can bind to other things, but higher affinity for receptors)
– lots on cell membrane (some inside cell) – signal = change in receptor shape
• Affinity is the measure of propensity of a drug to bind receptor; the force of attraction
between drug and receptor
• Drug-receptor binding triggers a signal cascade of events known as signal transduction,
through which the target tissue responds
• Types of bonds between drug and receptor (Van der Waals force, ionic, covalent)

Multiple bonds are involved in the stereospecific interaction between a receptor and its

ligand

Drug-receptor interaction (not permanent, few ms): Drug molecule - in most cases the binding is
transient (Molecule binds and dissociates, binds again and so on) - Each binding triggers a signal

• Equilibrium between drug molecule and its receptor- association (bound) and dissociation
• If we put two drugs acting at same receptor, they will compete for the receptor due to
the transient binding – Competitive binding
o The drug with a higher [ ] will have a greater chance of

binding Equation for drug receptor interaction [D] + [R]  [DR] 

effect [drug conc] [receptor con] k1/ k2 alpha

• at equilibrium: [D] x [R] x k1 = [DR] x k2

o K1/K2 = affinity constant (Ka) K2/K1 = dissociation constant (Kd) (reciprocal)
So that: [DR/([D][R]) = k1/k2 or k2/k1 = [D][R]/[DR]

DR is response, response is a measure of efficacy, maximal effect or efficacy is denoted by Emax

Kd = K2/K1 the lower the Kd the more affinity the drug has for the receptor

How do we measure or quantify a drug-receptor interaction  Dose response curve (hyperbolic)

• Lowest dose and highest dose that will get a response – Emax = max concentration, more
dose will NOT change it
o Multiple drugs binding to the same receptor may change Emax
• Log dose response curve: Transforms hyperbolic curve to a sigmoid (almost straight line –
easier to analyze) Compresses dose scale, Proportionate doses occur at equal intervals
o EC50 – dose or [ ] of a drug that produces 50% of maximal response
o Emax- maximal effect produced by a drug. It is a measure of efficacy of a drug
o Efficacy (or intrinsic activity)- ability of a bound drug to change the receptor in a way
that produces an effect; some drugs possess affinity but not efficacy

Agonist: a drug which binds to the receptor and produces an effect. Has affinity + intrinsic activity

• Changes the shape of the receptor, conformational change triggers a signal

Partial agonist: has affinity for a receptor but less intrinsic activity (lower efficacy compared to an agonist
acting at the same receptor)

Antagonist: a drug which binds (thus competes for binding against other ligands), but does not activate
receptor. Has affinity but no intrinsic activity

• Some bind to receptors and prevent the receptor from other binding – no signal given,
just inactivates the receptor (antibody drugs)
o Competitive (reversible)
o Non-competitive (irreversible) – very dangerous

Agonist and Partial agonist: A partial agonist has less efficacy and a lower Emax compared to an
agonist at the same receptor (Morphine- agonist, Buprenorphine- partial agonist at u opioid receptors)

• Can determine agonist vs partial agonist by Emax, compare at least 2 molecules

Partial agonist usefulness: A partial agonist produces less than full effect when given alone and acts as
an antagonist in the presence of a full agonist (blocks the full effect of an agonist)

• Therapeutic use of a partial agonist: Buprenorphine, an opioid analgesic - Has lower abuse
potential (addiction), Lower level of physical dependence, greater safety in overdose
compared with full agonist morphine
• Antagonist properties of a partial agonist can be useful, provide some agonist activity and at
the same time block the endogenous full agonists
o Pindolol for high blood pressure and abnormal heart rhythms
▪ Will reduce the excessive stimulation due to norepinephrine in a person
with high sympathetic nervous system activity
 ▪ When adrenergic receptors are unoccupied the partial agonist will stimulate
and increase heart rate and blood pressure - but not as much as a full agonist
(70  80 bpm)
▪ When the adrenergic receptors are occupied by the full agonist
• NE (80  100 bpm)
▪ When pindolol displaces NE and occupies receptor it will still stimulate
and increase HR from resting 70 to 80 bpm
▪ But it will appear to come down from 100 to 80 bpm
Competitive Antagonism (can determine from response curve): When the agonist is alone, a lower dose
can produce maximal effect. The higher the dose of antagonist competitive (reversible), the more agonist
require to reach the same Emax

• Rightward shift of DR curve, EC50 increases, Emax stays the same

Irreversible (non-competitive) antagonism: In presence of an irreversible (non-competitive) antagonist

even a higher dose of agonist cannot produce maximal effect

• Emax is depressed, (Less maximal effect (Emax) – agonist + non-competitive antagonist)

Inverse agonist: Some receptors have intrinsic (constitutive – don’t require stimulation, no molecule
bound) activity even when no ligand is bound to them. When a ligand binds to them, their basal activity
is reduced. Such agonists are called inverse agonists. Inverse agonist has activity, when bound the
activity is reduced.

• They are like competitive antagonists with a major difference that on their own they
reduce receptor activity whereas competitive antagonists have no effect on their own
• Examples of receptors with basal activity: benzodiazepine, histamine, opioids, dopamine
• Examples of inverse agonist drugs: famotidine, risperidone

Allosteric Interaction: When ligand (B) binds to a site close to the site of an agonist on a receptor, it can
affect the binding and/or response to agonist (A)

• Ligand (B) can potentiate the response to agonist (ex. Benzodiazepine drugs potentiate (shift
DR curve left) the response to gamma aminobutyric (GABA) when they bind to GABA A
receptor)
• Sometimes the ligand will reduce or completely inhibit the response or binding of agonist A
to the receptor

Clinical Relevance: It is easier to treat overdoes or poisoning caused by a competitive (reversible)

receptor or enzyme blocker drug e.g. atropine (competitive muscarinic receptor blocker) poisoning can
be treated by increasing acetylcholine at the receptor with an acetylcholinesterase inhibitor
(physostigmine)

• Poisoning caused by an irreversible inhibitor is difficult to treat e.g. inhibition

of acetylcholinesterase by organo-phosphorous compounds

Quantal dose response curve: Indicates sensitivity of a given population (single organ/tissue for
study) to the doses of a drug for a given effect. Different doses of a drug are given to a group of
people and a defined response is noted
 • Frequency distribution (more than 1 person tested) - Each bar shows the # of people
responding to that dose, excludes people responding to lower doses. Only shows how many
people are responding, NOT to which dose they are responding to
• Cumulative frequency - Each bar shows the # of people responding to that dose, and to
lower doses. Different ppl can have different responses to the same dose, allows for range

Therapeutic index: Safe dose range  TD50 / ED50 (high ratio = safe drug, low value = easy toxicity)

• ED50 – effective dose in 50% of people, TD50 – toxic dose in 50% of people, LD50 – lethal
dose in 50% of people
• Therapeutic window reflects a plasma [ ] rang that provides efficacy w/o unacceptable toxicity
o Therapeutic window is the difference between the minimum effective concentrations for
a desired response and an adverse response

A dose-(concentration)-response curve shows graded responses in a single individual, produced by

increasing [ ] of a given drug

A quantal dose-response curve shows a specific response (quantal – all or none, either present or
absent) in a group of individuals (population) produced by a drug (shows sensitivity of the population to
a drug for a given effect- so different doses may be required for the same response in diff individuals)

Signal Transduction Pathways: Drug-receptor interaction - Produces a response. The events involved in
this response are known as signal transduction

• Common responses in body: Transient increases in intracellular free calcium levels –

muscle contraction, Activation of enzymes for various biochemical reactions,
Neurotransmission, Secretion of NTs and hormones

Signal Transduction Mechanisms: 1-3 ALL in cell membrane, 4 inside cell

1. G-protein coupled receptor (2nd fastest) systems

a. GPCRs, metabotropic receptors
b. Half of all known drugs work through GPCRs
2. Ion-channel receptors (fastest)
a. Ionotropic receptors
3. Enzymes as receptors (third fastest)
a. Tyrosine, serine, threonine kinases

4. Nuclear receptors (extremely slow)

G-protein coupled receptor: Agonist binding (draws in g-protein)  gamma and betta subunit release
from alpha  GTP (needs energy for its action) binds to alpha and GDP released  activate enzyme -
adenylyl cyclase

• Activated pathways: Three secondary messengers are activated.

o cAMP IP3 DAG
• Activated G protein  K+ channel OR Phospholipase C-b ( IP3  increase Ca2+ OR  DAG
Protein kinase C) OR Adenylyl cyclase ( ATP to cAMP  protein kinase A)
Enzyme Receptors: a Pair of protein molecules (monomers) that are separate when inactive. An agonist
causes them to interact and form a dimer (bound monomers drawn together, become active)

• The interaction phosphorylates tyrosine in the intracellular region of the receptor and
the receptor becomes an active enzyme
• The active receptor enzyme then activated a number of other enzymes that interact with
the active tyrosine of the receptor (Insulin receptor, growth factor receptors)

Ion channel receptors: The receptor is a protein with a channel in the centre. An agonist causes the
channel to open and allows specific ions to cross

• Nicotinic Ach receptor - conducts Na+ ions – causes muscle depolarization and contraction
• GABA receptor – conducts Cl- ions – inhibits neurotransmission

Nuclear Receptors: mostly in the cell cytosol. An agonist enters the cell and binds to the receptor

• The drug-receptor complex then enters the nucleus and stimulates gene transcription. This
leads to synthesis of new proteins and enzymes (extends over hours to days) Long time for drug
to react/be removed
o Receptors for steroids, retinoids, and thyroid hormones

Up-regulation and down-regulation of receptors: Agonists tend to desensitize receptors. Very

commonly, frequent stimulation of a receptor by its agonist results in a decreased response -
desensitization of receptors. Several mechanisms have been proposed: decreased receptor number
(downregulation) or decreased signal transduction

• Homologous desensitization - when only a given receptor is desensitized (will affect agonists
at the same receptor, doesn’t affect other receptors)
o If desensitized look for another treatment to work with another receptor
• Heterologous desensitization - when desensitization of one receptor by an agonist also
causes desensitization of other receptor types
o Related to signal transduction pathway - When the signal transduction pathways of two
receptors cross each other
• Antagonists tend to upregulate receptors (try to increase receptor with antagonist)
o Treatment with a beta receptor antagonist causes withdrawal rebound effect when
the antagonist treatment is stopped suddenly
o This is because the receptor # has increased and when antagonist is suddenly removed
from the receptor, there are more receptors available for agonist resulting in a
rebound response
• Clinically: it is important to gradually decrease the dose of any antagonist to prevent such a
rebound – if treatment is stopped early, blocked receptors unblock, won’t see rebound
Therapeutics: Drug therapy in specific patient groups- pregnancy, neonates, pediatric and geriatric

Drug use during pregnancy: At least 1 prescription for a category D or X was filled in 7.8% of pregnancies

• Drug use during first trimester (12 weeks) (most important period of organ and
fetal development – most sensitive to drugs)
 o Most common prescription drugs were oral contraceptives (dangerous after pregnant),
amoxicillin, progesterone, albuterol, promethazine (nausea), and estrogenic
compounds
o Most common OTC drugs included acetaminophen, ibuprofen, docusate (stool
softener), pseudoephedrine, aspirin, and naproxen
• Factors that affect drug transfer across placenta:
o Molecular weight of drug
▪ Drugs with mol WT >500D have an incomplete transfer across placenta
▪ Most drugs have mol WT less than 500D (most drugs cross over to
fetal circulation)
o pKa of the drug and degree of ionization - ionized drug transfers incompletely across
the placenta (not always true - ampicillin and methicillin are strong acids and are
ionized (wouldn’t normally cross) but have bulky lipophilic group on their side chains
which allow complete transfer)
o protein binding of the drug
o placental drug transporters - placental expression of drug transporters such as p-
glycoprotein, breast cancer resistance protein (BCRP) and multidrug resistance
protein (MRP) protects the fetus by efflux of drugs from fetal to maternal circulation

Drugs in pregnancy – Previous US FDA Classification A B C D X – identification on ALL drugs

• A: safe; lots of data, B: likely safe; animals OK, C: uncertain; risk vs benefit, D: likely unsafe;
risk vs benefit, X: unsafe; do not use
• Labeling replaced in 2015, BLLR system

Effect of age on response to drugs: Clinical trials not usually performed on old people and children 
data not readily available

• Patients at two extremes of the age range differ markedly in their response to drugs
o Main reason is the differences in physiology at the extremes of the age rang-
dose adjustments are necessary

Principles of drug treatment in children: Pharmacokinetics data not well defined, Variability in
pharmacokinetics can be expected to be greatest when the body physiology is changing
(newborn/premature baby or during puberty)

• In the premature and newborn babies dose adjustments and therapeutic drug monitoring
for drugs with narrow therapeutic indices becomes necessary for safe and effective
treatment
• Drug clearance values do not vary linearly with either body weight or body surface area
o Meaning that one-year old infant will not necessarily have lower clearance values
when compare to a ten-year-old – need to monitor babies’ plasma on drugs
• Hepatic drug metabolizing enzymes are not fully developed in infants, especially premature
• Clearance values of most drugs are different in children than those in adults
Metabolic enzymes in infants: Most drug-metabolizing enzymes are expressed at low levels at birth

• Different isoforms start getting expressed at different times (CYP3A4 is expressed w/in 1 week)
o any drug metabolized by CYP3A4 is likely toxic when administered to a new born or 1-
2 day old infant
 • newborns are unable to conjugate glucuronic acid during phase 2 metabolism (broad
spec antibodies – only use if NO other treatment)

Kidney function in neonates: Renal elimination is reduced in neonates. GFR is only 2-4 ml/min/1.73 m^2
instead of 100-130 in adults (further reduced in premature infants)

• GFR increases to adult levels by 8-12 months of age

o Dosing for drugs should be reduced to account for reduced renal clearance to
avoid toxicity (e.g. aminoglycoside antibiotics)

Pharmacodynamic differences in children: Antihistamines and barbiturates cause sedation in adults but
they cause hyperactivity in children

• Children have increased sensitivity to sedating effects of propofol

o Resulted in cases of overdoses with myocardial and multiorgan failure, and metabolic
acidosis
• Glucocorticoids can attenuate linear growth of bones
Drugs in elderly: Percentage of elderly people is increasing w/ increasing life expectancy (about 15% of
population above 65yrs)

• Take 1/3 of all drugs prescribed, Take average of 5 drugs/patient, Report 25% of drug
adverse reaction

Principles of drug treatment in the elderly: Some common physiologic changes that take place in elderly
people affect pharmacokinetic and dynamic responses to drugs:

• Reduction in lean body mass - reduction in muscle mass (can’t give drugs based on body weight)
• Reduction in serum albumin - will decrease amount of protein bound to drug
• Reduction in total body water (affects drug distribution)
• Increase in % of body fat - will increase the volume of distribution of lipid soluble drugs (more fat
= drug stays longer)
o All of these factors alter the distribution of drugs depending on their degree of lipid
solubility and protein binding
• Kidney and liver function should be assessed and the dose of drugs eliminated/metabolized
by these organs should be adjusted accordingly

Kidney function in elderly: GFR, an indicator of renal function, declines at an average of 0.8
ml/min/1.73m2 after age 30, decline accelerates after age 65-70

• An 85 yr old male  GFR of 55-60 (50% decrease from age 30)

• Significantly reduced renal clearance of drugs and a carefully calculated dose reduction of
drugs would be necessary

Liver function in elderly: Hepatic blood flow and drug metabolism reduced (great deal of variability
though) – drugs can’t be metabolized as well

• Hepatic CYP activity reduced, but conjugating enzymes not affected

• Pharmacodynamically elderly are more susceptible to depressants, psychotropic drugs
can produce more hypotension
AUTONOMIC NERVOUS SYSTEM

Divisions of the nervous system: PNS  Autonomic NOT under conscious control (Parasympathetic and
Sympathetic – often organs will have opposite effects), Somatic (Sensory and Motor – supplies skeletal
muscle under voluntary control). CNS  Brain and Spinal cord

Autonomic nervous system: Autonomous - independent, not under conscious control of the brain

• ANS: a branch of the PNS innervating smooth muscle tissue, glands, organs whose activity is
not under conscious control

Parasympathetic nerves: From medulla (upper cranial outflow, origin of nerves near brain) and
sacral spinal cord (reproduction). Craniosacral outflow – Long postganglionic fibers, originate from
ganglion, short preganglionic

Sympathetic nerves: From thoracic and lumbar spinal cord. Thoracolumbar outflow – Long
preganglionic fibers, extend to ganglion, Short postganglionic

• Includes adrenal medulla, which releases norepinephrine and epinephrine into blood

Neurotransmitters (NT): nerve fiber release - Ach - parasympathetic NT, NE - sympathetic NT.
Postganglionic cells release E – epinephrine, N - nicotinic receptors

Ach released at: Preganglionic para nerves at ganglia. Preganglionic sympa nerves at ganglia and at
synapses in adrenal medulla. Postganglionic para nerves at organ/tissue receptors. Preganglionic sympa
nerves at synapses in adrenal medulla. Somatic motor nerves at neuromuscular junction in skeletal
muscles. Postganglionic fibres of sympa system innervating all sweat glands (except palms), and skeletal
blood vessels release Ach

Norepinephrine (causes vasoconstriction) released at: Postganglionic sympa nerves at their

organ/tissue receptors. Sympa fibres innervating sweat glands in palms (adrenergic sweating)

An important source of EP and NE in the blood: Adrenal medulla releases EP (80%) and NE (20%)
into circulation when stimulated by preganglionic sympa nerves

• Clinical significance: phaeochromocytoma- a tumor of the adrenal medulla that releases

large amounts of EP and NE into circulation. BP and heart rate of such patients are high

Synthesis of Ach: From choline and acetyl coenzyme A (released by nerves, short lasting time). Stored in
neuronal vesicles, and released by nerve stimulation

• Botulinum toxin block Ach release – muscle paralysis

• Cholinesterase breaks down Ach – if not broken down, just collects and causes buildup
o Increase cholinesterase with cholinesterase inhibitor blocker

Synthesis of dopamine (precursor for NE), NE, and EP: Benzene ring with two OH groups is a catechol
plus the amine side chain - Catecholamines

• NE, EP, and dopamine synthesized from tyrosine

Cholinergic receptor types- stimulated by Ach

 • Cholinergic receptors
o Nicotinic  Neuronal Nn (Adrenal, Immune cells, CNS, Ganglia) OR Non-neuronal
(skeletal muscle) Nm – useful muscle relaxant
o Muscarinic (can contract some smooth, and relax others)  M1, M3, M5 (branch
group), M2, M4 (branch group) – NO specific blockers, ALL blocked

Nicotinic receptor: are sodium ion channels – locations:

• Nm (neuromuscular) - Location: skeletal NM junction - Effects: skeletal muscle contraction

• Nn (ganglionic or peripheral neuronal) - Location: autonomic ganglia (para, sympa,
adrenal medulla) - Effects: postganglionic excitation
• CNS - Location: CNS synapses (pre and post junctional) - Effects: CNS effects
Adrenergic receptor: stimulated by NE - Adrenergic receptors:

• Alpha 1: a1A, a1B, a1D (agonist and antagonist – a1 used for most drugs)
• Alpha 2: a2A, a2B, a2C (used in hypertension – prevents further release of NE)
• Beta: b1, b2, b3 (selective for b1 and b2)
Parasympathetic and sympathetic nerve stimulation: Stimulation of sympa and para has opposite
effects in most organs but not always

• Para is active during rest and digest (relaxation) – almost always active
o Heart: dec rate, dec contractility (relaxed state), Blood vessels: relaxed, BP normal,
partial vessel constrction/dialation Kidneys: normal renin secretion, Urinary bladder:
normal contraction, relaxed sphincter (go to washroom), Bronchi lungs: normal tone
and secretion (no need for more air), GIT including mouth: normal or excess salivary
and GIT secretions, active peristalsis, Liver: normal function, Eyes: focus on near objects,
pupil constrict esp. in bright light
• Sympa more active during fight or flight (stressful)
o Heart: in rate, in contractility, Blood vessels: pump more blood in stress, constricted,
inc BP, however skeletal, pulmonary, and coronary vessels dilate, Kidney: inc renin
secretion (help vasoconstriction), Urinary bladder: contraction inhibited (urine
retention), constricted sphincter, Bronchi and lungs: need more O2 relaxed bronchial
muscle (help ventilation, O2 supply to body and blood), GIT: reduced GIT secretions,
reduced or inhibited peristalsis, Liver: increased glycogenolysis (more glucose for blood
and muscles), Eyes: focus on distant objects, pupils dilate
Dominant Tone: Branch of ANS (para or sympa) in organ that innervates that organ is dominant or more
active

• Drugs (esp antagonists) affecting the system which is dominant will have a more
noticeable effect
• Blockers have effect on dominant tone

Dominant Parasympathetic: Heart (except ventricle), Urinary Bladder – Detrusors muscle & Sphincter,
Salivary & Parotid gland, GI smooth muscle
Dominant Sympathetic: Vessels, Kidney, Urinary Bladder Sphincter, Liver, Uterus, Eye – pupillary and
ciliary muscle

Muscarinic M2: dec Heart

Muscarinic M3: Blood vessels

Muscarinic M2 & M3: Urinary Bladder, Tracheal & Bronchial smooth muscle, Salivary & Parotid gland, GI
smooth muscle, Inc peristalsis

Muscarinic receptor: SA node – heart, Sweat glands, Bronchial smooth muscle, Ciliary muscle -eye

Muscarinic Agonist: Treat acute angle glaucoma, Inc saliva – treat dry mouth, Drain Aqueous humor,
Empties bladder

Muscarinic Antagonist (inhibit): Pupil dilation - mydriasis, Inhibit sweating, Dry mouth, Cause
constipation, Asthma

Inhibition of Muscarinic receptors in certain areas of the brain relieves muscle rigidity of Parkinson’s
disease

Beta B1: Inc Heart, Kidney – Inc renin, GI smooth muscle, Inc HR, Bronchodilation

Beta B2: Inc Heart, Tracheal & Bronchial smooth muscle, Liver, GI smooth muscle, Uterus, Inc HR, Uterine
smooth muscle

Beta B3: Urinary Bladder

Beta Agonist: Treat glaucoma,

Beta 2 Blocker: Treats wide angle glaucoma, prevent Glycogenolysis & Gluconeogenesis, Bradycardia

Beta 1 Blocker: prevent Glycogenolysis & Gluconeogenesis, Bradycardia

Non-selective Beta Blocker: Treats Hypertension – bad for asthma and diabetics

Alpha A1: Blood vessels – vascular smooth muscle, Urinary Bladder – sphincter, Salivary & Parotid gland,
GI smooth muscle, Miosis in Iris, Inc BP

Alpha A2: GI smooth muscle, reduce aqueous humor production, Inc BP

Alpha Agonist: Pupil dilation, Bradycardia

Alpha 1 Blocker: Sphincter contraction – empty bladder

Adrenergic receptors: Alpha 1, Beta 1, Beta 2

Nicotinic receptor blocker: Tachycardia, Constipation, Pupil dilation – mydriasis, (Nerves blocked)

AcH Inhibitor: Bradycardia

Heart: Dominant tone: para (except ventricles) – stabilize ventricle first, then atrium

• Para: Muscarinic agonists

o Ach  M2  lower heart rate and Atrioventricular (AV) conduction
 o Muscarinic receptor blockers: increase HR and AV conduction (e.g. atropine)
• Sympa: Beta 1 agonists
o NE, EP  B1  increased HR, AV conduction, and contractility
o Beta 1 blocker: decreased HR, AV conduction and contractility (when sympa activity
is increased)

ANS drugs and the heart: To treat hypertension, arrythmias, congestive heart failure, angina pectoris,
and myocardial infarction  MAIN drug for ALL is b blocker (selective and non-selective) - Work on
autonomic receptors

• Beta receptor blockers (widely used): dec HR (treat hypertension and arrythmias), dec AV
conduction (treat arrythmias, protect ventricles when atrial rate is high) (bradycardia or heart
block is a serious side effect), dec contractility (on ventricular muscle) (for heart failure,
angina and myocardial infarction)
• Beta receptor agonists (NOT widely used): inc HR and contractility (treat cardiogenic shock).
Precipitate arrythmias as a side effect – easy to cause excessive stimulation
• Muscarinic receptor blockers: inc HR (useful for bradycardia esp. after cholinergic poisoning)
• Alpha receptor blockers cause reflex (indirect) inc in HR (tachycardia) by causing
peripheral vasodilation and alpha agonists can cause reflex bradycardia

Blood Vessels: Dominant tone: sympa - Most blood vessels do not have cholinergic innervation

• Para: Ach, muscarinic agonists  M3 on endothelium  vasodilation (dec in Blood Pressure)

o Muscarinic receptor blockers - little or no effect
• Sympa: Alpha 1 agonist
o NE, EP  a1  contraction, inc vascular resistance and BP
o A1 blockers will cause vasodilation, decreased PR and BP
• Skeletal muscle, pulmonary, abdominal viscera, renal and coronary vessels have beta 2
receptors which cause vasodilation and decrease vessel resistance
o EP will dilate vessels, NE will not (little beta 2 activity)

Baroreflex – change in blood pressure (from blood vessel to brain) – fights against some drugs if they
target blood vessels (vasoconstriction – most /vasodilation - some)

ANS drugs and blood vessels: A1 blockers  vasodilation (treat hypertension) can cause reflex
tachycardia. OPPOSITE  A1 agonists  vasoconstriction (treat hypotensive shock) can cause reflex
bradycardia if BP increases

• Stimulation of Beta 2 with EP on blood vessels of skeletal muscles, lungs, abdominal

viscera, kidneys and heart will cause vasodilation

Kidney: Dominant: sympa - No cholinergic innervation of kidney

• Sympathetic Stimulation: NE, EP, beta 1 agonists  beta 1  inc renin secretion (increased
angiotensin and BP)
• Alpha 1 receptor stimulation will decrease the secretion of renin, but beta 1 effects predominate
• Clinical use: beta 1 blockers will decrease secretion of renin (which will decrease angiotensin
and reduce blood pressure)
Urinary bladder: Dominant tone: para (detrusor muscle – M receptor ALWAYS active), para and
sympa (sphincter – a1 controls constriction). Internal sphincter and detrusor muscle have to work
together to empty the bladder

• Para: Ach, muscarinic agonists (methacholine, cholinesterase)  M3, M2  detrusor

contraction, sphincter relaxation (emptying of the bladder)
o Muscarinic blockers (antagonist) will relax detrusor muscle and contract sphincter
to prevent bladder emptying
• Sympa: NE, beta 2 and 3 agonists  beta 3  relax detrusor muscle (but para dominates)
o NE, alpha1 agonists  alpha 1  contract sphincter (prevent bladder emptying)
o Alpha 1 blocker will relax sphincter to allow bladder emptying (used clinically)

ANS drugs – urinary bladder: Autonomic drugs used to treat urinary incontinence, urinary retention
and benign prostatic hypertrophy

• Muscarinic agonists (esp. cholinesterase inhibitors) contract the detrusor muscles and help to
empty bladder if there is urinary retention (e.g. spinal cord injury – nerve damage) (make
sure there is no physical obstruction to urine flow like bladder stones)
o Side effect of muscarinic agonists: urinary urgency and inc frequency (when used
for other conditions)
• Muscarinic receptor blockers prevent detrusor muscle contraction and are useful to treat urinary
incontinence (nocturnal enuresis) – blockers for hypertension relax bladder muscles
o Side effect of muscarinic antagonists: urinary retention
• In benign prostatic hypertrophy: enlarged prostate constricts neck of bladder causing urinary
retention and alpha 1 blocker is used to relax external sphincter and help micturition
(nothing wrong w/ detrusor muscle in BPH so do not use muscarinic agonists – only sphincter
causes problems)
Tracheal and Bronchial smooth muscle – use M blocker and b2 agonist together

• Para: Muscarinic agonists (methacholine) - Ach  M2, M3  contraction of bronchial smooth

muscle, increased secretions
o Antagonist muscarinic blocker used in surgery – before anesthesia to reduce secretions
• Sympa: Beta 2 agonists - Albuterol, EP  beta 2  relax bronchial smooth muscle (sensitive for
asthma – NO non selective b blockers)

Bronchial smooth muscle and glands: Beta 2 agonists are potent bronchodilators. 1st choice Treat
asthma (good for children). NO Beta 2 Blocker for asthmas = brachial restriction

• Limitation: produce desensitization w/ repeated use

• Non-selective beta blocker (to treat hypertension) will contract the bronchial
muscle (propranolol not given to asthmatics – sever constriction)
• Muscarinic blockers  relax the bronchial muscle - Treat asthma and COPD
Salivary and parotid glands: Dominant: para - Muscarinic agonists (AchE inhibitors)

• Ach  M3, M2  stimulate salivary and mucus secretions

o Muscarinic blocker will inhibit salivary gland and mucus secretions
 • Sympa: Alpha 1 agonists
o Adrenergic agonists  alpha 1  stimulate salivary secretions mildly
Clinical significance of autonomic innervation of the mouth

• Muscarinic agonists  treat dry mouth

o Xerostomia (autoimmune disorder = dry mouth) caused by radiation therapy of
head and neck
• Dry mouth in Sjogren syndrome  autoimmune disorder in women  dry eyes, less moisture
producing glands throughout body
o Muscarinic agonists help salivary secretion, hydration of mouth, and eases
swallowing provided there are still functional glands left
• Dry mouth  side effect of muscarinic antagonists used for other conditions (overactive
bladder)
• Muscarinic antagonists to reduce excessive secretions during anesthesia and surgery
(intubation) (excess secretions can cause obstruction to airways)

GIT smooth muscle: Dominant: para – peristalsis is constant

• Para: Muscarinic agonists (AchE inhibitors – inhibit enzymes)

o Ach  M3, M2  contraction of GI smooth muscle (stimulate peristalsis), in intestinal
secretions) (M1 will inc HCl secretion in stomach)
o Muscarinic blockers will inhibit peristalsis and intestinal gland secretions
• Sympa (much milder): Adrenergic agonists  beta 1 and 2, alpha 1 and 2  relaxed GI smooth
muscle (inhibited peristalsis), inhibited secretions, contraction of sphincters
o Alpha 1 will contract sphincters, alpha 2 will inhibit intestinal gland secretions
o Adrenergic blockers will not have noticeable effects on GIT (sympa b/c not dominant)

GIT muscle and glands: Due to dominant para tone  muscarinic agonist and antagonist mainly used

• Autonomic drugs treat: Excessive peristaltic activity/secretions (Diarrhea, Irritable bowel

syndrome, Salivation, Acid) OR Decreased peristalsis and secretions (Gastric atony (loss
of muscle strength), Paralytic ileus, Dry mouth)
• Muscarinic agonists will stimulate or inc peristalsis, relax sphincters and inc intestinal
gland secretions
o useful to treat gastric atony, paralytic ileus, dry mouth
• Muscarinic agonists  inhibit or dec peristalsis, constrict sphincters, and dec intestinal gland
secretion (dicyclomine)
o treat cramping, diarrhea, irritable bowel syndrome, gastric acidity
o Excessive peristalsis = overactive = cramping muscles, M antagonist to treat

Liver: Dominant: sympa innervation - Beta 2 receptor agonists

• EP beta 2  glycogenolysis, gluconeogenesis

o Inc plasma glucose in response to hypoglycemia (release glucose from liver)
• If plasma Glu decreases in patients’ with type 1 diabetes taking insulin, the sympa stimulation
of liver releases glucose and corrects hypoglycemia and reduces risk of hypoglycemic coma
 o Non-selective beta blockers – prevent glycogenolysis and gluconeogenesis
▪ Not allow plasma glucose to increase in response to hypoglycemia
▪ For diabetics likely death b/c unable to correct
▪ Beta 2 blocker bad for diabetics (and asthma)
o Clinical relevance: type 1 diabetic patients on insulin are prone to develop
hypoglycemia and coma as a serious side effect of insulin

Uterus: Sympa innervation - Beta receptor agonists

• short acting (less risk to fetal heart) beta 2 agonists – SABAs  beta 2  relaxation of uterine
smooth muscle
• beta 2 agonist will relax uterus, reduce contractions and early birth, short acting, less fetal risk
o Clinical relevance: SABAs can be used to prevent premature labour
o Oral beta agonists are not indicated for any obstetric condition. Only parenteral
SABAs given for a max of 48 h

Eyes: Two sets of muscles have autonomic innervation which is clinically important

• Iris muscles (circular and radial fibers)- control pupil size

o a1 receptor for radial – agonist receptor for dilation
o M receptor blocker to dilate pupil
• Ciliary muscles (circular and longitudinal fibres) – control aqueous humor production, Lens
shape and image focus on retina

Eyes - pupillary muscles, ciliary muscles - Dominant: para

• Para - Muscarinic agonists (for miosis & glaucoma) - Contraction of circular (sphincter fibres)
of iris and miosis (narrowing of pupil). Muscarinic blocker - Cause mydriasis (dilation of pupil)
• Sympa - Alpha 1 agonists - Contraction of radial muscle and mydriasis, Vasoconstriction
o Adrenergic receptor blockers will have little or no effect (sympa not dominant)

Eyes - glaucoma: Increase in intraocular pressure b/c Inc production of aqueous humor and Dec
outflow (drainage) of aqueous humor – TREAT with cholinesterase inhibitor, M agonist, Beta receptor
agonist

• b2 blocker decreases blood flow = decreased secretion of aqueous humor (behind lens)
vitreous humor (in front of lens)
• pupillary dilation causes obstruction to aqueous outflow, M drugs to constrict and allow to drain
• Aqueous humor: Produced by secretion form ciliary processes and flows from posterior
chamber through pupil into anterior chamber and leaves eyes primarily by trabecular meshwork
and canal of Schlemm. Then drains into episcleral venous plexus and systemic circulation
o Pathway accounts for 80-95% of outflow and is target for cholinergic drugs
• Para blocker: Circular ciliary M relaxed (Muscarinic blockers), Zonule fibres stretched, Lens
pulled flat- focusses on distant objects
o Para effect: Circular ciliary M contraction (Para effect or muscarinic agonists),
Zonule fibres relaxed, Lens bulges – focusses on near objects

Para stimulation or cholinomimetic drugs:

 1. Muscarinic agonists (M3, M2) contraction of longitudinal ciliary fibres causes opening of
trabecular meshwork and drainage of aqueous humor – reduced intraocular pressure – used
for glaucoma
2. Muscarinic M3, M2 receptors on ciliary muscles will cause spasm of accommodation
3. M3, M2 receptors on lacrimal glands will cause

lacrimation Sympa stimulation or sympathomimetic drugs:

1. Beta 2 receptors on ciliary epithelium and blood vessels – stimulation increases blood flow and
aqueous humor secretion – beta 2 antagonists, reduce blood flow and decrease aqueous
humor secretion and pressure
2. Alpha 2 agonists, reduce aqueous production (presynaptic action – reduce NE release and
its effects; postsynaptic action – reduce aqueous production by reducing cAMP)
3. Beta 2 receptors – relax ciliary muscles and increase tension of fibres holding the lens
which becomes flatter (focusses on far- blurring of near)

Skeletal muscle: Motor nerves - No adrenergic innervation

• Stimulation of motor neurons

o Nicotinic agonists (Ach, reversible AchE inhibitors)
o Ach  Nm  muscle contraction
o Neuromuscular blockers will cause skeletal muscle relaxation
• Competitive nicotinic receptor antagonists and depolarizing blockers are used to induce
skeletal muscle relaxation during surgery
• Muscle paralysis caused by irreversible ChE inhibitors cannot be reversed by drugs
o Competitive irreversible inhibitor OR agonist which can’t be broken down by ChE,
causes muscle paralysis
• Na+ channels on muscles want Ach to go to the channel to depolarize. Enzymes near the channel
breakdown the Ach, Blocker for enzyme stops breakdown = more Na+ channels working
• Two type of NM blockers: Competitive (d-tubocurarine), Depolarizing (succinylcholine)
o Succinylcholine is an agonist, which causes persistent stimulation and depolarization
(not rapidly metabolized by cholinesterase), so muscle cannot recover (repolarize)
and becomes paralyzed
o Irreversible ChE inhibitors have same effect as succinylcholine- cause
depolarizing paralysis
Brain: Cholinergic and adrenergic receptors

• Para - Stimulation of muscarinic receptors in brain (M1 in hippocampus) plays role in

memory (ChE inhibitor, allows more Ach to improve memory), in striatum (M3, M4) it
interacts with dopamine to control muscle contraction (Parkinson’s)
o Ach  M1, M4  memory, coordination of muscle contraction
• Indirect cholinergic agonists (Ach deficient) - ChE inhibitors are used clinically for
Alzheimer’s disease (loss of cholinergic function)
• Muscarinic antagonists (Ach excess) - are used for Parkinson’s (excess cholinergic function)
o Need Ach and dopamine balance – opposite treatments for Alzheimer’s and Parkinson’s
Drugs to modulate PNS

• Parasympathetic effects can be mimicked by:

o Muscarinic receptor agonists - direct acting: carbachol, pilocarpine
o Acetylcholinesterase inhibitors (increases Ach) - indirect acting: these drugs delay
the breakdown of Ach and prolong its action
• Parasympathetic effects can be blocked by:
o Muscarinic receptor antagonists (e.g. atropine)
o Skeletal neuromuscular junction blockers (e.g. tubocurarine)

Therapeutic uses of parasympathomimetic - Cholinergic agonists used to:

• Reduce intraocular pressure in glaucoma

o M agonist drugs work on ciliary muscle to allow drainage of aqueous humor, can
also restrict iris muscle
o Pilocarpine eye drops (better tolerated than anticholinesterases) cause contraction
of ciliary muscle and open trabecular meshwork to facilitate outflow of aqueous
humor
▪ ChE to block receptor and drain
o They do not affect aqueous
production
o Also used in narrow angle glaucoma to cause miosis (pupillary constriction) and
facilitate drainage of aqueous humor
• Increase the motility (peristalsis) of GI tract
o Bethanechol is used in cases of postoperative abdominal distension, gastric
atony, gastroparesis, congenital megacolon, postoperative ileus (hypomotility)
• Increase motility of the urinary tract (bladder contractions)
o Bethanechol used in urinary retention (postoperative and postpartum),
hypotonic bladder
• To increase salivary secretions
o Treat xerostomia - following head and neck irradiation or associated with Sjogren’s
syndrome (autoimmune disorder in women whom salivary and lacrimal secretions
are reduced) - pilocarpine is given orally (can cause excessive sweating)
▪ Reduced secretion can be in many organs
Cholinesterase inhibitors: Ach released at synapse acts for a few milliseconds before it is metabolized
in synapse. Whole Ach molecule is not taken back into presynaptic neuron like NE, therefore we do not
have clinically used uptake blockers for Ach

• Enzyme is acetylcholinesterase (AchE) - It is present in synaptic cleft on outer membrane of

the postjunctional cell (neuron or effector organ)
• Hydrolysis of Ach is one of the fastest known enzymatic reactions – approx 104 molecules of
Ach/ second by a single enzyme molecule

Cholinesterase (mainly in plasma & liver): Two types of ChE enzymes: AchE, Butyryl-cholinesterase
(BuChE, plasma or pseudoChE) – inhibitor blocks BOTH

• BuChE located at non-neuronal sites, mainly in plasma and liver

 o Metabolizes certain drugs, including some local anesthetics, and succinylcholine
(muscle relaxant)
• Most enzyme inhibitors used clinically do not discriminate between the two types of ChEs
• Acetylcholinesterase inhibitors increase the duration of action of released Ach at
synapse (indirectly acting parasympathomimetic)
• Potentiated responses due to stimulation of muscarinic and skeletal neuromuscular
nicotinic receptors are seen

Therapeutic relevance: Compounds that bind to cholinesterase can produce one of three chemical
rxn, Ser-OH represents the catalytic region

• Acetylation - caused by Ach: acetylated enzyme – rapid recovery

• Carbamylation - reversible therapeutically used drugs – ChE inhibitors: carbamylated
enzyme- recovers more slowly 3-4 h
• Phosphorylation - irreversible, poisons the enzyme: nerve gases, organophosphate insecticides

Cholinesterase inhibitors (blocks enzyme = inc Ach): AchE hydrolyzes Ach and enzyme become
acetylated. AchE deacetylates rapidly, enzyme recover fast (normal) – Ach binds to enzyme, broken
down diffuses = reversible

• Reversible inhibition (therapeutic): reversible AchE inhibitor such as neostigmine

causes carbamylation of enzyme – longer lasting inhibition, reversible, useful without
toxicity
o Hydrolysis of carbamylated enzyme occurs slowly (3-4h), causing reversible
inhibition of enzyme
• Irreversible inhibition (poisoning - toxicity): bonds to enzyme, covalent bond
almost irreversible, body needs to synthesize more enzyme to replace
o Irreversible inhibitor (di-isopropyl fluorophosphate) causes phosphorylation of enzyme
o Dephosphorylation and recovery (if it occurs at all) takes several hours
o After some hours phosphorylated enzyme loses a chemical group (aging) and
drug enzyme complex forms a new chemical with no enzyme activity
o An oxime such as 2-PAM, if administered before aging occurs, can bind to and
release the phosphate moiety attached to enzyme, process reverses enzyme
inhibition
▪ Need within 6 hours of poisoning
Reversible ChE inhibitors (therapeutic): These drugs will increase cholinergic activity where it is lacking
or decreased

• Eye- aqueous humor outflow facilitated and decrease in intraocular pressure

o Treat glaucoma, Can cause cataracts with long-term use
▪ Used only in aphakic patients (lacking a lens), or in cases in which other
agents are ineffective
o These drugs and muscarinic agonists have many side effects so not much used
• Topical application to conjunctiva causes miosis (narrowing of pupils)
• Ciliary muscle contraction - lens focusses on near objects, but far vision is blurred
ChE inhibitors: locations and uses

• CNS - to treat memory loss of Alzheimer’s

 o Donepezil and tacrine have higher affinities and partition into lipids and cross
blood brain barrier – reach brain easily b/c highly lipid soluble
• Intestine - to stimulate peristalsis in postoperative ileus, congenital megacolon (in which there is
atony of smooth muscle)
o ChE inhibitors also relax sphincters to facilitate peristaltic mvt
• Urinary bladder - to treat urinary retention due to atony of smooth muscle
• Skeletal muscle neuromuscular junction- activate nicotinic receptors
o Low doses increase the force of contraction and are used to treat patients
with myasthenia gravis (neuromuscular disease – weakness in skeletal
muscle)
• Also used for the diagnosis of myasthenia gravis
• Intermediate doses of ChE inhibitors can cause muscle fasciculations and fibrillations due
to desynchronized depolarizations from multiple receptor stimulation
• High doses cause persistent depolarization blockade and muscle paralysis
• To reverse skeletal muscle paralysis produced by competitive NM blockers used during surgery
• Anti-ChE agents will reverse antagonism created by competitive NM blockers such as d-
tubocurarine, but they will add to the depolarization and paralysis caused by succinylcholine
and
make it worse

Muscarinic Receptor Agonists/ChE inhibitors – Side effects: Inc urinary frequency/urgency, diarrhea and
cramping, nausea/vomiting, bradycardia, hypotension, inc salivation, miosis, difficulty in visual
accommodation with blurred distant vision, inc bronchial secretions and bronchoconstriction, sweating

• NO M agonist or ChE inhibitor - in patients with asthma, chronic obstructive pulmonary

disease, obstruction of urinary or GI tract, acid-peptic disease, bradycardia, and hypotension

Botulinum toxin: A toxin released by bacteria clostridium botulinum. Botulinum toxin blocks Ach release
(inhibits release from terminal), Paralyzes skeletal muscle in cases of excessive involuntary skeletal
muscle tone

• Clinical uses (BOTOX): strabismus (unaligned lines of vision between a pair of eyes),
blepharospasm (contracted eyelid – fix with local injection), hemifacial spasm. Cosmetic:
remove facial wrinkles. – local drugs safer in both clinical and cosmetic

Muscarinic cholinergic receptor blockers: Parasympatholytics, Belladonna alkaloids – natural occurring -

(Atropine, Hyoscyamine, Scopolamine), Semisynthetic and synthetic (Dicyclomine, Glycopyrrolate,
Ipratropium, Oxybutynin, Tropicamide) – try to synthesize to selectively inhibit M drugs

Muscarinic Receptor Antagonists (therapeutic):

• Heart: to treat severe bradycardia produced by organophosphorus insecticides and nerve

gas poisons (irreversible cholinesterase inhibitors) – excess Ach at synapse = inc HR
• Eyes: cause pupil dilation (mydriasis – dilate pupil with drug for better examination)- used
for examination of retina and measurement of refraction; inflammatory uveitis
• GIT: to treat excessive peristalsis of irritable bowel syndrome, cramping (dicyclomine as
an antispasmodic) – relieved by M blocker
• To decrease gastric acid secretion (pirenzepine- selective for M1 receptors – in patients w/
peptic ulcers) – rarely used – much safer drugs
 • Urinary bladder: Urinary incontinence (daytime urinary frequency), Nocturia, Urgency
o Incontinence: Decrease excessive contractile activity, relatively selective for
M2/M3- more selective for urinary bladder (uroselective) and cause fewer effects
such as dry mouth and blurred vision
• block M1 receptor in vestibular apparatus - to treat motion sickness (scopolamine – lipid soluble,
absorbs directly through skin)
• treat chronic obstructive pulmonary disease (COPD)
o ipratropium and tiotropium- derivatives of atropine- administered by inhalation to
patients w/ obstructive lung diseases (asthma, emphysema, and chronic bronchitis)
- cause bronchodilation - not absorbed into systemic circulation - produce few
adverse effects
• inhibit excessive salivary and respiratory tract secretions (glycopyrrolate - given preoperatively)
• Parkinson’s disease to treat uncoordinated muscle contraction (e.g. trihexyphenidyl
and benztropine)
• Some antihistamines, tricyclic antidepressants, and antipsychotics have prominent
anti- muscarinic side effects – Can block M receptors – too many side effects
Scopolamine vs atropine: Scopolamine (more lipid soluble) well absorbed orally, and reaches brain more
readily than atropine. Scopolamine approx 10 times more potent at producing CNS effects

• Greater fraction of scopolamine present in unionized form at physiological pH than

atropine- facilitates its absorption through skin
• Scopolamine used for motion sickness as a transdermal patch placed behind ear (duration
of action 3 days)

Muscarinic Receptor Antagonists – Side effects: Urinary retention, constipation, tachycardia (caused by
blocked SA node), dry mouth, mydriasis, blurred vision, inhibition of sweating, toxic psychosis

• NOT USED in patients with atony of bowel, urinary retention, or prostatic hypertrophy
• Ophthalmological use NOT USED in elderly and in patients within narrow angles
Neuromuscular Junction Blocker: Nicotinic cholinergic receptor is blocked

• Ach-gated sodium channel (ion channel receptor) – drugs can bind to either isoform of receptor
o Polypeptide pentamer: Alpha, beta, delta, and epsilon subunits
o Ach binding to receptor causes sodium influx, membrane depolarization, release
of calcium from sarcoplasmic reticulum and muscle contraction
o Nicotinic receptors at autonomic ganglia and in brain have different subunit composition
• Two types based on electrophysiological differences in their mechanism of action (2 ways
to paralyse)
o Competitive (antagonist) - Competitively antagonize actions of Ach at nAchR.
Chemical structure different than Ach, ex. Curare
o Depolarizing agents (agonist – NOT broken down by ChE) - Drug occupies and activates
nicotinic receptor (agonists) for a prolonged period of time, prevents repolarization
and makes the muscle fibre refractory to further nerve impulses – depolarizing block.
Chemical structure similar to Ach ex. Succinylcholine
Competitive neuromuscular blockers: Native south Americans used certain plant extracts as arrow
poison, caused muscle paralysis – only injections paralyze tissue

• D-tubocurarine (plant extract) - Purified extracts in patients with tetanus and spastic disorders
o Used for muscle relaxation in general anesthesia
• Block the action of Ach at nicotinic receptor - Produce flaccid paralysis
• Contraction is partially impaired when 75-80% of receptors are occupied
• Contraction is totally inhibited when 90-95% of receptors are occupied
• Block can be reversed by increasing the concentration of Ach
• ChE inhibitors - neostigmine - are used clinically to reverse neuromuscular block caused
by competitive blockers

Sequence of muscle paralysis: I.v. competitive blocker- motor weakness progressing to total flaccid
paralysis: Small rapidly moving muscles paralyzed first (eyes, jaw, larynx)  Limbs, trunk  Intercostal
muscles  Diaphragm (respiration stops) – can use lower dose to paralyze all but diaphragm

• Recovery occurs in reverse order

Competitive neuromuscular blockers – main side effects:

• Ganglionic blockade (non-specific blockers): Fall in blood pressure, Tachycardia (when

vagal block)
• Nm Blocker cause Histamine release (non specific): Bronchospasm, Hypotension
(vasodilation), Increased bronchial and salivary secretions

Depolarizing neuromuscular blockers: Only one clinically - Succinylcholine

• Binds to and activates muscle nicotinic receptors

• Not metabolized by AchE (remains in synapse longer)
• Causes persistent receptor stimulation
• Succinylcholine is hydrolyzed by butyrylcholinesterase (pseudocholinesterase) in plasma
– broken down by other Ach in plasma

Depolarizing (DP) Nm blockers: Succinylcholine (Sch)- short duration of action – rapidly broken down if
injected

• Rapid hydrolysis by plasma butyrylcholinesterase – mutation = NO Sch breakdown

• Certain patients exhibit several variants of this enzyme, which lead to prolonged and
potentially dangerous durations of NM block

DP Nm blockers - side effects: DP agents can release K+ rapidly from intracellular sites

• Hyperkalemia (below 5mmol), rhabdomyolysis (more serious with muscle breakdown), and
cardiac arrest. Hyperkalemia can be dangerous in heart failure patients on digoxin or
diuretics (alter K+ levels)
• DP blockers should be avoided in patients with soft tissue trauma or burns b/c
muscles compromised, release large K+ if on drugs
• Avoid in rhabdomyolysis, ocular lacerations, spinal cord injuries w/ paraplegia or quadriplegia
or muscular dystrophies
 • Not given to children under 8

Innervated muscle: Systemically administered Sch reaches all of muscle membrane but depolarizes only
junctional receptors because AChRs are only located in this area. With denervation, muscle (nuclei)
express not only extrajunctional AChRs but also AChRs throughout muscle membrane. Systemic Sch in
contrast to Ach released locally, can depolarize all up-regulated AChRs leading to massive efflux of
potassium resulting in hyperkalemia

Malignant (toxic) hyperthermia (inc heat production in body) – a side effect Sch

• Seen after certain anesthetics (halothane, isoflurane, sevoflurane) and Nm

blockers (succinylcholine). Can be life threatening
• Genetic abnormality - mutation in ryanodine receptor = increased Ca2+ release
form sarcoplasmic reticulum of skeletal muscle = high muscle activity = inc heat
• Contracture, rigidity, heat production from skeletal muscle, hyperthermia, accelerated
muscle metabolism, metabolic acidosis, and tachycardia
• Treatment: dantrolene - block Ca2+ release
Therapeutic uses of Nm blockers: In surgical anesthesia to obtain relaxation of skeletal muscle,
particularly in abdominal wall

• Reduces the need for deeper anesthesia associated with respiratory and CV depression
• Orthopedic procedures - correction of dislocations and alignment of fractures
• To facilitate tracheal intubation - laryngoscopy, bronchoscopy, esophagoscopy (along
w/ anesthetic)
• To prevent trauma during electroshock therapy (causes skeletal muscle contraction)
• Administered mostly by trained anesthesiologists and clinicians
• Facilities for respiratory CV resuscitation should be available
Drugs to modulate sympathetic nervous system: Sympathetic effects can be mimicked by:

• Adrenergic receptor agonist (direct acting, e.g. epinephrine, albuterol)

• Norepinephrine uptake blockers (indirect acting, e.g. cocaine, imipramine (non-specific
blocker, also blocks serotonin uptake)
• Monoamine oxidase and COMT inhibitors (these drugs delay the breakdown of NE and
prolong its action) (indirect acting, e.g. pargyline, entacapone)
• NE releasing agents (from nerve terminal, indirect acting, e.g. amphetamine)
Sympathetic effects can be blocked by: Adrenergic receptor antagonists (e.g. prazosin, propranolol)

Termination of NE action at synapse - reuptake into nerve terminal - Uptake 1 - The released
transmitter is taken up back into presynaptic nerve terminal

• Uptake 1 can be blocked by several drugs including cocaine

• Uptake 1 blockers will increase sympa activity
Response of the heart to changes in blood pressure: Baroreceptor control of blood pressure and heart
rate. SNS, PNS – if HR falls, sympa will dominate to fix
 • Stretch receptors in blood vessels in blood vessels in the carotid sinus or in aortic arch
respond to changes in blood pressure
o PNS: decrease heart rate SNS: increase heart rate and force of contraction

Adrenergic receptor agonists: Relative activity or sympathomimetic amines at adrenoceptors

• EP - equipotent at alpha and beta receptors, NE (NO NE for asthma – not a good brachial dilator)
- activate alpha and beta1, has little activity at beta2 - Little less potent than EP at alpha
• EP and NE decrease blood flow to kidneys
• Isoproterenol - most potent sympathomimetic amine - acts exclusively on beta
• Dopamine - activates cardiac beta1 receptors, dopamine receptors in kidneys cause
increased renal blood flow

NE: Decreased HR (reflex bradycardia), Increased blood pressure Increased peripheral resistance (a 1)

EPI: Increased heart rate (beta 1), No change in blood pressure, Decreased peripheral resistance (beta 2)

Therapeutic uses of adrenergic drugs:

• Allergic reactions - anaphylactic shock e.g. epinephrine - increased heart rate and contractility,
constricts some and dilates some vessels to maintain BP, bronchodilation
• Bronchodilators (asthma) - albuterol, beta 2 agonist - inhaled drugs 1st choice for asthma
• Nasal decongestion - e.g. ephedrine - activate both a1 and a2 receptors - a2 can cause
damage (constricts mucosal vessels to decrease secretions)
• CNS stimulants - for ADHD or narcolepsy
• Anorectic - phentermine (Decreased appetite - receptor in hypothalamus control)
• Cardiac stimulants - e.g. dobutamine, beta 1 agonist (inc contraction in heart) used
sometimes for heart failure when other drugs prove ineffective
• As pressor agents (hypotension) - e.g. EP or NE (hypovolemic shock)
• For local vasoconstriction - e.g. EP (cause vasoconstriction) it is combined with local
anesthetic to prevent systemic effects of the latter when it is injected subcutaneously
Therapeutic uses of adrenergic receptor blockers:

• Hypertension: Metoprolol beta 1 blocker decreases heart rate and contractility, Prazosin alpha
1 blocker causes vasodilation, Clonidine alpha 2 blocker decreases sympathetic outflow from
CNS in treatment of hypertension
• Emergency treatment of hypertension - labetalol (a1, b1, b2)
• Hypertension in pheochromocytoma - phentolamine (a1, a2), metoprolol (b1), atenolol (b1)
o Decreased HR and contractility and work load of heart
• Cardiac arrythmias - e.g. propranolol, sotalol (dec HR and AV conduction)
• Migraine headache - propranolol
• Benign prostatic hyperplasia - tamsulosin (a1), prazosin (relax external sphincter of bladder
to help micturition)
• Glaucoma - timolol (dec secretion of aqueous humor)