Pharmacology Part 2
 Pharmacology consists of pharmacodynamics and
pharmacokinetics
 Pharmacodynamics describes how a drug acts in the
body
 Pharmacokinetics describes how the body acts on the
drug
Drugs and mechanisms of action
 A drug’s mechanism of action is how a drug acts in the
body specifically and this is the term used in drug
monographs packaged with the drugs and used in
references
 Typically a drug has a pharmacological target. A
pharmacological target is a target in a cell of the body that
the drug acts on to produce its effect. Its called sometimes
as the drug’s “site of action”
 Pharmacological targets
 Cell membrane receptors
 Cellular enzymes
 Cell organelles (mitochrondrion)
Drug Receptor Interaction
 Drug that produces its effect on a receptor is often called an
agonist or antagonist
 A receptor is a molecule, usually on the surface of a cell,
that binds to a hormone, neurotransmitter, or a drug. The
receptor once it binds its ligand triggers a series of
chemical reactions in the cell that produces a response.
 For example, a beta receptor is a receptor that is present on
the heart and lungs. When the beta receptor binds to
norepinephrine or adrenalin, it signals to the heart to begin
contracting stronger and at a faster rate.
Ligand and Receptor Interaction
Example is the heart
Cell= cardiac myocyte
Ligand= norepinephrine
Receptor= Beta Receptor
Cellular response is the
opening of Na+ and Ca++
channels to produce a
faster and more forceful
contraction
Courtesy of http://cc.scu.edu.cn
Examples of Receptors in the Body
 Alpha receptors in the arteries of the body
 Beta receptors in the lungs and the heart
 Insulin receptors on fat cells and muscle
 Muscarinic receptors on the eyes, GI tract, and many
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other organs including the heart
Nicotinic receptors on skeletal muscles
Histamine receptors in the skin and brain
Vasopressin receptors in the kidney and arteries
LH, FSH receptors on testes/ovaries
 An agonist is a drug that binds to a receptor and
triggers the receptor.
 An antagonist is a drug that binds to a receptor and
blocks its activation.
Drugs that target enzymes
 An enzyme is a protein in the cell that catalysts and
enables a chemical reaction to take place in the cell.
 Examples
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Glucokinase= enzyme that initiates metabolism of glucose
Pyruvate Dehydrogenase= enzyme that allow lactic acid to be
regenerated in glucose
Cytochrome C oxidase= one of the enzymes that uses oxygen
to “create” energy
DNA polymerase= enzyme that allow the replication of DNA
Drug Enzyme Interaction
E= HMG CoA reductase (a enzyme that
allows the liver to make cholesterol)
S= HydroxymethylGlutaryl CoA
Reaction= Cholesterol formation after a
long reaction
I= Statin drugs
Some Enzyme Inhibitors are POISONS
E= Cytochrome C oxidase
S= oxygen and cytochrome C
I= cyanide ion
No reaction= complete inhibition of
Courtesy of :
cellular respiration and death of the
http://www.mrothery.co.uk/enzymes/enzymenote
organism
s.htm
Examples of Enzyme Inhibitors
 An example is an enzyme required to breakdown fats in your diet
and is called Pancreatic Lipase which is secreted by the pancreas
into the bile ducts into the small intestine and catalyzes the
reaction in the breakdown of fats to fatty acids and glycerol.
 The drug Oristat or Xenical ® is a drug that blocks the enzyme
pancreatic lipase from working. This will cause the fats to not be
broken down and not absorbed. Xenical ® was marketed as an
anti obesity drug.
 The class of drugs called statins (lipitor® and Zocor®) are
inhibitors of the enzyme, HMG CoA reductase in the liver, which
is required to make cholesterol.
 Viagra® is a cGMP phosphodiesterase inhibitor. The enzyme
causes the sexual organs to lose blood. If it is blocked, erections
are prolonged and sustained
Drugs that target cellular
organelles
 Not every common mechanism of action.
 Examples of cellular organelle and their function:
 Mitochondria: site of action of energy generation in fatty
acid oxidation and carbohydrate metabolism
 Nucleus: houses DNA and site of genetic transcription
 Rough endoplasmic reticulum (RER): site of protein
synthesis
 Golgi Apparatus: site of protein modification in the cell
 Lysosomes: site of digestion of cellular macromolecules
 Common among antibiotics
 Beta lactam Abx- bind to PBPs that are involved in cell
wall synthesis
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Penicillins , Cephalosporins, and carbapenems
 Ex: Penicillin G, Ceftriaxone (Rocephin®), Ceftazidime
(Fortaz®) and Cefepime (Maxipine®)
 Aminoglycosides- targets the ribosome (RER)in
bacteria.
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Ex: Gentamicin (Garamycin®), Amakacin (Amakin®)
 DNA intercalation agents
 In chemistry , a intercalation agent binds to a macromolecule
in a specific way between two chemical groups
 Ex: Daunorubicin is a drug that intercalates between DNA
bases (Guanine and cytosine nuceotides) and interferes with
DNA replication among rapidly dividing cancer cells
Image source:
http://www.photobiology.com/photoiupac2000/pierard/Interactionmain.ht
ml
 Daunorubicin is an chemotherapy drug used in the
therapy of acute lymphocytic leukemia.
 It is a good example of how most chemotherapy drugs
work by intercalation
 Duanorubicin (also called Duanomycin) and
Doxirubicin are both isolated from a soil bacteria
called Streptomyces peucetius
 This bacterium also produces the antibiotic
Streptomycin which was originally used for
Tuberculosis
 proteasome: a cellular structure composed of proteins
that degrade old or damaged protein in the cells.
Important for cell cycle and replication
 A proteasome inhibitor (not the same as protease
inhibitor for HIV) is a drug that interfere with the
function of this complex
 In 2003, bortezomib (Velcade®) was the first
proteasome inhibitor to be approved for use in the U.S.
for multiple myeloma
Drug that bind to Ion channels
 Ion channels are protein channels that span a cellular
membrane that provides a pathway for the flow of ions
 Ions important for human physiology are Na, K, Ca, Cl
and Mg
 Clinically the important ones are the channels for Na,
K and Ca.
 Under normal conditions some channels are open or
closed. When the cell is stimulated by a chemical
trigger (neurotransmitter, hormone, or a drug agonist)
the state of the channel either opens or closes
Sodium Ion Channel Blockers
 These drugs can be used to treat cardiac arrhythmias,
seizures, and to induce localized anesthesia
 Sodium channels are open in responds to hormones and
other electrical triggers. The flow of sodium begins nerve
impulse conduction in neurons.
 Sodium Blockers include:
 Lidocaine (Xylocaine®) used to block sensory neurons for
anesthesia purposes and the treat ventricular tachycardias.
 Procainamide (Pronestyl®) used to treat cardiac arrhythmias
 Quinidine is an older drug used before procainamide
 Phenytoin (Dilantin®) is a drug used to treat epileptic seizures
Calcium Channel Blockers
 Drugs that block calcium ion channels
 Clinically a very important group of drugs
 Blocking calcium flow into the heart as two effects
 Lowers the heart rate
 Decrease the force of contraction
 Blocking calcium flow in the smooth muscles of
arteries relaxes them.
Calcium Channel Blockers
 Dihydropyridine type : used to treat HTN
 Amlodipine (Norvasc®)
 Felodipine (Plendil®)
 Isradipine (Dynacirc®)
 Nicardipine (Cardene®)
 Nifedipine (Procardia®)
 Non dihydropyridine: used to slow rapid heart rates
 The two to remember are:
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Verapamil (Calan® and others)
Diltiazem (Cardizem®)
Drug Interactions
 Drug Interactions typically involve pharmacodynamic
interactions in which the way the two drugs work on the
body can produce synergistic effects or antagonistic effects.
 Synergistic drug interactions:
 Agonists are the same receptor: epinephrine and
norepinephrine
 Drugs with different mechanisms of action producing same
effect: epinephrine (agonist at the beta receptor) and atropine
(antagonist at the muscarinic receptor) both receptor in the
heart
 True case in point: IV Metoprolol ( beta blocker)+ IV
Diltiazem (Calcium channel blocker) + IV lidocaine (sodium
channel blocker) to produce severe bradycardia and cardiac
arrest
 Antagonistic drug interactions
 Two drugs that work on a receptor one as an agonist and
one as an antagonist. For example, albuterol (agonist on
beta receptor) and metoprolol (beta blocker). Effect is
variable but both drug cancel the others effect.
 Two drugs with different mechanisms of action to
produce opposite effects. Example. Insulin NPH 25
units at bedtime and prednisone 20 mg bid. One drug
lowers blood glucose and the other raises it
Pharmacokinetic Drug Interaction
 Some drug interactions involve pharmacokinetics in that
one drug effects the way the body handles or metabolize
the other drug. One drug may block the metabolism of the
other or it can accelerate the metabolism of another
 The body primary detoxifier is the liver. The liver has a
series of enzymes the job of which is to metabolize drugs or
chemicals to inactive forms. The system is called the
cytochrome P450 system or CYP450 for short.
 Some drugs block the activity of this system
 Some drugs activate or induce the system
Important Interactions every
Pharmacy Technician should know
 If you come across such drug interactions it is important to let the
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pharmacist aware of the situation
Interaction 1: warfarin vs. many drugs. Warfarin or coumadin ® has
many drug interactions. Critical ones involve NSAIDS like ibuprofen
and diclofenac and aspirin. Other interaction involve herbals like
gingko and garlic. These interaction increase the risk of fatal bleeding
Interaction 2: ACE inhibitors (enalapril, lisinopril) and potassium
supplements like KDUR. Potassium levels in the blood can become
very high and can be dangerous
Interaction 3: Statin drugs with CYP450 inhibitors. Statin level will rise
in the blood and can result in rhabdomyolysis, a muscle disorder. Any
patient with muscle pain and taking a statin like Lipitor ® should be
counsel by the pharmacist immediately
Interaction 4: Digoxin and Amiodarone: elevated digoxin levels and
fatal cardiac effects
Dose Response Curve
 In a dose response curve , as the dose increases the
response increase slowly at first, then dramatically and
then the response levels off, this is called a ceiling
effect
 The ceiling effect is sometimes called pharmacological
tolerance and notably occurs with opiate analgesics
 ED50 is the dose of drug that produces 50% of the
maximal drug effect
Pharmacokinetics
 The study of the way that body handles the drug
 The pharmacokinetics of a drug involves its absorption,
distribution, metabolism and the elimination of the drug
or the “ADME” of a drug
 Pharmacokinetics most often involve the time course of a
drug. Time course include its “onset of action”, “duration
of action” and its “elimination” or wearing off.
 Absorption and distribution constitute the “onset of
action” of a drug and its “duration of action”.
 The metabolism and elimination are involved in the
“wearing off” effect.
Absorption
 The absorption of the drug begins at a body surface
 It could be in the stomach, the small intestine, or the skin.
 The factors that influences absorption of drugs include solubility of a
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drug, ionization of drugs, and the dosage form.
Not all of the drug that is given is actually absorbed. Some of the drug
passes into the feces.
In addition, once a drug is absorbed in the GI tract. Its travel through
the hepatic portal vein into the liver where the drug is partially
metabolized by the CYP450 system. Thus the fraction of the drug that
makes it into the body is called the bioavailability.
The passing of an oral dose through the liver is called the “first pass
effect”
The first pass effect is why IV administration of a drug is more potent
that the oral route
Distribution
 Passive Diffusion: Drug passes through the membrane intact
 Facilitated Diffusion: Drug passes through the membrane with
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assistance by membrane carrier proteins
Active Transport: Drug passes through the membrane with the
help of a carrier against a concentration gradient
Part of the distribution of a drug is how it travels in the blood
and lymphatic system. Most drugs travel in the bloodstream
bound to an plasma protein like albumin
Binding to albumin allows a drug to remain in the body longer
A drug that is highly protein bound keep the drug confined to
the blood and lower its volume of distribution.
Volume of distribution is used by the pharmacist to calculate
loading doses of some critical drugs
Metabolism
 The liver and the kidney and sometimes other organs
are involved in the metabolism of drugs to inactive
metabolites. Mostly the liver does this for the body
Elimination
 When drugs are converted to inactive metabolites they are then
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transported into the blood to the kidneys
The kidney then filters out the drug metabolites into the urine.
At times the metabolites that the liver produces are not
completely inactive. Thus in elderly patients and in people with
renal disease that have bad renal function are at high risk for
drug metabolite accumulation and severe side effects
A commonly used measure of renal function is the creatinine
clearance. A clearance of 30 ml/min is considered renally
impaired
When taken together the metabolism and elimination of a drug
is called its clearance.