Pharmacology Part 2Pharmacology consists of pharmacodynamics

and pharmacokineticsPharmacodynamics describes how a drug

acts in the bodyPharmacokinetics describes how the body

acts on the drug

Drugs and mechanisms of actionA 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 targetsCell membrane receptorsCellular enzymesCell organelles (mitochrondrion)

Drug Receptor InteractionDrug that produces its effect on a receptor is often

called an agonist or antagonistA 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.

Examples of Receptors in the BodyAlpha receptors in the arteries of the bodyBeta receptors in the lungs and the heartInsulin receptors on fat cells and muscleMuscarinic receptors on the eyes, GI tract,

and many other organs including the heartNicotinic receptors on skeletal musclesHistamine receptors in the skin and brainVasopressin receptors in the kidney and

arteriesLH, 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 enzymesAn enzyme is a protein in the cell that catalysts and enables a chemical

reaction to take place in the cell.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 organellesNot 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 transcriptionRough endoplasmic reticulum (RER): site of protein

synthesisGolgi Apparatus: site of protein modification in the cellLysosomes: site of digestion of cellular

macromolecules

Common among antibioticsBeta lactam Abx- bind to PBPs that are involved in

cell wall synthesis Penicillins , Cephalosporins, and carbapenems

Ex: Penicillin G, Ceftriaxone (Rocephin®), Ceftazidime (Fortaz®) and Cefepime (Maxipine®)

Aminoglycosides- targets the ribosome (RER)in bacteria. 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.html

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 BlockersThese drugs can be used to treat cardiac arrhythmias,

seizures, and to induce localized anesthesiaSodium 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

arrhythmiasQuinidine is an older drug used before procainamidePhenytoin (Dilantin®) is a drug used to treat epileptic

seizures

Calcium Channel BlockersDrugs that block calcium ion channels Clinically a very important group of drugsBlocking calcium flow into the heart as two

effectsLowers the heart rate Decrease the force of contraction

Blocking calcium flow in the smooth muscles of arteries relaxes them.

Calcium Channel BlockersDihydropyridine type : used to treat HTN

Amlodipine (Norvasc®)Felodipine (Plendil®)Isradipine (Dynacirc®)Nicardipine (Cardene®)Nifedipine (Procardia®)

Non dihydropyridine: used to slow rapid heart ratesThe two to remember are:

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

norepinephrineDrugs 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 interactionsTwo 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 InteractionSome 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 systemSome 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

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

PharmacokineticsThe study of the way that body handles the drugThe 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.

AbsorptionThe 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 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

DistributionPassive Diffusion: Drug passes through the membrane intactFacilitated Diffusion: Drug passes through the membrane with

assistance by membrane carrier proteinsActive Transport: Drug passes through the membrane with

the help of a carrier against a concentration gradientPart 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 longerA 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

MetabolismThe 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

EliminationWhen drugs are converted to inactive metabolites they are

then transported into the blood to the kidneysThe 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.