Pharmacology Part 2

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.

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 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. • 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 lactamAbx- 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 Streptomycespeucetius • 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: • Verapamil (Calan® and others) • Diltiazem (Cardizem®)

Ion Channel Agents found in nature • Not all drugs that effect ion channels are man made • Some are found in nature • Some are very toxic to humans • Tetrodoxin is a toxin that is produces by species of the genus: tetrodontiformes which includes pufferfish, blowfish, porcupinefish, and some toads • Tetrodoxin blocks the fast sodium ion channels in muscles and nerves caused death by paralysis (of the diaphragm) • Lethal dose is about 10 mcg/kg in man

Aconitum • Flowering plants that grows in mountains valleys in the northern hemisphere • Called by the names of “wolfsbane”, “Devils helmet” or “Monkshood” • Opens sodium ion channels and triggers activation of many nerves • Highly toxic • Referenced in Harry Potter series as an antidote to keep werewolves sanity

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

CYP450 Inhibitors • The most important drug inhibitors of this system are the following: • Protease Inhibitors: Lopinavir/Ritonovir (Kaletra®) is an example • Azole antifungals: examples are ketoconazole and Fluconazole (Diflucan®) • Macrolides: some are strong inhibitors (Clarithromycin (Biaxin®) and some weaker (Erythromycin) • Some calcium channel blockers: (Diltiazem) • Some herbals: Valerian, and Grapefruit juice

CYP450 inducers • Important Inducers of CYP450 are the following drugs • Barbiturates: Phenobarbital (luminal®), secobarbital (Seconal®) • Anti seizure drugs: Phenytoin (Dilantin®), Carbamazepine (Tegretol®) • The antibiotic Rifampin use to treat some infections • Some herbals like St. John’s Wort used for depression • Some Steroids like Prednisone

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

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 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 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 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.

Pharmacology Part 2