General Pharmacology II-nd part

Dheryan Lusine

Metabolism (Biotransformation)
Effects
Transformation to less active metabolite/s Formation of active metabolite /PRODRUG/ Transformation to more active metabolite/s Enhancement of solubility

Liver = primary site Liver disease

Slows metabolism Prolongs effects

Hepatic First-Pass Metabolism

Affects orally administered drugs Metabolism of drug by liver before drug reaches systemic circulation Drug absorbed into portal circulation, must pass through liver to reach systemic circulation May reduce availability of drug

Orally ingested drugs

Metabolism of drugs by liver enzymes

Parenteral / IV drugs etc.

Liver

Pharmacodynamic activity in body hepatic vein

GIT
Kidney Renal artery First pass metabolism through liver via hepatic portal vein

Excretion of metabolites and intact drugs in urine

First - pass metabolism

Cytochrome P450 (microsomal) enzymes are a large family of enzymes found in the liver that are part of the bodys defence mechanism against toxic substances The body treats drugs as foreign, potentially toxic substances Microsomal enzymes change drugs by biochemical reactions. There are several families of these enzymes, the most clinically significant being CYP1, CYP2 and CYP3 (CYP = CYtochrome P450).

First - pass metabolism

The various cytochromes have specific affinities for particular drugs. This is why there is so much variation in the metabolism of drugs half life etc. The products of drug metabolism, the metabolites, are generally excreted via the kidney in the urine although some are excreted via the bile duct in the faeces

Elimination
Urine, Bile, Exhaled air, Breast milk, Sweat, Feces and saliva

Elimination
Kidneys = primary site
Mechanisms dependent upon:
Passive glomerular filtration Active tubular transport

Tubular secretion Partial reabsorption Hemodialysis

Renal disease
Slows excretion Prolongs effects

Elimination of the drugs

Tubular reabsorption

Glomerular filtration

Tubular secretion

Glomerular filtration

Small Protein-free
Hydro-, lipophilic drugs

C-pl P-osm.blood GBFR

Tubular reabsorption
Lipophilic Ph >7, ROH Ph< 7, HA

Passive diffusion

Tubular secretion

Active transport

Urine pH and Elimination

A patient has overdosed on phenobartital. Phenobarbital is an acid. If we alkalinalize the urine by giving bicarbonate what will happen to the phenobarbital molecules as they are filtered through the renal tubules?

They will ionize...

How will this affect phenobarbital reabsorption by the kidney?

Non-ionized
HA

Ionized
H+ + A-

Decreased reabsorption

Increased elimination

Clearance
Clearance is a volume of plasma from which drug is completely removed in a measure of time i.e. clearance characterizes the speed of drug elimination from the body. There are total (TC), renal (RC) and organ(OC) clearances.

Clearance
TC = RC + OC RC = (Cm*Vm)/Cp, Cm urine concentration of the drug Cp - plasma concentration of the drug Vm volume of the urine excreted in a measure of time.

Biological Half-life (t 1/2)

Unit of the time during which drug dose is reduced in a twice Shorter t 1/2 may need more frequent doses Hepatic disease may increase t1/2

A drug has a half life of 10 seconds. You give a patient a dose of 6mg. After 30 seconds how much of the drug remains?
Time Amount

0 sec 10 sec 20 sec 30 sec

6 mg 3 mg 1.5 mg 0.75 mg

Maintaining drug levels in the body

Maximum safe concentration

Minimum effective concentration

Pharmacodynamics

Dosage

Plasma Site of Concen. Action

Effects

Pharmacokinetics

Pharmacodynamics

Drug Receptors and Pharmacodynamics (how drugs work on the body)

The action of a drug on the body, including receptor interactions, doseresponse phenomena, and mechanisms of therapeutic and toxic action.

Mechanism of Action
A drug may produce its effect through: Receptor mediated action. Non-receptor mediated action.

Non-Receptor Mediated Mechanisms

Drugs act on enzymes: Nitric oxide (NO) penetrates the cell membrane stimulating cytoplasmic guanylyl cyclase enzyme leading to increase of intracellular cGMP. Digitalis inhibits Na+/ K+ ATPase enzyme. Drugs Act on Plasma Membrane: Polymixins and amphotricin B increase the permeability of bacterial plasma membrane. Drugs Act on Subcellular Structures: Erythromycin and chloramphenicol inhibit protein synthesis in bacteria by binding to 50 S ribosomal subunit. Tetracyclines and aminoglycosides bind 30 S ribosomal subunit.

Drugs Act by Chemical Action: Antacids neutralize gastric acid secretion. Protamine (alkaline & +ve charge) antagonizes heparin (acid & -ve charge). Drugs Act by Physical Means: Osmosis e.g. mannitol. Lubricant e.g. liquid paraffin. Adsorbent e.g. kaolin and charcoal. Demulcent e.g. bismuth salt and olive oil.

Mechanism of Action
Receptor Mediated Action
Receptor: receptor is a special molecular component of the cell (protein macro-molecule or DNA) which is capable of selectively recognizing and binding a drug, hormone, mediator or neurotransmitter, thereby eliciting a cellular response. Kd = dissociation constant = concentration of drug at 50% binding to the receptors.

Kd Drug ( D) Re ceptor ( R) D / R Complex (Re sponse)

Affinity: it is the ability of a drug to bind a receptor. It is determined by the dissociation constant (Kd) (the lower the Kd the higher the affinity). Intrinsic mimetic activity: it is the ability of a drug receptor complex to produce an effect. Maximal effect produced if a maximal dose is given. It is determined by the graded doseresponse curve.
R e s p o n s e

Dose

Graded dose-response curve

General classification of drugs

Agonist = stimulant. Partial agonist. Antagonist = blocker. Agonist: a drug has affinity, high efficacy and rapid rate of association and dissociation with its receptor e.g. adrenaline, morphine and histamine. Partial agonist: a drug has affinity, weak efficacy and moderate association and dissociation. It produces an effect < the full agonist when it has saturated the receptors. It acts as antagonist in the presence of full agonist e.g. nalorphine, ergotamine, succinylcholine and oxprenolol. Antagonist: a ligand having affinity, but no efficacy and slowly associated and dissociated from the receptor.

Agonists and antagonists

agonist has affinity plus intrinsic activity antagonist has affinity but no intrinsic activity partial agonist has affinity and less intrinsic activity competitive antagonists can be overcome

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Agonist Drugs
drugs that interact with and activate receptors; they possess both affinity and efficacy two types Full an agonist with maximal efficacy Partial an agonist with less then maximal efficacy

Agonist Dose Response Curves

Full agonist
Partial agonist

Response

Dose
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Antagonist Drug
Antagonists interact with the receptor but do NOT change the receptor they have affinity but NO efficacy two types
Competitive Noncompetitive

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Types of Receptor Antagonists

1. Competitive Antagonist (surmountable): The antagonist binds reversibly with the receptor and could be displaced by excessive dose of agonist. The competitive antagonist decreases the potency of the agonist but does not alter its maximal effect. The dose response curve shows parallel shift to the right. Examples: Propranolol antagonizes adrenaline on beta-adrenergic receptors. Prazosin antagonizes adrenaline on alpha-adrenergic receptors. Atropine antagonizes acetylcholine on cholinergic muscarinic receptors.

Action of drugs on enzymes

Enzyme

Drug

Enzyme

Stimulants
Activity

Inhbitors
Non specific Specific

Induction

Action of drugs on enzymes

Specific inhibitors

Competitive
Catalytic centre

Non competitive
Inhibition

Reversible Irreversible

Allosteric centre

Receptors
Physiological Drug

Silent

Recognising domain

Effector domain

Types of receptors
Enzyme receptors

Ionic channel receptors

G-protein coupled receptors

DNA-transcription regulating recep

Signal transduction

1. enzyme linked (multiple actions)

2. ion channel linked (speedy)

3. G protein linked (amplifier) 4. nuclear (gene) linked (long lasting)

Enzyme receptors

Tyrosine-kinase receptors
Structure: Receptors exist as individual polypeptides Each has an extracellular signal-binding site An intracellular tail with a number of tyrosines and a single helix spanning the membrane

Signaling Mechanisms
Receptors located on membrane-spanning molecules that bind separate intracellular tyrosine kinase molecules
These receptors have extracellular and intracellular domains and form dimers.
After receptor activation by an appropriate drug, the tyrosine kinase molecules (Janus kinases; JAKs) are activated, resulting in phosphorylation of "STAT" molecules (signal transducers and activators of transcription).

STAT dimers then travel to the nucleus, where they regulate transcription.

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Figure 2-9. Mechanism of activation of the epidermal growth factor (EGF) receptor, a representative receptor tyrosine kinase.
Copyright 2004 by The McGraw-Hill Companies, Inc. All rights reserved.

Figure 2-8. Cytokine receptors

Copyright 2004 by The McGraw-Hill Companies, Inc. All rights reserved.

Examples
When insulin, epidermal growth factor (EGF) and platelet derived growth factor (PDGF) bind their surface receptors, a tyrosine-kinase (on the inner part of the receptor) is activated. This leads to phosphorylation of certain protein on its tyrosine residue producing the specific cellular function.

T.K

Ion channel coupled receptors

Signaling Mechanisms
Receptors located on membrane ion channels
Receptors that regulate membrane ion channels may directly cause the opening of an ion channel
Ex: acetylcholine at the nicotinic receptor Or, modify the ion channel's response to other agents

Ex: benzodiazepines at the GABA channel.

Ion channel receptors

Structure:
Protein pores in the plasma membrane

Figure 2-9. The nicotinic acetylcholine receptor

Copyright 2004 by The McGraw-Hill Companies, Inc. All rights reserved.

G-protein coupled recptors

G protein-linked receptors
Structure:

Single polypeptide chain threaded back and forth resulting in 7 transmembrane helices
Theres a G protein attached to the cytoplasmic side of the membrane (functions as a switch).

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G-protein coupled receptors

Gs
Gi Gq

Activation of adenilatcyclase and cAMP/, Ca, PKA

Inhibition of adenilatcyclase and decrease of cAMP/, K

Activation of phospholipase C / IP3, DAG/

Go

Closing of Ca channels

Table 2-1. G proteins and their receptors and effectors

G Protein Gs Receptors for: -Adrenergic amines, glucagon, histamine, serotonin, and many other hormones 2-Adrenergic amines, acetylcholine (muscarinic), opioids, serotonin, and many others Odorants (olfactory epithelium) Neurotransmitters in brain (not yet specifically identified) Acetylcholine (eg, muscarinic), bombesin, serotonin (5-HT1C), and many others Photons (rhodopsin and color opsins in retinal rod and cone cells) Effector/Signaling Pathway Adenylyl cyclase , cAMP

Gil, Gi2, Gi3

Several, including: Adenylyl cyclase , cAMP Open cardiac K+ channels , heart rate Adenylyl cyclase , cAMP

Golf

Go

Not yet clear

Phospholipase C, IP3, diacylglycerol, cytoplasmic Ca2+ cGMP phosphodiesterase (phototransduction)

Gq

Gt1, Gt2

CAM

Examples Stimulation of 1 & 2 adrenergic receptors stimulate Gs increase cAMP. Stimulation of 1 adrenergic receptors Gq increase DAG, IP3. Stimulation 2 adrenergic receptors Gi decrease cAMP.

Receptors regulating DNA transcription

Receptors regulating DNA transcription

Drugs actiong on ionic channels

Potential dependent Ionic channels

Drugs acting on genes

Inhibition of expression Switching off of gene expression Replacement of the mutagen gene

Intracellular receptors
Not all signal receptors are located on the plasma membrane. Some are proteins located in the cytoplasm or nucleus of target cells. The signal molecule must be able to pass through plasma membrane.

Examples: ~Nitric oxide (NO) ~Steroid (e.g., estradiol, progesterone, testosterone) and thyroid hormones of animals).

Second Messengers
Small, nonprotein, water-soluble molecules or ions Readily spread throughout the cell by diffusion

Two most widely used second messengers are:

1. Cycle AMP 2. Calcium ions Ca2+

Calcium Ions (Ca2+) and Inositol Trisphosphate

Calcium more widely used than cAMP used in neurotransmitters, growth factors, some hormones Increases in Ca2+ causes many possible responses: Muscle cell contraction

Secretion of certain substance

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Cell division

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Summary
most drugs act through receptors there are 4 common signal transduction methods the interaction between drug and receptor can be described mathematically and graphically agonists have both affinity (kd) and intrinsic activity () antagonists have affinity only antagonists can be competitive (change kd) or non-competitive (change ) when mixed with agonists agonists desensitize receptors. antagonists sensitize receptors.

Receptor Regulation
Sensitization or Up-regulation 1. Prolonged/continuous use of receptor blocker 2. Inhibition of synthesis or release of hormone/neurotransmitter Denervation Desensitization or Down-regulation 1. Prolonged/continuous use of agonist 2. Inhibition of degradation or uptake of agonist

Effectiveness, toxicity, lethality

ED50 - Median Effective Dose 50; the dose at which 50 percent of the population or sample manifests a given effect; used with quantal dr curves TD50 - Median Toxic Dose 50 - dose at which 50 percent of the population manifests a given toxic effect LD50 - Median Lethal Dose 50 - dose which kills 50 percent of the subjects

Quantification of drug safety

Therapeutic Index =

TD50 or LD50
ED50

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