Pharmacology basic principles



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PHARMACOLOGY BASIC PRINCIPLES
Drug: a molecule that when introduced into body alters body’s functions by interaction at molecular level; most are molecular weight 100-1000, which allows efficient absorption and distribution; 25% of drugs are chiral (stereoisomeric)

Xenobiotics: chemicals not synthesized in living system


Drug-body interactions

Pharmacodynamic: effects of drug on body (drug receptor concept, dose-response relationships)

Pharmacokinetic: the way the body handles the drug (absorption, distribution, metabolism, elimination)
Methods of Drug Permeation

Body protected by membrane barriers which drugs must cross


1) Aqueous diffusion: limited capacity

Epithelial cells: only molecules MW 100-150 can pass through as cells joined by tight junctions

(eg. Li, methanol)

Capillaries: v large pores; MW 20,000-30,000 can pass (most brain capillaries aren’t this leaky except at pituitary and pineal gland, median eminence, choroid plexus)


2) Lipid diffusion: through membrane driven by conc grad; must be lipid soluble, though must be dissolved in water in order to reach membrane
3) Facilitated diffusion (via carriers): eg. Needed to cross BBB, for weak acids in PCT of kidney
4) Pinocytosis (receptor mediated endocytosis): for drugs MW>1000
Factors Affecting Drug Permeation
Rate of diffusion determined by Fick’s law of diffusion

Related to area of diffusion (eg. Lung>stomach)

thickness of barrier

conc grad – determined by gradient source (ie. Amount of drug administered)



gradient sink (ie. Rate of removal of drug near source)

- so high blood flow will keep high conc grad, so vasodilating drugs

absorbed faster
pKa (for lipid diffusion):

Weak acids/bases are more water-soluble when ionized (polar) and more lipid soluble when unionized  pH of environment determines ionization according to Henderson-Hasselbalch equation which measures amount of dissociation:


Log (protonated form/unprotonated form) = pKa – pH
IN WEAK ACIDS: the PROTONATED is LIPID-SOLUBLE and UNIONISED

If result of this calculation is >0 (before doing antilog) then more is PROTONATED (ie. Reabsorbed, not excreted)

If result is <0 (before antilog) then more is UNPROTONATED (ionised  water soluble  excreted)

IN WEAK BASES: the PROTONATED is WATER SOLUBLE and IONISED

If result of calculation is >0 then still more protonated, but this time it’s excreted

If result is <0 then still more is unprotonated, but this time it’s lipid soluble and reabsorbed


Acids: HA (protonated form) ↔ H+ + A- (unprotonated form)

Alkali: H+ + RNH2 (unprotonated form) ↔ RNH3 (protonated form)


pKa: the pH at which conc of ionized and unionized forms are equal

If pKA is alkaline  in alkaline urine it will be ionized  poorly soluble in lipids  not reabsorbed  excreted; in acidic urine it will be unionized  lipid-soluble  reabsorbed

Vice versa if pKa is acidic
Degree of ionization v important in body compartments where pH often changes (eg. Gastric, urine) (eg. Phenobarbitol cleared in alkaline urine as pKa is 7.4)

Note, some drugs are NOT significantly influenced by pH (eg. Penicillin)


Drug Absorption
Route of administration:

PO: absorption in gut is via lipid diffusion as cells joined by tight junctions; absorption favoured by large SA of GI tract, mixing of contents, pH differences at different levels; can be destroyed by acid (eg. Some penicillins) and enzymes (eg. Insulin is hydrolysed) and microbial activity

INH: can be used from agents that vaporize easily (eg. Amyl nitrite) or can be dispersed in aqueous droplets (eg. Ergot derivatives); large SA and high blood flow of lungs aid rapid absorption

TOP: transdermal route is using top drugs for systemic effects, slow absorption can cause prolonged drug levels; absorption through skin is through lipid barrier

BUCCAL: for drugs that are too rapidly deactivated by liver to be administered PO as portal circ will remove 90% therefore can use lower dose; high blood flow in buccal mucosa, into veins NOT portal circ

IV: bypass absorption barriers

IM: rapid absorption; depot injections are dissolved in oil to slow absorption

SC: slow absorption; if wish to give large amounts must add hyaluronidase to aid spread of injected solution

Intra-arterial or intra-thecal: for high local conc of drug; can use higher conc of drug than would be tolerated systemically
Drugs Distribution

Blood  compartments



  • Held in blood if strongly binds plasma proteins (eg. Heparin)

  • V. large molecules also stay in blood

  • Water-soluble molecules freely distribute in TBW (eg. Ethanol, mannitol)

  • Lipid-soluble molecules distribute to fat (eg. DDT)

  • Some ions (eg. Heavy metals, lead, fluoride) go to bone

  • Otherwise rate at which leaves blood determined by permeability principles


Apparent volume of distribution: total drug present in body / measured plasma conc of drug

Since some drugs are 100% bound to tissue structures  small amount in soln  v large apparent vol of distribution


Determining factors:

1) Protein binding: measured as % drug in blood that is not dialyzable; drugs is bound to inert binding sites on proteins  can’t diffuse/interact with receptors; in equilibrium with free drug, so alterations in free drug will change amount but not % bound; inert binding sites aren’t specific so diff drugs can compete (inert binding sites must be concentrated for drug to reach therapeutic levels  if another drug added and displaces drug  toxic levels); may also bind to proteins outwith vascular compartment

2) Blood flow: determines rapidity of delivery and conc gradient between blood and tissue; liver and kidneys have high blood flow; heart and skin have low blood flow; brain has mod flow, but since small receives high % cardiac output to reaches high conc; muscle has high flow but since large vice versa

3) Membrane permeation

4) Tissue solubility
Termination of Drug Effect

1) Excretion

a) Kidneys: by glomerular filtration: passive; non-saturatable; removes small molecules; cleared

from blood at rate equal to CrCl; can’t occur if bound to plasma protein



by tubular secretion: active; in PCT; saturatable (eg. Weak acids such as diuretics,

may have to compete with endogenous acid such as uric acid)

once in urine, lipid-soluble drug may be reabsorbed, water-soluble readily excreted;

metabolism of drugs can produce less lipid-soluble metabolites



b) Liver: important in drug metabolism  drug and metabolites secreted into bile (eg. Cardiac

glycosides, ABs)  duodenum  some drug may be reabsorbed from intestine into blood (enterohepatic circulation)



c) GI tract: drugs may cross lipid membrane from blood to lumen via passive diffusion (eg. Weakly basic morphine (pKa 7.9) diffuses into acidic stomach  7.9 – 2.0 = 5.9 therefore more is protonated, therefore it’s 100% ionized and water-soluble  won’t be reabsorbed and can be lavaged (not excreted, as when passes to alkaline intestine will become un-ionised again)

d) Lungs: mostly for gaseous anaesthetics

e) Minor routes: sweat and salivary glands, milk
Early distribution phass = Extravascular equilibration: steep initial decr in conc of drug as drug passes from vascular into other compartments; this wouldn’t be demonstrated if drug remained in vascular compartment, only in 2-compartment kinetics

Slower elimination phase = Exponential decay curve: steep rise in conc when add drug  slow decr in levels as excreted, rate of decr decreases as the conc gradient driving drug out decreases as it level decreases in blood stream
2) Biotransformation: from active to inactive products

DRUG RECEPTORS AND PHARMACODYNAMICS
Receptors

The component of a cell/MO that interacts with a drug biochemical events drug effect

  • Receptors determine relation between conc of drug and effect of drug

    • A receptors affinity for a drug determines conc of drug required to form significant no of drug-receptor complexes

    • Total no of receptors limits max effect a drug can produce

  • Receptors determine selectivity of drug action

    • Change in chemical structure of drug change affinities for diff classes of receptors

  • Receptors mediate actions of pharmacological antagonists

    • Pure antagonists bind receptors without altering them  prevent binding of agonists

Receptor may be:



  1. Enzyme – can be inhibited/activated by binding of drug (eg. Dihydrofolate reductase)

  2. Transport protein – eg. Digitalis on Na-K ATPase

  3. Structural protein – eg. Colchicine attaches to tubulin


Receptor Desensitisation:

Usually reversible, which separates it from down-regulation

Eg. β-receptor – binding of receptor  begins to interact with G protein  phosphorylation of cytoplasmic OH terminal via serine β- adrenoceptor kinase  receptor gets high affinity for β-arrestin  bind, decreasing receptors ability to interact with Gs protein  reversed when agonist unbinds; Nicotinic Ach receptor
NB. There may be multiple receptors for any endogeous ligand, drugs often need to be more selective


Signalling Mechanisms and Drug Action
Mechanisms of transmembrane signaling:


  1. Using a lipid soluble ligand: cross membrane and act on intracellular receptor (can be sited in cytoplasm or nucleus)  bind to DNA sequences (enhancers)  stimulate transcription of genes

There is a lag-time before effect as it takes time to make proteins; effects can persist long after drug eliminated from system 2Y to slow turnover of enzymes and proteins

Eg. Corticosteroids (binding to receptor triggers release of Hsp90 which was covering DNA-binding portion of receptor), mineralocorticoids, sex steroids, vit D, thyroid hormones




  1. Using a transmembrane receptor protein:

Protein causes intracellular enzymatic actions

Consists of extracellular hormone-binding domain and cytoplasmic enzyme domain with protein tyrosine kinase activity

Hormone binds  conformational change in receptor  receptors bind together  protein kinases brought together  become enzymatically active  tyrosine residues become phosphorylated (cross-phosphorylation which may last longer than receptor activated)  cellular events (eg. Phosphorylation of substrate protein, transcription factor activation etc…)

Regulated by down-regulation (endocytosis and breakdown of receptors) – this process requires tyrosine kinase activity

Eg. Insulin, epidermal GF, PDGF


  1. Using a ligand-gated channel:

Ligand binding opens/closes channel  change in ion transport  change in membrane potential

V fast response; for transfer across synpases

Eg. Ach (opening of nicotinc Ach channel, a pentamer, Ach binds α subunit  Na into cells  depolarisation , gamma-aminobutyric acid, excitatory aa’s (all synaptic transmitters)


  1. Using a transmembrane receptor protein G protein:

Ligand binds serpentine receptor (extracellular amino terminal, intracellular carboxyl terminal)  receptor activates (via interaction at 3rd cytoplasmic loop of receptor) G protein on cytoplasmic side of cell membrane swapping of GDP for GTP (length of response may be related to length of GTP-bound Gs molecule as opposed to length of binding of ligand-receptor  amplification of original signal; this creates spare receptors)  via enzyme / ion channel G protein generates intracellular 2nd messenger  effect terminated by hydrolysis of GTP

Eg. Gs (α-receptors, glucagons, histamine, serotonin), Go (NT’s), Gq (Ach, serotonin), G1+2 (rods and cones), G1+3 (α1-receptors, Ach, opioids, serotonin)


Second messengers
Pathways may oppose eachother or work together

Reversible phosphorylation is common theme and can result in:



  • Amplification: attachment of phosphoryl group to serine/threonine/tyrosine  amplification via creation of molecular memory, memory erased by dephosphorylation

  • Flexible regulation: multiple protein kinases regulated by multiple 2nd messengers, many branches, many diff responses possible




  1. cAMP made via adenyly cyclase:

 stimulate cAMP-dependent protein kinases via cAMP binding to R dimer of kinase  C chains released which diffuse through cytoplasm  transfer phosphate from ATP to (eg.) Lipase in adipocytes, myosin in smooth muscle, glycogen synthase in liver  agonist binding stops  cAMP effects terminated by phosphatases, cAMP degraded to 5’-AMP by cyclic nucleotide phosphodiesterases (NB. Caffeine and theophylline prevent this degradation)

Effects: mobilization of stored E, conservation of water by kidney, Ca homeostasis, increased contractility of heart, regulates production of adrenal/sex steroids, relaxation of smooth muscle

Activated by: ACTH, catecholamines via β-receptors, FSH, glucagons, LH, histamine, PTH, vasopressin via V2, serotonin via 5-HT1


  1. Ca/phosphoinositides:

May be via G proteins/tyrosine kinase; stimulation of phospholipase C  hydrolyses PIP2 into diacylglycerol ( activates protein kinase C) and IP3 (triggers release of internal Ca stores)  Ca binds calmodulin  activates other enzymes. Reversed by dephosphorylation of IP3, phosphorylation of diacylglycerol, active pumping of Ca from cytoplasm

Activated by: lithium, Ach, angiotensin, catecholamines via α-receptors, PDGF, serotonin via 5-HT2, vasopressin via V1


  1. cGMP:

Ligand binds  guanylyl cyclase produces cGMP  cGMP-dependent kinase activated; action terminated by dephosphorylation of cGMP and breakdown of substrate

Effects: relaxation of vascular smooth muscle (via dephosphorylation of myosin light chains)

Activated by: ANF, EDRF, NO (in response to Ach and histamine)
Receptor-Effector Coupling
Coupling: the transduction process between occupying receptors and drug response; effect of full agonists are more efficiently coupled to receptor occupancy than partial agonists; also determined by biochemical events that transduce receptor occupancy  cellular response
Spare receptors:

When max response achieved by agonist when not all available receptors occupied – increase sensitivity to drug

eg. Max inotropic response to catecholamine can be achieved even if 90% β-receptors blocked by irreversible antagonist

Allows agonists with low affinity for receptors and hence rapidly dissociate from receptors, to produce full responses at low concs



Occurs because receptor activation may greatly outlast agonist-receptor interaction or if intracellular components rather than receptor limits coupling
Explains why sensitivity of tissue to certain conc of agonist doesn’t only depend on affinity of receptor/drug but on concentration of receptors. Eg. There are 100 receptors:

  • If 90% receptors are spare  10 receptors need to be occupied for full response  EC50 occurs at 5 receptors occupied  EC50 < Kd

  • If receptor conc doubled to 200 and 5 receptors occupied needed for EC50  drug will still bind same percentage as above which will be higher no of receptors now and only 2.5% of receptors need be occupied  ↓EC50 as lower conc drug needed


A: max response achieved

B: higher conc needed to achieve max response, EC50 increasing

C: max response still achieved 2Y to spare receptors used, EC50 still higher



D + E: can no longer achieve max response as spare receptors filled with antagonist
HAgonists



  1. Partial agonists:

Produce lower response at full receptor occupancy

Curve similar to that of full agonist in presence of irreversible antagonist

May occupy all binding sites but fail to produce maximal effect despite having high affinity for receptors

May competitively inhibit responses produce by full agonists



Changes receptor confirmation but not to extent for full activation of receptor

Efficacy of drug: relation between occupancy of receptors and pharmacologic response

  1. Full agonists:

Produce higher response at full receptor occupancy
Competitive/Irreversible Antagonists
Antagonists bind receptors but don’t activate them  prevent agonists from binding.



  1. Competitive Antagonist:

High conc antagonist prevents agonist effect, high agonist can prevent antagonist effect

Presence of antagonist increases conc of agonist required for given effect  agonist conc-effect curve will shift to R

Ratio of conc required from certain effect in presence of antagonist v. conc required in absence of antagonist is called dose ratio and is related to Kd (named Kl) of antagonist using Schild equation.

- Degree of inhibition depends on conc of antagonist AND agonist, influenced by its metabolism and excretion




  1. Irreversible Antagonist

May form covalent bonds with receptor

If enough antagonist present may not be possible to achieve max agonist response

Duration of response not dependent on elimination of antagonist but on rate of turnover of receptors

Will prevent response to varying and high level of agonist

Eg. Phenobenzamine (α-antagonist) to control ↑BP 2Y to pheochromocytoma


  1. Chemical Antagonist

Antagonist binds DRUG not RECEPTOR

Eg. Protamine binds heparin preventing its action




  1. Physiologic Antagonism

Preventing effect of a drug by preventing effect via a different pathway; effects are less specific and easy to control

Eg. Giving insulin to prevent hyperglycaemia caused by steroids






Drug Conc and Response

Generally response to drug increases proportional to dose; but as dose increases incremental response decreases until incr in dose has no effect  hyperbolic curve made using equation:

E (effect observed at conc C) = Emax (mac response produced by drug) x C (conc)

C (conc) + EC50 (conc of drug producing 50% max effect)


Similar to curve made predicting assoc of 2 molecules with given affinity, with equation:
B (amount of receptor-bound drug) = Bmax (total conc of receptor sites) x C

C + Kd (equilibrium dissociation constant, conc



of free drug at which half-maximal binding observed)
Kd demonstrates receptor’s affinity for drug – if Kd is low, binding affinity is high.

Graph above can be transformed into sigmoid graph with linear midportion by plotting drug effect against log of dose/conc  makes it easier to compare 2 dose-response curves.


Drug Dose and Response

1) Potency:

Conc/dose (EC/ED50) of drug required to produce 50% of THAT drugs max effect

B is most potent, then A (even though A has higher max efficacy), C, D

Note B is partial agonist

Depends on Kd (affinity of receptors for drug) and efficiency of drug-effector coupling

Determines dose of drug – only comes into play if low potency means drug has to be given in large amounts

Relative potency used to compare 2 drugs
2) Maximal efficacy:

Reflects limit of dose-response relation on response axis (ie. A,C,D higher than B)

This determines clinical effectiveness of drug

Affected by drug’s interaction with receptors and efficacy of drug-effector coupling


3) Shape of dose-response curve:

Steep curves (eg. D) can result in accidental toxicity esp. if drug has several diff co-operative interactions (eg. Negative inotrope and vasodilator). Can occur if most receptors must be occupied before response seen.


Quantal dose-effect curves
Made using population data rather than specific drug levels; rather than showing max efficacy of drug, reveals variability of response to drug on Y axis

Can calculate median effective dose (ED50) – dose at which 50% population exhibit specified quantal

effect

Median toxic dose (TD50) – dose for 50% animals to show toxic effect

Median lethal dose (LD50)

Potency of drugs (ED50 of 5mg more potent than ED50 500mg).

Specificity: comparing ED50 of 2 different quantal effects (eg. Cough suppression vs

sedation) shows specificity



Therapeutic index: relation of dose of drug for required effect to dose that produces toxic

effect (ratio of TD50 to ED50) – clinically acceptable risk of toxicity depends on severity of disease being treated


Variation in Drug Responsiveness
Idiosyncratic response: usually 2Y to genetic diff in metabolism of drug / immune mechanisms

Can be hypo/hyperreactive drug (referring to efficacy)



Tolerance: becoming hyporeactive to drug

Tachyphylaxis: when response diminishes rapidly after administration of drug
Mechanisms causing variation:

  1. Altered conc of drug reaching receptor:

Change in rate of absorption / distribution / rate of clearance

Can be estimated by age / weight / sex / renal or liver function




  1. Altered conc of endogenous receptor ligand:

Eg. Propanolol will ↓HR of someone whose endogenous catecholamines are ↑ed, but won’t affect heart of marathon runner


  1. Altered no / function of receptors:

Incr no receptors / incr efficiency of coupling

Agonist may cause down-regulation / desensitization (antagonist may prevent down-regulation, when antagonist withdrawn get large agonist effect – overshoot phenomenon) (may get bad withdrawal when remove agonist 2Y to ongoing down-regulation) – may make it dangerous to discontinue drugs, must wean

Sometimes incr in no receptors is caused by other hormones (eg. Thyroid inc β receptors)

May explain tolerance, tachyphylaxis




  1. Changes in response distal to receptor:

Largest cause of variation; physiological mechanisms may compensate to prevent effect of drug
Drug Selectivity
Drugs bind to many receptors, but will bind to some tighter than others
Can be measured in therapeutic vs toxic effects – different effects can occur by 3 mechanisms:


  1. Both effects mediated by same receptor-effector mechanism:

Toxic effect is direct pharmacological extension of action of drug (eg. Bleeding in anticoagulation, postural hypotension with methyldopa)

Manage dose of drug carefully; use other drugs in combination so can decr dose of SE drug




  1. Effects mediated by same receptor but different effector pathway:

Eg. Digitalis glycosides – incr cardiac contractility; cause GI effects and vision changes; glucocorticoids treat inflammation but cause psychosis

Use lowest dose possible, use other drugs as above, use a different route of administration (eg. INH)




  1. Effects mediated by different type of receptor:

Eg. α and β receptors, serotonin, histamine, nicotinic/muscarinic; morphine, MAOI, tricyclics, thiazide diuretics

PHARMACOKINETICS: ABSORPTION, DISTRIBUTION, ELIMINATION
Drug effect controlled by bioavailability, distribution, clearance

Relationship exists between therapeutic/toxic effect of drug and con of drug in readily accessible site of body; must weight up toxic effect and efficacy


Volume of Distribution
Measure of apparent space in body available to contain drug
Vd = amount drug in body / conc in blood or plasma
Normal plasma vol = 3L

Normal blood vol = 5.5L

Normal extracellular fluid (minus plasma) = 12L

Total body water = 42L


Use ideal body weight to determine. Pt’s with oedema/ascites etc… have incr Vd to aminoglycosides
Depends on pKa, partition coefficient in fatty tissues, and degree of plasma protein binding

Doesn’t represent real vol but size of pool of body fluids required if drug was distributed evenly throughout all body – if you calculate dig level based on plasma conc (low) Vd will be large - but it’s wrong as dig mostly in muscle and adipose tissue. Also if you calculate a drug that strongly binds plasma proteins Vd may be artificially low as drug will be mostly in blood (eg. Frusemide, warfarin).


Clearance
Rate of elimination of compound relative to plasma drug conc

Related to blood flow to extracting organ and extraction ratio


CL = rate of elimination / conc in blood or plasma

Rate of elimination = (Q(blood flow to organ) x Ci(drug conc entering)) – (Q(blood flow out of organ) x

Co(drug conc exiting)

Extraction ratio = (Ci – Co) / Ci



Dosing rate = CL x Css(steady-state conc)

0 order: rare, only alcohol, aspirin and phenytoin; elimination NOT related to conc, therefore is saturable

1st order: all the others; elimination α conc, unsaturable; line will be straight on a log scale
May need to alter for poor renal function, estimated via CrCl and predicted Cr production rate (lower in women due to decr muscle mass; decr in renal function with age is independent of Cr prod rate
Can be blood clearance (CLb), plasma clearance (CLp), clearance based on unbound/free drug conc (CLu)

Plasma clearance may also assume proportions that aren’t ‘physiological’ - if drug binds mainly to RBC rather than stays in plasma clearance rates can be incredibly artificially high (eg. Imipramine)

Steady-state when dosing rate = clearance rate
Max clearance possible determined by blood flow to clearing organ; to determine clearance you must do above equation for conc presented to each organ involved (ie. It’s additive CLrenal + CLliver + CLother = CLsystemic)

Major sites: Liver: 1500ml/min; via biotransformation or excretion into bile (eg. Hydralazine, imipramine,

lidocaine, morphine, nortriptyline, propanolol, verapamil)

If drug absorbed from GI tract, bioavailability determined by extent of hepatic extraction



Kidney – renal clearance is level of unchanged drug in urine

Poorly extracted by liver – chlordiazepoxide, theophylline, phenytoin, warfarin


Half-Life (t1/2)
Time required to attain 50% steady state or to decay 50% from steady-state conditions after a change in rte of drug administration
T1/2 = 0.693Vd / CL
Depends on Vd and clearance – can be affected by disease state

If drug distributes into multiple compartments, true ½ life will be underestimated

Difficult to measure in prolonged release formats

The longer the half life, the longer to reach steady state

NB. 50% of drug remaining after each half life is eliminated in each successive half life; takes 5 half lifes after cessation of therapy for 97% of drug to have gone (opposite relationship occurs with multiple dosing)
Bioavailability
Fraction of unchanged drug reaching systemic circ following administration – reflected by AUC (area under curve) = availability

Can also be used to describe rate (as opposed to extent) at which drug reaches general circulation – reflected by speed at which drug reaches peak conc in plasma


A+C have identical AUC therefore same AVAILABILITY

B has lower availability

A would reach MEC faster. B would be crap. A+C could be used but A would have higher peaks and lower troughs, but same average concs


Important as there is MEC (minimum effective conc) needed to elicit effect, so needed for efficacy – can be dependent on both the rate and fraction as described above, EXTENT more useful than RATE in measuring amount of drug in body; rate important in drugs given as single dose (eg. Sleeping tablets)
IV: bioavailability = unity

PO: may incompletely absorbed, metabolized in gut/portal blood/liver; may undergo enterohepatic cycling with some excretion in bile


Extraction Ratio and First Pass Effect
Disposition: what happens to drug after it reaches a site in circ where measurement of drug can be made; can markedly affect extent of availability. Drug given PO must pass through liver before can be measured therefore affect here on availability may be large – first pass effect. May need to give large doses to reach therapeutic levels, but this will result in large no of metabolites.

Large amount of first pass in – propanolol, lidocaine

Avoid first pass (eg. SL, PR) – PR passes into IVC (except for 50% anastomosis  some go to portal), UNLESS moves up into rectum  still hits portal circ
Extraction ratio: may be dependent on hepatic function and blood flow if excreted by liver; decr extraction ratio  incr bioavailability of drug (eg. In disease states, intra/extra-hepatic circ shunting) can have large effect on drug conc
Dosage Regimes
Main determining factor is CLEARANCE, not vol of distribution of half life
Must decide on

Amount drug to administer

Route of administration

Interval between doses: aim to maintain steady-state; rate of drug input = rate drug loss

Dosing rate = CL x Css - allows you to calculate it; note that after multiple doses, conc becomes

average plasma conc over dosing interval

Maintenance dose = dosing rate x dosing interval

Remember that in this time there will be peak and trough levels unless being continuously infused.

How long to continue drug administration
Loading dose: administer dose to promptly raise conc of drug in plasma to steady-state value; amount given is equal to amount that must be IN BODY (as opposed to average conc when in intermittent dosage scheme) when steady state reached – affected by Vd

Loading dose = Css x Vd

This is assuming there is only 1 compartment ignoring distribution phase; if absorption faster than distribution (always true if IV) the initial conc may be higher than steady-state  toxicity (eg. IV lidocaine); makes rate of administration important
Therapeutic Drug Monitoring
Pharmacokinetic Variables

Absorption: depends on pt compliance; on extent of transfer from site of administration to blood

Clearance: impaired kidney, liver, heart function; hepatic disease does not always affect hepatic clearance; measure CrCl

Volume of distribution: binding to tissues makes apparent vol larger, binding to plasma makes apparent vol smaller; old people have less skeletal muscle mass decreasing Vd of digoxin, theophylline distributes in TBW so Vd is proportional to body weight; abnormal accumulation of fluids (eg. Ascites, oedema) can incr Vd of hydrophilic drugs (eg. Gentamicin)

Half life: increases with age 2Y to change in Vd, NOT 2Y to change in metabolism
Pharmacodynamic Variables

Max effect: every drug has conc at which incr in conc will not cause incr effect

Sensitivity: reflected by EC50; measure drug conc and compare with conc that are usually assoc with therapeutic effect; sensitivity may decr 2Y to abnormal physiology (eg. Incr K decr efficacy of dig), drug antagonism (eg. Ca channel blockers decr inotropic response to dig)
Interpreting Drug Conc Measurements
Avoid drawing blood until 2 hours after PO dose (when absorption is complete); dig and lithium take several hours to distribute to tissues (dig wait at least 6 hrs, lithium as trough); sample near midpoint of dosing interval will be close to Css
Clearance: most important factor in determining drug conc; affected by


  1. Dose of drug

  2. Organ blood flow

  3. Function of liver and kidneys


Protein binding: may make you think there’s a change in clearance when it’s actually unaltered; factors are

  1. Albumin conc: may be low in disease states; albumin binds phenytoin, salicylates

  2. Alpha1-acid glycoprotein conc: increased in inflamm processes; binds quinidine, lidocaine, propanolol

  3. Capacity-limited protein binding: binding to proteins is conc-related; total drug conc will increase less rapidly than dosing rate would suggest as protein binding approaches saturation



DRUG BIOTRANSFORMATION
Xenobiotics: foreign substances to which body is exposed

Biotransformation may occur in: liver (during first pass, eg. morphine), gut wall (eg. Clonazepam, midazolam, chlorpromazine, cyclosporine, catecholamines), MO’s in lower gut, gastric acid (eg. Penicillin), digestive enzymes (eg. Insulin), lungs, skin, kidney. Pt in liver failure will increasingly rely on gut metabolism

Biotransformation in liver may be so great that PO route is useless (eg. Lidocaine)
Biotransformation for clearance: pharmacologically active molecules tend to be lipophilic + poorly ionized  readily reabsorbed from glomerular filtrate; may be bound to p proteins and not filtered into urine  prolonged duration of action unless metabolized to polar metabolites that can be excreted or inactivated by metabolism

Eg. Important for excretion of thiopental, Phenobarbital


Biotransformation for activation: metabolism may enhance effect of drug

Eg. Steroid hormones, cholesterol, Vit D, bile acids


Types of Biotransformation
Phase I reactions: convert drug into more polar metabolite by introducing/unmasking functional group (eg. OH, NH2, SH)  inactive/enhanced product
Phase II reaction: product of phase I reaction may be conjugated with glucuronic acid / suphuric acic / acetic acid / amino acid using transferases (catalytic enzymes located in microsomes/cytosol)  drug conjugates (highly polar product) which are usually readily excreted or inactive.

May produce an active product (eg. NSAID, isoniazid)

Since substrate combined to drug is endogenous, nutrition plays important role here.

Reactions can be glucuronidation (morpine, paracetamol, diazepam, digoxin)

Acetylation (eg. Sulfonamides, isoniazid, clonazepam)

glutathione conjugation (eg. paracetamol)

glycine conjugation (eg. Aspirin)

sulfation (eg. Paracetamol, methyldopa)

methylation (eg. Dopamine, epinephrine, histamine)

water conjugation (eg. Carbamazepine)


If drug already has functional group, phase II reaction may occur before phase I
Biochemistry of Biotransformation

Drug-metabolising enzymes in membranes of smooth endoplasmic reticulum:



Mixed function oxidases / monooxygenases – catalyse oxidation-reduction process requiring reducing agent (eg. NADPH) and molecular oxygen  product becomes oxidized with water as by-product; this is a very non-specific process, all that is needed is for drug to be lipophilic

Eg. NADPH-cytochrome P450 reductase

Eg. Cytochrome P450
Specific steps in CP450 drug oxidations:

  1. Oxidised P450(Fe3+) combines with RH (drug)

  2. NADPH donates electron to cytochrome P450 reductase

  3. CP450R reduces P450(Fe3+)-RH complex to P450(Fe2+)-RH complex

  4. Another electron donated to CP450R from NADPH

  5. CP450R reduces molecular O2  O2-

  6. \O2- binds with P450(Fe2+)-RH complex

  7. P450(Fe2+)-RH-O2- complex oxidizes drug  P450(Fe2+)-ROH

  8. ROH is oxidized drug product

In human liver, many diff types of CP450 – CYP3A4 metabolised >50% drugs metabolized in liver


Enzyme Induction / Inhibition

Many lipophilic drugs may remain bound to lipid ER membrane  induce microsomal enzymes / competitively inhibit metabolism of simultaneously administered drug.


INDUCTION: (sedatives, antipsychotics, anticonvulsants, antitubercular)

CP450 induced by enhanced rate of synthesis and reduced rate of degradation  incr metabolism  decr pharmacological action of drugs / increase action of active metabolites (eg. Need higher doses of warfarin)

If you discontinue an inducer, then you may get reduced metabolism of another drug you are taking due to loss of induction.

May result in tolerance (progressively reduced therapeutic effectiveness due to increased metabolism) if drug induces its own enzymes


Inducers: smoking, insecticides, omeprazole, rifampicin, Phenobarbital, barbiturates, ethanol, St John’s wart, carbamazepine, glucocorticoids, phenytoin. These inducers increase transcription and translation of CP450 genes.

Clotrimazole and alcohol increases CP450 by substrate stablisation (ie. Decr degradation)


INHIBITION:

May result in toxic levels of drugs – be careful with anticoagulants and sedatives



Competitive inhibition: drug may bind CP450 heme iron hence preventing CP450 from metabolizing via competitive inhibition (eg. Ketoconazole, cimetidine)

Drug may bind CP450 heme iron and render it catalytically inactive (eg. macrolide AB’s)



Suicide inhibitors: CP450 may be bound by metabolic substrate of a drug and hence altered (eg. Chloramphenicol, spironolactone, clopidogrel, grapefruit juice)
Other inhibitors: clopidogrel, trimethoprim, fluconazole, quinidine, paroxetine, disulfiram, erythromycin, clarithromycin, allopurinol, fluconazole, grapefruit juice, cimetidine
Production of Toxic Products

May be esp important in OD

Eg. Paracetamol (95% glucuronidation and sulfation, 5% with glutathione)  on OD 95% pathway saturated quickly, glutathione (GSH) mops up as much as poss, but then rest goes down CP450 pathway  N-acetylbenzoiminoquinone  hepatotoxicity. Antidote to this metabolite is N-acetylcysteine.
Variations in Drug Metabolism

Individual differences: metabolism of certain drugs may differ 30x in diff people

Genetic factors: usually autosomal recessive

Abnormal enzymes (eg. Pseudocholinesterase and succinylcholine; warfarin)

Abnormal level of enzymes (eg. acetylation of isoniazid - slow acetylation type)

Debrisoquinsparteine oxidation polymorphism – faulty expression of P450 gene  poor drug

Metabolism

Aromatic (4)-hydroxylation of CYP2C19 polymorphism – decr metabolism of mephenytoin

CYP2C9 – mutuation may lower affinity for substrate or impair interaction with P450 reductase  decr tolerance for warfarin

CYP3A5 – affects metabolism of midazolam



Diet: charcoal-broiled foods and cruciferous veggies induce CYP1A; grapefruit juice inhibits CYP3A

Environment: smoking and pesticides induce

Age: extreme of ages have slower metabolism

Sex: males metabolise faster

Drug-drug interactions: see inhibitors/inducers

Interactions with endogenous compounds: different drugs may compete for same conjugating compounds

Diseases: liver disease affects biotransformation (incr halflife of diazepam), heart disease decreases blood flow to liver preventing metabolism of even very easily metabolisable drugs (eg. Amitriptyline, imipramine, isoniazid, lidocaine, morphine, propanolol, verapamil), lung disease (decr metabolism of procainamide), hypothyroidism incr half life of digoxin and beta-blockers

GI TRACT DRUGS
Anti-Ulcer Medication
Caustic effect of acid/pepsin/bile overwhelms GI mucus and bicarb secretion, PG’s, blood flow, regeneration.

Decr gastric acidity  decr bioavailability of drugs needing acid to be absorbed (eg. Ketoconazole, digoxin)


Production of Acid:

1) Ach / gastrin binds parietal cell  incr cytosolic Ca  stimulates protein kinases  acid secretion from H/K ATPase on canalicular surface

2) Ach / gastrin binds enterochromaffin-like (ECL) cellshistamine release  binds to H2 receptor on parietal cells  activation of adenylyl cyclase  incr intracellular cAMP  activates protein kinases  acid secretion by H/K ATPase

NB. Ach works via M3 receptors in gut


Muscosal Protective Mechanisms

1) Gastric mucous – prevent back-diffusion of pepsin and acid

2) Epithelial cell-cell tight junctions – prevent back-diffusion of pepsin and acid

3) Bicarb secretion – pH gradient within mucous layer

4) Blood flow – carries bicarb and nutrients to gastric mucosa

5) Mucosa – quick regeneration of damage, by migration of cells from gland necks

6) Mucosal PG’s – for blood flow and bicarb secretion
Antacids:


Action

Weak bases that react with HCl  salt and H2O

May promote PG production



Indication

Dyspepsia

Route of administration

PO

Dose




Dosing Interval

1 hour after a meal

Absorption




Bioavailability




Half life




Duration of Action

2 hours

Distribution




Metabolism




Excretion

Renal

Side effects

Bloating, belching (Na bicarb / Ca carb due to production of CO2)

Metabolic alkalosis (Na bicarb / Ca carb alkali absorption) (less in MgOH / AlOH due to efficiency of action)

Fluid retention 2Y to NaCl absorption (Na bicarb)

Hypercalcaemia (Ca carb)

Renal insufficiency (Ca carb)

Diarrhoea (MgOH; osmotic)

Constipation (AlOH)


Contraindications

Renal insufficiency  metabolic alkalosis

Heart failure, HBP  fluid retention



Drug interactions

Can affect absorption of other meds by binding them or altering gastric pH and hence drugs dissolution/solubility (eg. Tetracyclines, flurorquinolones, itraconazole, iron)

Pregnancy




Examples

Na bicarb (baking soda, alka seltzer): reacts rapidly; forms CO2 and NaCl

Ca carb (Tums, Os-Cal): less soluble, slower; forms CO2 and CaCl2

MgOH, AlOH: slow; forms MgCl/AlCl and H20

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