The drug passage through cell membranes

1. Molecular size and shape
2. Degree of ionization
3. Relative lipid solubility (of ionized and nonionized forms)
4. Binding to serum and tissue properties

absorption

distribution

elimination

pharmacologic effect at site of action

Will there be an inhibiting enzyme?

Or a Receptor Agonist?

Large molecules do not readily cross membranes.

True or False?

The more charged a drug molecule, the more water soluble and the less lipid soluble it is.

True or False?

Uncharged drugs readily crosses membranes; charged molecules do not.

True or False

1. Aqueous (Passive) diffusion
2. Facilitated Diffusion
3. Active Transport
4. Endocytosis and exocytosis

• Specific carrier proteins involve in absorption.
• Can be saturated
• Energy dependent requiring ATP
• Can move drugs against a concentration gradient
• (i.e. low to high)
• Can be inhibited (eg ATP by metabolism).

Endocytosis and exocytosis

• Substance is engulfed by the cell membrane and carried into the cell or out of the cell (pinches off the cell membrane, and is released).
• Energy dependent, saturable process.
• Carries drugs of exceptionally large size (>1000).

Facilitated Diffusion

• Requires specific carrier proteins
• Can be saturated.
• Driven by concentration gradient (high to low)
• Can be inhibited

Aqueous (Passive) diffusion

Driven by concentration gradient (high to low).

Spontaneous and bidirectional.

Occurs in large body interstitial space, cytosol, etc.

Not saturable and cannot be inhibited

Shows low structural specificity. This is the most common form of transport used by drugs to get into the cells.  

Route of administration depends upon:

1. physical and chemical drug properties
2. desired site of action
3. state of the patient
4. required rapidity and duration of response
5. convenience
6. cost

1. Generally the safest route

2. Economical

3. Convenient for owner

4. No need for sterile equipment

5. Systemic distribution

1. Absorption may be variable
2. Gastric irritation may cause vomiting
3. Not useful if patient is vomiting
4. Requires cooperation of patient
5. Drug may be destroyed by gastric acidity, gut flora, mucosal enzymes, liver enzymes
6. Onset of effect is slow
7. Drug dilution

Most drug absorption from the gut occurs in the proximal

duodenum due to the large surface-to-volume ratio in the duodenum

Enteric Coating

1. prevents dissolution in the acidic gastric contents
2. some enteric-coated preparations of a drug also may resist dissolution in the intestine, reducing drug absorption.
3. helpful for drugs such as aspirin that can

   cause significant gastric irritation in many

   patients.

Extremely lipid-soluble compounds enter the _______

Controlled-Release Preparations:

1. reduction in frequency of administration (compliance)
2. Maintenance of a therapeutic effect
3. good for 1/2 life drugs such as antidepressants where patient needs to maintain consistent drug conc. levels
4. made by polymers, oils and smaller particles

placed under the tongue

does not undergo first pass metabolism

venous drainage from the mouth to the superior vena cava

ex. nitroglycerin

Will cause the drug conc to stay longer in the body because drug will continue to circulate from the liver back into the GI tract.

• • High molecular weight conjugates are subject to enzymatic cleavage of the conjugate bond by intestinal flora, leading to release of the parent drug back into systemic circulation. May delay elimination and prolong its effect.

   

1. 1. the patient is unconscious or vomiting.

   Useful in infants or when local rectal action is needed.

2. Rectal absorption is often erratic and incomplete and many drugs irritate the rectal mucosa.
3. Useful when oral ingestion is not possible:

    

1. ~ 50% of the drug absorbed will bypass the liver (less first pass than oral route)

1. Absorption can be irregular and incomplete
2. May cause irritation of rectal mucosa

1. Bioavailability (rate of absorption) is complete and rapid
2. Drug can be rapidly increase and can be adjusted by dripping rate
3. Irritant solutions can be given i.v at a slow rate (dilution in blood)

1. Only for drugs that are not irritating to tissues
2. Rate of absorption is usually slow and can provide a sustained effect
3. Particle size, protein complexation and pH can be altered to change rate of absorption

 

 

              - Insulin

              – Lidocaine/epinephrine

1. 1. Aqueous solutions are rapidly absorbed
   2. Can be a

   ffected by:

• Local heating

• Exercise

• Massage

• Fat distribution

3. Oily solutions can be a Depot administration (oily active compound released in a consistent way over a long period of time administered intramuscular)

1. Injection directly into artery: liver tumor, head/neck cancer
2. Diagnostic agents
3. Requires great care= only for experts. No liver/lung metabolism

Intrathecal Injection

Drug injected directly into subarachnoid space= directly into the CSF

• Gaseous and volatile drugs can be administered

• Access to the circulation is rapid since lung surface area is large

• Solutions can be atomized in fine droplets (nebulizer, inhalers, aerosols)

• Treatment of local conditions: bronchoconstriction,

emphysema

• Drugs of abuse and toxics from the environment

• Mucous membranes absorption:

–Conjuntiva, vagina, colon, urethra, oropharynx,

• Treatment of local conditions or within systemic absorption (antidiuretic hormone to nasal mucosa) 

1. Used for local effects
2. Systemic absorption may occur through nasolacrimal canal drainage (corticosteroids)

• Cardiac output: pts with cardiac conditions will pump less drugs to organs

• Regional blood flow: adipose tissue and bone have low blood flow

ex. cations get stuck in bone due to low blod irrigation and become stored

• Capillary permeability: CNS has tight junctions making it harder for drug to pass

• Liver

• Kidneys

• Brain

• Muscle

• Viscera

• Skin

• fat

• Lipid solubility
• transmembrane pH gradients

Fraction of Drug Bound depends on:

1. Drug concentration
2. Affinity of binding sites
3. Number of binding sites

1. Binding is reversible
2. Covalent binding rarely occurs
3. non-linear saturable process

Patterns of Distribution

1.  

    

   Drugs largely within the vascular system. Drugs that are strongly bound to plasma proteins approach this pattern.

2.  

    

    

   Drug uniformly distributed throughout the body water (i.e. ethanol)

3.  

    

    

   Drug concentrated in one or more tissues that may or may not be the site of action of the drug.

4.  

    

    

   Combination of 1, 2 and 3. Most common

can

bound and unbound portions of a drug are at equilibrium releasing a portion of bound drug will increase the percentage of unbound drug at 100 fold

P-glycoprotein (P-gp) and Organic anion transporter (OATP)

Membrane Transporter that act as efflux carriers: remove large number of chemicals from the cells.

Meningeal and encephalic inflammation may increase local permeability

Drug transfer may depend on :

• Ion trapping of basic drugs)
• Placenta express export will limit fetal exposure

Drugs may be altered into more polar, water-soluble products in four ways:

1. Active drugs to inactive drugs
2. Active drugs to an excretable metabolite
3. Inactive prodrug to an active drug
4. Unexcretable metabolite to an excretable metabolite

Majority of drugs must be biotransformed into more polar

or hydrophilic metabolites before elimination primarily by _______

Orally administered drugs may be immediately inactivated in either the liver or intestines before it ever reaches the systemic circulation.

1. Use sublingual or buccal route
2. larger oral dose

3. administer drug parenterally

Convert hydrophobic molecules into more hydrophilic

compounds by adding or exposing polar functional  Groups such as hydroxyl (-OH), thiol (-SH), or amine (-NH2) groups.

1. N- and S- Oxidation

2. Hydroxylation

3. Oxidative Deamination

4. Dehalogenation

5. Desulfuration

6. N- O and S-Dealkylation

7. Hydrolysis

8. Sufoxide/sulfone formation

9. Reductions

• Called cytochrome P450 based on spectral properties-Pigment with a peak at 450 nm (when in the reduced form).
• The term CYP is used as a preface and is composed of the first two letters in cytochrome and the first letter of P450.

• CYP450 SUPERFAMILY
• FAMILIES: CYP plus Arabic Numeral (>40% homology in aminoacid sequence; e.g. CYP1)
• SUBFAMILY: Additional Arabic letter or numeral (>55% homology of amino acid sequence; e.g. CYP1A2
Italics for gene (CYP2D6) and normal (CYP2D6) for enzyme
Italics for gene (CYP2D6) and normal (CYP2D6) for enzyme
• Italics for gene (CYP2D6) and normal (CYP2D6) for enzyme

Absent in 15%-20% of Asians and 2%-5% of whites

Absent in 7% of whites (caucasians europeans)

CYP2E1

Activity increased by alcohol

CYP3A4

Wide range of activity in liver and GI tract

• Occurs in the cytosol primarily by conjugation reactions
• Polar conjugates are generally inactive and  rapidly excreted in urine or feces- virtually all phase II metabolites are pharmacologically inactive.
• Glucoronidation
• Sulfation

 

 

Acetylation

 

 

Acetylation

 

 

Acetylation

•  

   

  Glutathione conjugation

• N, O and S-methylation

Orientals have a different affect on drugs that are metabolized by ______

CYP2C19

1. Induction
2. Inhibition
3. Naturally Occuring Substances
4. Genetic Factors
5. Racial Differences
6. Physiological Conditions

1. ketoconazole
2. diltiazem
3. erythromycin
4. narangenin (grapefruit component)

1. carbamazepine

2. rifampicin

• CYP3A4 is most abundant

• Occurs in both liver and intestinal wall

• No evidence for polymorphism as of 1997

• Wide range of inter-individual variability in metabolism

• Wide range of drug substrates:

1. Glomerular filtration

Glomerular filtration

1. Occurs in the bowman’s capsule

2. filters molecules of low molecular weight (<60,000 D) from blood.

3.  

4.  

5. Most drugs filtered unless tightly bound to plasma proteins.

6. The normal Glomerular filtration rate (GFR) ranges from

   110 to 130 mL/min (~180 L/day).- measured using insulin.

7.  

    

   Only 10% of drugs that enter the blood is filtered.

more than 90% of the filtrate is reabsorbed by the _______

Proximal tubule

• reabsorption of water and active secretion of some weak electrolytes (weak acids).
• Requires a carrier and energy.
• May see competitive inhibition of the secretion of one

  compound for another.- eg probenicid inhibition of

  penicillin excretion.

• There is passive excretion and re-absorption of lipid soluble (nonionic) drugs.
• Filtered lipids will be extensively reabsorbed. Concentration gradient is in the direction of re-absorption since filtrate is now concentrated due to re-absorption of water in the proximal tubule.

Acidic urine

weak acids re-absorbed (less ionized);

weak bases eliminated (more ionized)

weak bases re-absorbed less ionized);
weak acids eliminated (more ionized)

• excreted into bile mainly by active transport.
• Primarily for drugs with MW of 300 to 500 and more.
• Competitive process which may be modified by other drugs
• Drugs in the bile are secreted into the GI for reabsorption

1. sweat
2. tears
3. saliva
4. breast milk (milk is more acidic than plasma)

The rate is proportionate to the amount of drug present in the body.

A constant fraction of drug in the body is eliminated per unit time.

The fraction of drug eliminated is constant. The half life is constant.

• The rate of the drug entering the body is independent of dose or amount of drug present. Eg ethanol

• Saturable

• The absolute amount of drug eliminated is constant.

• The half life is not constant

• Slow distribution across membrane to tissue or other body fluid.

• Elimination of unchanged drug by renal or biliary routes.

• Exhalation through pulmonary pathways

• Metabolism to active or inactive compound.

Relates the amount of drug in the body to the concentration (c

) of drug in the blood or plasma.

drugs that are highly lipid soluble have a very high Vd. Lipid insoluble drugs remain in the blood and have a low Vd.

v_d= dose/ [drug]_plasma

1.  Relates drug binding to tissue (body) versus plasma proteins (blood).
2. Used to calculate loading dose of a drug.
3. Can be used to indicate pattern of distribution of drug.

it has entered some other compartment.

1. plasma binding proteins
2. lipid solubility

the volume of plasma cleared of the drug with in a unit of time (1 min)

units= ml/min

Addititive

The higher the clearance the faster the drug will disappear.

T_1/2= .7(V_d)/CL or T_1/2= 0.693(Vd)/CL

• The time required for a drug concentration in the plasma to be decreased by half or 50%
• 4-5 half-lives are required to reach steady-state or
  eliminate a drug that follows first order kinetics.
• Important concept for calculation of maintenance
  dose!

• route of administration
• extent of absorption
• first pass effect.

• Contain the same active ingredients
• Be identical in strength and concentration
• Have the same rates and extent of bioavailability under test conditions (in vitro dissolution testing).

Loading Dose

Loading Dose=Vd x Desired plasma C
(steady state concentration)
Or
(target plasma concentration)

a dose of drug sufficient to produce a plasma concentration of drug that would fall within the therapeutic window after only one or very few doses over a very short interval. It is larger than the dose rate needed to maintain the concentration within the window and would produce toxic concentrations if given in repeated doses.