Pharmacodynamics: Pharmacokinetics:

The study of how a drug binds to its target binding site and produces a pharmacological effect. The study of how a drug is absorbed, distributed, metabolized and excreted (ADME) .
( i.e what the drug does to the body ?). ( i.e what the body does to the drug?).
Physicochemical parameters of the drug and drug absorption:
I- Stability: II- Solubility: Most oral drugs obey Lipinski’s rule:
 * Oral drugs have to be chemically stable to survive the stomach  * The drug should have the correct balance of water versus 1) A molecular weight less than 500.
 HCl and metabolically stable to survive the digestive enzymes in fat solubility (passive diffusion). 2) No more than 5 hydrogen bond donor groups.
 GIT and metabolic enzymes in liver (mainly cytochrome P450).  * Oral drugs should be sufficiently polar to dissolve in the GIT and 3) No more than 10 hydrogen bond acceptor groups.
 * Insulin, local anesthetics and first penicillins are acid labile so  blood supply, but sufficiently fatty to pass through cell membranes 4) A calculated log P value less than + 5.
 they can't be taken orally but are given parentrally.  (optimum hydrophobic / hydrophilic balance).

A- Polarity: B- Ionization: Drug absorption:

 * Polar drugs break these rules are usually poorly absorbed  * The presence of the weak ionizable -NH- group (pKa value 6-8) Henderson-Hasselbalch equation
 and have to be administered by injection.  in many drug structure would have three advantages: * Pka = PH + Log [unionized] / [ ionized ]
 1. Good solubility due to =NH2+ cation in stomach acid. * Weak acids have high pka while weak bases have low pka.
 * Highly polar drugs will dissolve in GIT but they will fail to 2. Good absorption due to conversion to non-ionized form in * Acids are more active at lower pH while bases are more active
 be absorbed through the lipid cell membrane of the gut wall. intestine in slightly alkaline pH. at higher pH.
 3. Good target interactions due to participation * When pKa = pH this mean that 50% of the drug is ionized and
of ammonium ion in them. consequently 50% are unionized.
 * Non polar drugs will be poorly soluble in the GIT instead
 they will dissolve in the fat globules leading to poor surface C-Size:
 contact with cell membranes resulting in poor absorption, too.  * Large molecular weight drugs generally have poor absorption
 because they mostly have a large number of polar groups which
 will lead to poor absorption of these drugs.
Drug absorption mechanisms:
* Most drugs with proper solubility in both water and lipid will be absorbed through the lipid cell membrane of the gut wall cells.
* Carrier proteins are essential to a cell’s survival as they transport highly polar building blocks required for various biosynthetic pathways.
 * Some polar drugs are absorbed by special carrier proteins such as levodopa, fluorouracil, lisinopril, methotrexate
 and erythromycin, which are similar in structure to (or bear a structural resemblance to) one of the building blocks
 (such as amino acid) then it too may be smuggled into the cell.
 * Other polar drugs with high molecular weight are absorbed by pinocytosis (without passing through the membrane).
 * Some polar drugs with low molecular weight (<200) are absorbed by passing through the pores between cells lining
 the gut wall.
 ( Thus polar drugs are orally active if they are small enough to pass through pores between the cells of the gut wall or
 Are recognized by carrier proteins or are taken across the gut wall by pinocytosis) .
*N.B: Sometimes drugs are designed to be highly polar to be retained in the gut and not absorbed to treat gut
infections as some antibacterial agents for gut infections.
(8) Drug design -optimizing pharmacokinetic properties:
* Aim: To improve pharmacokinetic properties of lead compound. *Notes:
* To optimize chemical and metabolic stability (stomach acids / digestive enzymes / metabolic enzymes). * Drugs must be sufficiently polar to be soluble in aqueous conditions and to interact
* To optimize hydrophilic / hydrophobic balance (solubility in blood / solubility in GIT / solubility through with molecular targets .
cell membranes / access to CNS / excretion rate). * Drugs must be sufficiently ‘fatty’ to cross cell membranes and to avoid rapid excretion.
* Drugs must have both hydrophilic and lipophilic characteristics.

Ibrahim Salem 8 Dr. Hend (4)

 1-Solubility and membrane permeability (absorption):
1- Vary alkyl substituents: 2- Masking or removing polar groups: 3- Adding polar groups: 4- Vary pKa:
Rationale: Rationale: Rationale: Rationale:
* Varying the size of alkyl groups varies * Masking or removing polar groups decreases  * Adding polar groups increases polarity and  * Varying pKa alters percentage of drug which is

the hydrophilic / hydrophobic balance of polarity and increases hydrophobic character.  decreases hydrophobic character.  Ionized.
the structure. Disadvantage:  * Useful for targeting drugs vs. gut infections.  * Alter pKa to obtain required ratio of ionised to
* Larger alkyl groups increase  * Polar group may be involved in target binding.  * Useful for reducing CNS side effects.  unionised drug.
hydrophobicity. *Methods: Method:
 * Vary alkyl substituents on amine nitrogens.
Disadvantage:  * Vary aryl substituents to influence aromatic amines
May interfere with target binding for
 or aromatic carboxylic acids.
steric reasons.

2-Drug stability (metabolism):

1- Steric Shields: 2- Electronic shielding of NH2: 3- Stereoelectronic Effects: 4- Bio-isosteres:
Rationale: Rationale: Rationale: Rationale:
* Used to increase chemical and metabolic * Used to stabilise labile functional groups * Steric and electronic effects used in  * Replace susceptible group with
stability by introduce bulky group as (e.g. esters). By replace labile ester with more combination to increases chemical and  a different group without affecting activity.
a shield that protects a susceptible stable amide as nitrogen of amide feeds metabolic stability.  * Bio-isostere shows improved pharmaco-
functional group (e.g. ester) from hydrolysis. electrons into carbonyl group and makes it less  kinetic properties.
* Hinders attack by nucleophiles or enzymes. reactive so increases chemical and metabolic  * Bioisosteres are not necessarily isosteres.
stability. Examples:
Du122290
(dopamine antagonist)

Ibrahim Salem 9 Dr. Hend (4)

 5- Metabolic blockers: 6-Remove / replace susceptible 7- Shifting susceptible metabolic 8- Introducing susceptible
metabolic groups: groups: metabolic groups:
Rationale: Rationale: Rationale: Rationale:
* Metabolism of drugs usually occurs at * Remove susceptible group or replace it with * Used if the metabolically susceptible  Used to decrease metabolic stability
specific sites so we introduce groups at a metabolically stable group. group is important for binding shift its and drug lifetime so used for drugs which
a susceptible site to block the reaction. e.g. modification of tolbutamide position to make it unrecognisable to ‘linger’.i.e: Too long in the body and cause side
* Increases metabolic stability and drug (antidiabetic): metabolic enzyme. effects.
life time. * Must still be recognisable to target. *Add groups known to be susceptible
E.g. Sulbutamol: to Phase I or Phase II metabolic
reactions.

9- Introducing chemically susceptible groups:

Rationale:
* Used to decrease drug lifetime and avoids reliance on metabolic enzymes and individual variations.
*N.B:
 * Stable at acid pH, unstable at blood pH (slightly alkaline).
 * Self-destructs by Hoffmann elimination and has short lifetime.
 * Allows anaesthetist to control dose levels accurately.
 * Quick recovery times after surgery.

3- Drug Targeting
1- Targeting tumor cell: 2-Targeting gut infections: 3-Targeting peripheral regions
over CNS
Rationale:  Rationale:  Rationale:
* The idea is to attach the active drug to an important building  * Design the antibacterial agent to be highly polar * By increase polarity of the drug
block molecule that is needed in large amounts by the rapidly  or ionised agent will be too polar to cross the gut so become less likely to cross the
divided tumor cells.
 wall so agent will be concentrated at the site of  blood brain barrier.
* Increases selectivity of drugs to target cells and reduces
toxicity to other cells.  infection.
eg: - highly ionised sulphonamides.
 *N.B: Alkylating group is attached to a nucleic acid base
 As cancer cells grow faster than normal cells and have a greater demand for nucleic acid bases so 
 the drug is concentrated in cancer cells by Trojan horse tactic. 

Ibrahim Salem 10 Dr. Hend (4)

 Prodrugs (Drug latentiation)
* Definition: Inactive compounds which are converted to active compounds in the body.
* Uses: 1) Improving membrane permeability 2) Prolonging activity 3) Masking toxicity and side effects 4) Varying water solubility 5) Drug targeting 6) Improving chemical stability.
1) Prodrugs to improve membrane permeability
Esters: N-Methylation of amines Trojan horse Strategy
 * Used to mask polar and ionisable carboxylic acids then  * Used to reduce polarity of amines then happen  * Prodrug designed to mimic biosynthetic building block transported
 hydrolysed in blood by esterases.  demethylation in liver.  across cell membranes by carrier proteins.
 * Used when a carboxylic acid is required for target binding Examples: Hexobarbitone.  Example: Levodopa for dopamine
 Leaving group (alcohol) should ideally be non toxic.
 Examples: Enalapril for
(Enalaprilate)
 (Antihypertensive).

2) Prodrugs to prolong activity: 3) Prodrugs to mask toxicity and side effects:

a) Mask polar groups: b) Add hydrophobic groups:  * Used when toxic groups are important for activity.
 * Reduces rate of excretion.  * Drug concentrated in fat tissue.  Example: Aspirin for salicylic acid
 Example: Valium for nordazepam.  * Slow release into blood supply and slow removal of
hydrophobic group.
 Example:
 Cycloguanil pamoate
 (Antimalarial)

4) Prodrugs to lower water solubility: 5) Prodrugs to increase water solubility: 6) Prodrugs used to target drugs: 7) Prodrugs to increase chemical stability:
 
* Used to reduce solubility of bad tasting orally * Often used for i.v. drugs.  * Example: Hexamine.  Example: Hetacillin for ampicillin
 active drugs to be less soluble on tongue so  * Allows higher concentration and smaller dose.
* Stable and inactive at pH>5.
 less revolting taste.  * May decrease pain at site of injection. * Stable at blood pH.
 Example:Chloramphenicol palmitate.  Example: Chloramphenicol succinate. * Used for urinary infections
where pH<5.
* Degrades at pH<5 to form :
Formaldehyde (antibacterial agent).

  Ampicillin is chemically unstable in solution due to the
 side chain NH2 group attacking the β-lactam ring
 Nitrogen atom in hetacillin is locked up within
 a heterocyclic ring.

Ibrahim Salem 11 Dr. Hend (4)