1. Drugs are divided into:
Medicinal drugs:
These are used in the prevention, treatment and diagnosis of disease
Non-medicinal drugs or social drugs:
These are used for purposes other than treatment e.g. illegal mood- altering substances such as cannabis, heroin and cocaine

2. Pharmacodynamics

3. Targets of drugs Receptors Enzymes Ion channels Carrier molecules
Physical or Chemical

4. Drug receptors Highly specific, highly sensitive binding site
Found on the surface of the cell membrane, enzyme molecules on nuclear membranes.

5. Receptor Specificity
There are a number of specific ligands and a number of associate receptors
Affinity
The extent to which the ligand is capable of binding and remains bound to a receptor
High affinity: The ligand bind well and remains bound for long enough to activate the receptor
Low Affinity: The ligand binds less well and may not remain bound long enough to activate the receptor

6. The receptor intrinsic activity
The extent to which the ligand activates the receptor
High intrinsic activity: the ligand produces a large effect on the post synaptic cell
Low intrinsic activity: the ligand produces a small or inconsistent effect on the post synaptic cell

7. Classes of Ligands Agonists High affinity High intrinsic activity
Antagonist
Low intrinsic activity

8. Agonists
An agonist is a drug that binds to a receptor and activates it to give a response
There are 2 types of agonists:
Full agonist: is a drug when bound to a receptor produces 100% of the maximum possible biologic response
Partial agonist: a drug that produce less than 100% of the maximum possible biologic response no matter how high their concentration

9. Antagonist
An antagonist is a drug that bind to a receptor and produce no response.
Type of drug antagonism:
Receptor antagonists
Competitive: the antagonists competes with the agonist at the same receptor site of an agonist and binds to it reversibly. By increasing the concentration of drug agonist the antagonism is abolished. E.g. antihistamine competes with histamine at its receptor site

10. Non competitive: the antagonist binds irreversibly to a different site on the enzyme e.g. than the agonist, noncompetitive agonists can not overcome by increasing the concentration of the drug agonist. E.g. succinylcholine is irreversible neuromuscular blocker.

11. AGONIST R R+
RESPONSE
Resting state
Activated state
-ve
-ve
ANTAGONIST

12. Continue …
Physiological antagonism: e.g. glucagon and insulin. Histamine and epinephrine
Chemical antagonist: is the type of a drug that acts by binding chemically to the compounds and inactivates it. E.g. chelating agents, charcoal (poisoning with iron)
Pharmacokinetic antagonist: by increasing the metabolism and excretion of a drug, e.g. enzyme induction to speed metabolism

13. Dose- response curve
The response to increasing doses of an agonist or antagonist are plotted graphically.
It can measure the following:
Efficacy: is the maximum effect (Emax) which can be obtained from a large dose of the drug.
Potency: is the amount (dose) of drug or concentration in the plasma that can produce a similar effect by a dose of another drug

14. EC50 (Effective concentration): is the concentration that produce 50% of the maximum effect.
ED50 (Effective dose): is the dose that produces the response of 50% of subjects
LD50 (Lethal dose): is the dose that cause death in 50% of subjects

15. Non competitive antagonist will bind irreversibly with the receptor leading to decrease in number of receptors available for binding with the agonist
This will cause the maximum effect of the agonist to be less than when it is used alone or with competitive antagonist

18. Therapeutic index
Is the ratio between the average maximum tolerated dose LD50 and the average minimal effective dose ED50
TI= LD50/ ED50
It indicates the margin of safety in use of a drug
The higher the TI the safer the drug

19. Type of receptor proteins
A. ligand gated ion cannels:
Ionotropic receptors
They are membrane receptors that compose an ion channel with ligand binding site (receptor) in the extracellular domain that stimulate the opening of the channel.
It increases Na, K permeability and possibly generates an action potential.

20. Typically are these the receptors which fast neurotransmitters acts (milliseconds).
E.g. nicotinic Ach receptor, GABA A receptor

22. B. G-protein coupled receptors
Know as metabotropic receptor, they are membrane receptors
They either stimulate an enzyme or a channel
The receptor is coupled with G protein

23. G-proteins comprises 3 subunits; α, β, γ
G-proteins comprises 3 subunits; α, β, γ . The α subunit consists of GTPase, which catalyzes the conversion of GTP to GDP and break down the G-proteins releasing the α subunit
The α-GTP diffuse in the membrane and associate with various enzymes causing activation or inactivation.
This process is terminated when the α subunit is recombined with the β, γ subunits

25. Classes of G- protein : Gi, Gs, Gq
Classes of G- protein : Gi, Gs, Gq. Gs & Gi either stimulate or inhibit enzyme Adenylate cyclase. Gq activates phospholipase C (PLC)
Example: cholera toxin acts by Gs
pertusis toxin acts by Gi
Targets of G- proteins:
1- adenylate cyclase (cAMP)
2- Phospholipase C PLC (IP3 “inositol trisphosphate” and diacylglycerol ”DAG”)
3- Ion channels (Ca+2 and K+)

26. C- Kinase- linked and related receptor:
They mediate the action of many different mediators including growth factors, cytokines, and hormones (insulin)
They have a common structure, a large extracellular (ligand- binding) domain connected by an α- helix to an intracellular domain (effector)

28. D- Nuclear receptors
These are ligand for: steroid hormones, thyroid hormones, vt.D and retinoic acid as well as lipid-lowering drugs and antidiabetics
From its name it is found in the nucleus (intracellular) so the ligand must enter the cell.
The compounds are usually lipophilic so they readily cross the lipid-bilayer.
They are important for gene expression, alter protein synthesis and drug metabolizing enzymes.
They are the slowest

29. Other GATING mechanisms:
1- voltage- gating channels:
They open when the membrane is depolarized (i.e. excitation) in the activation phase
It is short lasting
They are either Na+, K+, Ca+2 voltage- gated channel
2- calcium releasing channels:
They lie on the membrane of the endoplasmic reticulum

30. Functions of receptors
To propagate signals from outside to inside
To amplify signals
To integrate various extracellular and intracellular regulatory signals
To adapt to long term changes in maintaining homeostasis

31. Undesirable responses to drug therapy
Toxic effect :
When too much drug has collected in the patient.
It may be due to:
an acute high dose of a drug
chronic buildup over time
or increased sensitivity to the standard dose of a drug.

32. Drug allergy (hypersensitivity):
The body sees the drug as an antigen and an immune response is established against the drug.
This may be an immediate response or delayed

33. Adverse reaction-
undesirable drug effect.
Side effect-
This is similar to the term adverse reaction.
It is an unwanted but expected responses to a drug.

34. Adverse Drug Reaction Frequency of adverse drug reaction
ADRs are common.
About 2-6% of hospital admissions are for ADRs.

35. Types of ADR’s A: Augmented dose related
Related to pharmacology (toxic effect or side effect--for example, digoxin toxicity)

36. B
Bizarre
non-dose related,
Unrelated to pharmacology (idiosyncratic for example, malignant hyperthermia, or immunological--for example, penicillin rash)

37. C: 
Continuous or chronic
Dose and time related,
Related to cumulative drug use--for or chronic example, NSAID induced renal failure

38. D: 
Delayed,,
Delayed effect
Can be seen only some time after use of drug--for example Carcinogenic & teratogenic effects

39. E: 
End of use
Withdrawal
Related to discontinuation that is too abrupt--for example, addisonian crisis after steroid withdrawal

40. Factors affecting a patient’s response to a drug
Age.
The very young
The elderly.
Body weight.
Pregnancy and lactation.
Nutritional status.
Food-drug interactions. For example, orange juice (vitamin C) will enhance the absorption of iron sulphate, but dairy produce reduce the absorption of tetracycline..

41. Disease processes. Includes:
Changes in gut motility e.g. diarrhoea
Loss of absorptive surface in the small intestine, as occurs in Crohn’s disease will affect absorption.
Hepatic disease
Renal disease
Circulatory diseases
Mental and emotional factors.
Genetic and ethnic factors.

42. PHARMACOKINETICS

43. Translocation of drug molecules
Drug molecule move around the body in 2 ways:
in blood stream (bulk transfer), the chemical nature of a drug is of no importance to its transfer.
molecule by molecule, over short distance (diffusional transfer), the chemical nature of a drug is an important factor especially its ability to cross hydrophobic barriers. The rate of diffusion depends also on its molecular size, large molecules tend to diffuse more slowly than smaller ones.

44. Movement of drug molecule across cell barriers
Cell membrane form the barrier between aqueous compartments of the body
epithelial barrier such as GI mucosa or renal tubules, consist of a layer of cells tightly connected to each other
Vascular epithelium: Gabs between endothelial cells are packed with a loose matrix of proteins that acts as filters, retaining large molecules and letting smaller ones through.

45. In some organs, especially CNS and placenta, there are tight junctions between the cells and the endothelium is an impermeable layer.
These features prevent potentially harmful molecules from leaking from the blood to these organs.
In other organs (e.g. liver and spleen), the endothelium is discontinuous, allowing free passage between cells.

46. There are 4 main ways by which molecules cross the cell membrane:
by diffusion directly through lipids
by diffusion through aqueous pores formed by special aquaprotiens that traverse the lipids
by combination with transmembrane carrier protein that binds a molecule on one side of the membrane then changes configuration and release it to the other side.
by pinocytosis

47. PH ionization of weak acids and weak bases, the Handersons-Hasselbakh equation
The electrical charge of an ionized molecule attracts water dipoles and results in polar, relatively water soluble compound.
Since lipid diffusion depends on relatively high lipid solubility, ionization of drugs may markedly reduce their ability to permeate membranes.

48. Weak acid is best defined as a neutral molecule that can reversibly dissociate into an anion and a proton.
The protonated form is neutral and more lipid soluble
HA↔H+ +A-
Weak base is defined as neutral molecule that can form a cation by combining, with a proton,
the un-protonated form is the neutral form
B H+↔H+ +B

49. The HHE relates the ratio of protonated to unprotonated weak acids and weak bases to the molecules PKa and PH of the medium as follows:
Log 10 protonated = PKa _ PH
unprotonated
For bases:
PKa = PH + Log 10 [BH+]
[B]
For acids:
PKa = PH + Log 10 [AH]
[A-]
PKa: (ionization constant), is PH at which 50% of the drug is ionized.

50. Because the uncharged form is the more lipid soluble, more of weak acids will be lipid soluble in acidic medium and more weak bases will be lipid soluble in alkaline medium.

51. Ionization increases renal clearance of drugs
Both ionized and non-ionized forms of a drug are filtered
Only free unbound drug is filtered
Only non-ionized forms undergo secretion and active or passive reabsorption
Ionized forms of drugs are trapped in the filtrate
Here is a summary of why ionization is relevant to renal clearance. It goes this way.
First of all recognize that if a drug is in the blood and the blood supply is directed to the glomerular apparatus in the kidney, here is a mechanism for filtration. Filtration only allows for the drugs that are free to cross into the tubular lumen and bound drugs, if it is bound to a plasma protein, cannot cross through the glomerular apparatus. So you filter free drug into the lumen of the tubule of the kidney every time the blood gets into the glomerular apparatus. It doesn’t matter whether the drug is ionized or non-ionized regarding filtration because ions can be filtered and non-ionized forms of the drug can be filtered. However, only non-ionized forms of the drugs can be reabsorbed across the tubular membrane and only nonionized drugs can actually undergo secretion across that membrane. If a drug is in an ionized form it is struck into the lumen of the tubules and ultimately will pass down and be present in the urine and can be eliminated from the body by that mechanism. So in a sense filtration traps ions in the urine. And we that term sometimes, trapping of an ionized form of a drug and that would be in a form that is not readily reabsorbed across a biological membrane. So this is why we go through the Henderson-Hasselbatch. Largely because of the possibility to manipulate the urinary pH to enhance the elimination or restrict the elimination of a drug from the body by changes in pH.

52. DRUG DISPOSION Absorption Distribution Metabolism Excretion
DIVIDED INTO:
Absorption
Distribution
Metabolism
Excretion

53. Drug forms Tablets Capsules
Solution: for injections, either IM, IV, SC
Solution to drink
Preparation to apply to skin or mucus membranes
Vaginal tablets
Rectal preparation

54. Routes of drug administration
Oral
Sublingual
Rectal
Application to other epithelial surfaces (cornea, skin, vagina and nasal mucosa)
Injections (SC, IM, IV, intra-thecal)
Inhalation

55. BIOAVAILABILITY

56. Defined as the proportion of drug conc that reach the systemic circulation following administration.
This is measured by the area under the curve AUC
AUC= A / Ke
A: the point or concentration where the drug reach max plasma concentrated
Ke: elimination rate constant (0.7/ t½)
f = AUC PO/AUC IV

57. Ke: the time were the concentration of the drug in plasma drop by 50% (elimination constant)
IV doses have 100% bioavailability, f = 1

58. Factors affecting Bioavailability
A- Extent of absorption:
Usually any drug taken by oral administration is incompletely absorbed
B- First- pass metabolism:
After absorption of a drug it goes to the liver through portal circulation were it is metabolized to active or inactive compounds (can occur in the gut).
Some of these compounds are excreted in bile.

59. Hepatic Extraction ratio (ER)
It is affected by: rate of hepatic clearance of the drug and hepatic blood flow
ER= CL liver/ Q
CL liver: liver clearance of the drug
Q: hepatic blood flow

60. Systemic Bioavailability (F)
F= f(1-ER)
f: the extent of absorption of the drug
Example:
A drug like morphine if taken orally almost completely absorbed f=1 hepatic ER=0.67 so
F=(1-ER)=1-0.67=0.33
F= 0.33×100=33%

61. VOLUME OF DISTRIBUTION
Vd: relates to the amount of drug in the body to the concentration of the drug in blood or plasma
Vd= amount of drug in body C
It is affected by protein binding.
Only unbound drug (free fraction) exerts pharmacolological effects

62. The higher the Vd, the lower the plasma concentration and vice versa
Vd is low when a high % of drug is bound to plasma proteins

63. Special Barriers to Distribution
Placental
Most drugs cross the placental barrier, but fetal blood level is usually lower than maternal
Blood-Brain
Permeable to lipid soluble or very small drug molecules
Redistribution
Lipid-soluble drugs redistribute into fat tissues prior to elimination - repeated doses cause saturation – may prolong duration of action

64. DRUG ELIMINATION It involves the following:
1- Drug metabolism: which include enzymatic conversion of one chemical entity to another
2- Drug excretion: includes the elimination of drugs either unchanged or metabolized
It occurs through the kidney, hepato-billiary and lung.

65. Drug Metabolism
Lipophilic compound are not excreted by the kidney and they need to become more soluble or polar to be excreted.
Metabolism occurs mainly in the liver (CYP450 system)
Metabolism may result in formation of active metabolites (diazepam – nordiazepam)
Prodrugs lack activity until they undergo bioactivation (clorazepate – nordiazepam)

66. Metabolism involves two phases:
Phase -1 reaction: (catabolic)
it includes: oxidation, reduction, and hydrolysis reaction.
It is called “the microsomal mixed function oxidase system”.
Major phase 1 enzymes – localized in smooth ER of liver, GI tract, lungs, and kidneys

67. It includes two enzymes:
NADPH cytochrome reductase
CYP450 system
Require O2 and NADPH
Multiple CYP families vary by substrate specificity and sensitivity to inhibitors & inducing agents

68. CYP3A4 Major isoform with wide substrate range
Inhibited by cimetidine, macrolides, azoles & ethanol (acute)
Induced by carbamazepine, phenobarbital, phenytoin, rifampicin, & ethanol (chronic)

69. CYP2D6 Genotypic variations in hydroxylation (fast / slow)
Substrates include codeine, debrisoquin & metoprolol
Inhibited by haloperidol & quinidine; not inducible

70. Other Phase 1 metabolism
Non-microsomal oxidations
Monoamine oxidases metabolize NE, 5HT, and tyramine
Alcohols metabolized via alcohol dehydrogenase (ADH) to aldehydes then aldehyde dehydrogenoase (inhibited by disulfram)

71. Phase -2 reaction:
It include conjugation with other groups to make it more soluble.
Groups used in conjugation:
glucoronyl,
sulfate,
methyl,
acetyl,
glycyl
glutathione

72. This phase can occur in the kidneys
Acetylation is genetically determined. Fast acetylators and slow acetylators (develop SLE like syndrome when given INH, hydralazine, procainamid or INH
Transferases: usually inactivate drugs, but may activate (e.g. morphine, minoxidil). May follow a phase I hydroxylation, but also occur directly
Glucuronidation – inducible; reduced activity in neonate

73. RENAL EXCRETION
There are 3 main process for Renal excretion of a drug:
1- Glumerular filtration rate: (GFR)
This depends on the molecular weight of the drug and the extents of binding to plasma proteins.
2- Tubular secretion:
Here drug molecules are transferred by two independent and non-selective carrier systems i.e. Transport of acidic compounds or basic compounds

74. They transport drug molecules against conc
They transport drug molecules against conc. gradient so can reduce the plasma conc. of the drug to zero.
E.g. penicillin
3- Diffusion across the renal tubules:
Renal tubes can be freely permeable (the drug concentration in the plasma and in the renal tube is equal)

75. DRUG ELIMINATION (CLEARANCE)
Defined as the volume of plasma containing the amount of substance that is removed by the kidney in unite time
CL= Cu Vu Cp
CL: Clearance
Cu: Urine Concentration
Cp: Plasma Concentration
Vu: Volume of Urine

76. CLEARANCE Equals rate of elimination divided by plasma level
Total body clearance CL = CLR + CLER (extra renal)
With no secretion or reabsorption renal clearance is the same as glomerular filtration rate, CLR = GFR
If drug is protein bound then CLR = GFR x free fraction

77. There are two ways for drug elimination:
1- First Order Kinetic 2- Zero Order Kinetic

78. First Order Kinetic (un- saturable)
Defined as the amount of drug removed is direct proportion to its concentration in plasma.

79. ZERO- ORDER KINETICS (SATURABLE)
Here drugs are removed at a constant rate regardless the plasma concentration levels because it is an enzyme dependent process so it has limited capacity.
Example:
Ethanol
Phenytoin
Salicylates

80. t½
10.9
Blood Alcohol concentration
7.6
4.3
Alcohol is eliminated at a rate of 4mmol/l regard less the plasma concentration
TIME
Dose Administration

81. t½ HALF LIFE OF A DRUG
Is the time required by the body to eliminate 50% of the drug concentration
t½= Vd x 0.7 CL
It is important to indicate the time required to attain 50% of the steady state
This helps in the setting up of a dosage regime which produces:
Stable plasma drug concentrations
keeps the level of drug below toxic levels but above the minimum effective level

82. Loading Dose
This is given when an effective plasma level of drug must be reached quickly.
This requires a dose of the drug which is larger than is normally given.
This dose is given as a one off.
Maintenance dose:
This is the dose given when the required plasma level of drug has been reached.
It is the normal recommended dose.
This is then continued at regular intervals to maintain a stable plasma level .