1. Effectiveness

2. Safety

3. Selectivity

1. Reversible action--> ex. Anesthetic med

2. Predictability

3. Ease of administration--> improve compliance (#dose/day)

4.Freedom for drug reaction

5. Low cost

6. Chemical stability--> drug should be stable!

7. Possession of simple generic name

1. Preclinical testing (1-5 yrs)

*** test in animals**

*** test for toxicity, pharmacokinetic properties, useful effects.**

2. Clinical testing (2-10 yrs)

What group of pp will be tested on during phase I?

a. Healthy volunteer

b. Patients with diease

c. Large group of patients with disease

d. Large group of healthy people

Answer A!

Healthy people (25-50 pp)

Test for: metabolism & effects in human

         Clinical testing : Phase 2?

• Determine efficacy and dosage range
• Test on 100-200 pp

• Larger population
• Tested in 1000s patients with disease
• Tested for establish safety and feectiveness
• Submission of new drug application (NDA) to the FDA

• Post-marketing suveilance

• Limited info. for women and children
• Faliure to detect all adverse effects:

1. Relatively small number of pts.

2. Pts carefully selected in trials and do not represent full spectrum

3. Pts in trails take drug for relatively short period of time.   

What are three types pf drug names?

1. Chemical name
2. Generic name *** Prefer!
3. Trade name

Which name to use--Generic or Trade?

• Problem with generic names are

• Problem with trade names are:

• Contain the same dose of the same drug
• FDA approved generic as equal
• Rate and extent of absorption may differ and may be a concern for drug wuth a narrow therapeutic window

What is pharmacokinetics?

a. What the drug does to the body

b. What the body does to the drug

Answer B.

Study of the absorption, distirbution, metabolism, and excretion of drug ("ADME")

ADME!

Defines "Absorption"?

Defines "Distribution"

Defines "Excretion"

1. Channel and pore--> very few drug can cross this membrane (weight<200 can cross through)
2. Transport system
3. Direct penetration of the membrane--> "Passive diffusion"

Passive diffusion

• Movement of substance from higher concentration to lower concentration.
• Drug must be lipid soluble to cross a membrane

pH-dependent ionization

Most drugs are weak acids and bases --->ionization is determined by the pH of biological fluid

Ion trapping of drugs

- Occur when pH of biological fluids are different in each side of the cell membrane (i.e. stomache or plasma)

- The ionized form of a drug is trapped in the side where the pH most favors the drug ionization.

Tell me more about 

" Ion trapping!"

Acidic drug--> ionize in basic media--> will accumulate in basic (alkaline) side

Basic drug--> ionize in acid media--> will accumulate in acidic side.

What kind of drugs will be ion-trapped in the renal ultrafiltrate if the urine pH is lowered by large doses of ascorbic acid (Vit. C)?

a. Weak acid

b. Weak base

               Rate of absorption?

         Amount of absorption?

Answer Weak basic!

Because weak basic ionize in acid media, and stomach is very acidic (~2)

1. Rate of dissolution --> form and route of drug (i.e. syrup, capule)
2. Surface area ---> "large surface, better absorption"
3. Blood flow--> More rapidly absorbed from sites where blood flow is high
4. Lipid solubility--> Highly lipid soluble drugs are absorbed more rapidly
5. pH partitioning--> Enhanced absorption of drugs that will be preferentially ionized in the plasma.

Failure to detect all adverse effects:

1. Due to small amount of pts.

2. Pts. carefully selected in trails and do not represent full spectum.

3. Pts. in trails take drug for a reletively short period of time

1. Prescribed drug--> dose given, error, route, timing, adherence.

2. Administered dose--> Pharmacokinetic (ADME)

3. Concentration at site of action--> Pharmacodynamicthe drug's impact on the body (drug-receptor interaction, patient’s functional state, and placebo effects)

Q. Which part of cell membrane is hydrophobic?

a. Head

b. Tails

Answer is "TAILS" --> Hydrophobic is water-hating  !  

[image]

Passive diffusion--> From higher concentration to lower concentration.

***However, drug must be lipid solution in prior to cross the membrane.***

Concept of ion trapping

Weak acid will be trapped (ionized) in basic media which makes weak acid no longer able to cross or be absorbed! Remember, weak acid will get absorbed in acid area.

Weak base will be trapped (ionized) in acidic media which make weak basic no longer able to cross membrane. Remember, weak basic will get absorbed in basic environmet.

Matching

__1. Rate of absorbtion  

__2. Amount of absorption

a. how intense effects will be 

b. how soon effects will begin

Answer...

1. B

2. A

1. Rate of dissolution--> Dissolve fast, onset fast (syrup, capsule)

2. Surface area--> Larger surface=faster absorption (i.e. small intestine has a better absorption bcoz of its microvilli)

3. Blood flow--> More rapidly absorbed from sites where blood flow is high

4. Lipid solubility--> Highly lipid soluble drugs are absorbed more rapidly.

5. pH partitioning--> 

It is a following absorption portal blood delivers drug to liver.

**Drugs the are metabolized efficiently by the liver---> removed from circulation before distribution to the   body.  Also, rapid hepatic inactivation of certain oral drugs due to capacity of liver to metabolize certain oral drugs, inactivating drugs on first pass thru liver = drug has no therapeutic effect

1. Some oral drugs are excerted in to the bile and re-enter the small intestine via the bile duct.

** These drugs may:

1. Be absorbed into the portal blood and create a cycle of enterohepatic recirculation

2. Exit the body in the stool

Tablets !

**Chemical equivalence: 2 preparations that contain the same amount of the identical compound.

**Bioequivalence: drug is absorbed at the same rate & same extent

***Note: formulation may be chemically equivalent but not bioequivalent.

Where is the site of absorption of enteric coated drugs?

a. Intestine

b. Stomach

3. Both

IV (parenteral)

Pharmacokinetic

"Blood flow"

• In the first phase of distribution,  drugs are carried by the blood--> target (tissue, organ)
• Blood flow determines rate of distribution (& rate of absorption--recall)

Defines "Distribution"

1. Blood flow to tissue

2. The ability of drug to exit the vascular system

3. The ability of drug to enter the cell.

Exiting the Vascular system

1. Typical capillary beds

2. BBB

3. Placental drug transfer

4. Protein binding

Only lipid soluble drug! 

BBB- Tight junctions between cells that compose the walls of capillaries in the CNS prevent drugs from passing between cells to exit the vascular system. Therefore, drug must pass directly through cells of the capillary wall, which means drug must be lipid soluble in order to pass through cell.

Placental drug transfer

Placenta membrane seperate the fetal circulation to the maternal circulation--> do not constitute an absolute barrier to the passage of drugs--> same rules as for other membranes.

[image]

Answer is to increase

Q. Which one of these two drug will more likely to reach the target tissue?

a. Bound drug (bound with protein binding, albumin)

b. Unbound drug

Answer is A.

Defines Metabolism

1. Accelerated renal drug excretion

2. Drung inactivition

3. Increased therapeutic action

4. Increased toxicity

5. Decreased toxicity

CYP enzyme famillies

Which CYS enzyme is the most abundant, reponsible for 60% of metabolism?

a. CYP2D6

b. CYP3A4

c. CYP3D3

Matching

__1. Phase 1

__2. Phase 2

a. Functionalization

b. Conjugation

Answer 1. A

             2. B

• Increases the metabolism of drugs
• Decrease drug absorption--> think of women taking oral contraceptive and phenobarbital at the same time. 
• The inducer makes the drug loss their effectiveness.
• Decrease drug plasma.

• Inhibit the metabolism if drug
• Increase drug plasma
• Drug is more likely effective.

Answer Increase.

Note:

Answer Decrease.

Note:

Defines Excretion

• Removal of drugs from the body
• Urine pH
• Ionized metabolites are excreted
• Age, pathology--> change excretion
• Drugs and metabolites can exit the body in urine, bile, sweat, saliva, breast milk, and expire air

Which one is a renal route of drug excretion?

a. Bile

b. Sweat

c. Urine

d. Breast milk

Q. Which one is not correct about Excretion?

a. Nonionized metabolites are excreted

b. Age can pathology can change excretion

c. Nonrenal routes of drug excretion are saliva, breast milk, sweat.

Answer A.

Ionized drugs are excreted.

1. Glomerular filtration

2. Passive tubular reabsoption

3. Active tubular secretion

[image]

• Drugs bound to albumin are not filtered
• Most drug cross freely

What is Passive tubular reabsorption?

• Bcoz concentration in blood is lower than in the tuble
• Lipid soluble drugs move along this gradient back into blood
• Ions and polar drugs are excerted in urine.
• By converting lipid soluble drug to more polar form, drug metabolism reduce passive reabsorptionof drugs and thereby accelerates their excretion. 

• To achieve the therapeutic objective, we must control the time course of drug response
• Time course of drug response is directly related the concentration of drug in the blood

• 2 types--> minimum effective concentration (MEC), toxic concentration
• Clinical significance of plasma drug levels

• Range between the MEC and the toxic concentration
• To maintain plasma drug levels within the therapeutic range.

In the single-dose time course, the duration of effects is determined largely by the combination of.........?

Answer Metabolism and Excretion

[image]

Which one tends to have a 100% bioavailibility?

a. IV dose

b. Oral dose

Answer A. 

Bioavailibility is proportion of administered dose present in plasma

Because IV dose is assumed to have a bioavailibility of 100% while oral dose usually <100% (incomplete)

1. Apparent volume of distribution

2. Clearance

3. Half life (t_1/2)

• Volume of distribution
• V_D= total amount of drug in the body/ [drug plasma]
• Can exceed any physical volume bcoz it is the voloume apparently necessary to contain the amount of drug homogenerously at the concentration found in plasma.

Which would you expect to be cleared more rapidly?

a. drug with high V_d

b. drug with low V_d

Answer B. 

Becasue the drug with low V_d is likely polar and lipidphobic.

Defines "Clearance (CL)"

• measure of the ability of the body to eliminate drug
• CL = Rate of elimination/ [C]

*** C stands for plasma drug concentration

• First order elimination
• For most drug, rate of eliminatin is directly propertionl to drug concentration

Drug Half-Life

• t_1/2: time for drug level to decline by 50%
• Depends on both clearance and volume of distribution

Short half-lives?

• For a few drugs, elimination becomes saturated at high concentration and is independent of concentration (ie. aspirin)---> rate of elimination and clearance is no longer related to concentration.
• Steady state not achieved; plasma concentration can increase unpredictably if dose is increased.

Loading dose

Dose-response relationship

• To understand drug-receptor interaction, we need to quantify the relationship between the drug and the biological effect it product
• "Dose-response curve"

Maximum efficacy?

• Maximum efficacy= largest effect a drug can produce
• It is indicated by the height of the dose-response curve

Potency

Potency is how much drug must be administered to elicit the response

[image]  In this case taking a pain relief with meperidine requires higher doses than morphine.. THerefore, morphine is more potent than meperidine.

Pharmacodynamics

• Based on receptor theory: a drug must first be bound to receptive substance in order to produce an effect.
• Drug targets --> describes the cellular molecule to which a drug binds to initiate its effect.

Affinity ?

Affinity : Strength of the attraction between the drugs and its receptor---> tendency of drug to bind to receptors.

** Drug with high affinity are very potent

Intrinsic activity

• The ability of a drug to activate its receptor upon binding
• Drug with  intrinsic activity cause intense receptor activation high
• The intrinsic activity of a drug ---> reflected in its efficacy

Drug-receptor binding

" Type of binding "

Ionic--> interact between charge, strong bond

Hydrogen--> b/t H atoms & pairs of free electron on O and N atoms

Forces are summed: more bonds = better fit and higher affinity.

Yes! binding interaction is usually reversible

However, it can only be irreversible if electrons are share.

Ex. ASA binds covanlently to COX--> causing plateles inhibited for the life of it.

No. 

Partial agonist --> acts on same receptor but no maximun effect

• Has affinity but no intrinsic activity
• Many drugs used clinically as antagonists are actually partial agonists--> mixed effects (agonist and antagonist)

Which one in the following has affinity but not intrinsic activity?

a. Antagonist

b. Partial agonist

c. Full agonist

d. a,b are correct

Answer is A.

However, partial agonist has less intrinsic activity than full agonist

Pharmacokinetic

"Neonates & infants"

• Absorbtion: prolonged and irregular gastric emptying (pH>4)
• Distribution: protein binding limited--> increased free drug & intensified effects
• BBB not fully developed
• Hepatic metabolism: metabolizing capacity low
• Renal excretion: Renal blood flow & glomerular filtration low

• Absorption--> rate of absorption may be slow
• Distribution--> increase %body fat, decrease %lean body mass, decrease total water, reduce concentration of serum albumin 
• Metabolism (increase t_1/2)
• Excretion---> drug accumulation secondary to reduced renal function.

Antiviral Therapy

• Ability to treat viral infection remains limited
• Viruses use biochemical nachinery of host cells to reproduce --> difficult to suppress viral replication w/o doing harm to the host
• Anitvirals suppress biochemical processes unique to viral reproduction.

Prototype: Acyclovir [Zovirax]

Similar drug: Valacyclovir (prodrug of acyclovir)

** This drug family ends with -cyclovir

MOA of HSV and VZV

• Acyclovir inhibits viral replication by suppressing synthesis of viral DNA
• Inhibition of viral DNA polymerase 
• Becoming incorporation into the growing viral DNA strand, which block further stand growth.
• Acyclovir must be activiated by viral thymidine kinase then active species inhibit DNA synthesis.

Clinical use of Acyclovir

for HSV and VZV

HSV-2 ---> po acyclovir decrease severity of initial episode, decrease frequency of recurrence... Does not eliminate the virus!

HSV-1 --> po acyclovir can be taken to prevent herpes labialis (cold sore)

VZV---> High doses are effective to treat shingle (in older adult), effective for varicella (in children)

** Oral acyclovir is deviod of serious adverse effects.

What is a CMV?

CMV---->

• Cytomegalovirus; member of herpes family
• %0-85% of American age > 40 harbor the virus
• Virus remains for life
• Can be reactivated in immunosuppressive pt.
• Same MOA as acyclovir

B, C, D

: Hepatitis C --> Transmission through blood

1. Influenza vaccine: Inactivated vaccine, Live Attenuated Influenza Vaccine (LAIV)

2. Neuraminidase Inhibitors: Oseltamivir [Tamiflu], Zanamivir [Relenza]

3. Adamantanes: Amantadine [Summetrel], Rimantidine [Flumadine]

Which drug can treat both Inflenza A and Parkinson's disease?

a. Rimantidine

b. Amantadine

c. Acyclovir

d. Oseltamivir

Which drug is a HIV fusion inhibitor drug?

a. Enfuvirtide

b. Ritonavir

c. Raltegravir

d. Zidovudine

Answer A. 

Enfuvirtide prevents HIV fusion with lymphocyte cell membrane--> block HIV entry and replication

HAART is Highly Active Anti-Retroviral Therapy

3 or 4 drugs regimen:

1. Decrease plasma HIV to undetectable levels and delay loss of immune function

2. Expensive

3. Complex

4. Drug interaction

5. Must be lifelong

Preferred regimen have 3 drugs from different classes in order to:

1. reduce resistance

2. spare other classes for the future use.

** NNRTI-based regimen (1 NNRTI+ 2 NRTIs)

** PI-based regimen (PI+ NRTIs)

**INSTI-based regimen (INSTI+ 2 NRTIS)

Best way to memorize is that always (1)name of the base + (2) NRTIs

Inhibitory aspects of motor function

**Dysfunction causes tremor, rigidty, abnormal movement.

How Drugs Affect the brain?

1. Drugs affect communication between neurons at the synapse (communication point)

2. Most drugs effect are based on specificity for neurotransmitter receptors in the brain--> overestimated, some drugs are not receptor specific

3. Neuronal activation results in excitatory/inhibitory signaling

     3.1 Inhibit of inhibitory receptor resulting in release from inhibition

4. Adapt receptor expression to long-term treatment

• Bradykinesia
• Rigidity
• resting tremor
• postural instability, shuffling gait

Dopamine Pathways

1. Nigrostriatal pathway--> Substantia Nigra to Striatum

: Motor control

: Death of neurons in this pathway can result in Parkinson's disease.

2. Mesolimpic &Mesocortical pathway---> Ventral Tegmental Area to Nucleus Accumbens, Amygdala &hippocampus, Prefrontal cortex

: Memory

: Motivation and emotional response

: Reward and desire

: Addiction

: Can cause hallucinations and schizophrenia

3. Tuberroinfundibular pathway---> hypothelamus to pituitary gland

: Hormonal regulation

: Maternal behavior

: Pregnancy

: Sensory process

How can L-dopa get transported across the BBB?

L-dopa---> transported across BBB via amino acid transporter.

** Note!

• immediate precursor of dopamine
• converted to dopamine in brain by decarboxylase
• 75% of pts get 50% reduction in symptom severity
• Take several motns to get full effects, last for about 3-5 yrs
• Best absorbed on empty stomach.

1. Modulate neurotransmitter release

2.Modulate neurotransmitter clearance from the synaptic cleft

3.Modulate effects of the neurotransmitter at the post-synaptic receptor

MAO- B inhibitor

• Inhibit dopamine metabolism, prolong L-dopa effects
• May have neuroprotective effects, so should be asministered  in the disease course early

MOA of Entacapone

(Comtan)

** treatment for PD

MOA

1. Inhibits COMT (catechol-O-methyltransferase)

2. Increase plasma t_1/2 of L-dopa, thus increase availibility

3. Available in combination with carbidopa/L-dopa

Which dopaminergic drug helps to increase t_1/2 of L-dopa?

a. Carbidopa

b. Entacapone

c. MAO-B

Answer B.

MOA of dopamine aganist (D₂)?

• Use as monotherapy in youg pt: low risk of dyskinesias, may have neuroprotective effects
• Adjunctive therapy with L-dopa
• Ergot derivative--> older, less specific, more AE
• Non-ergot derivatives (ie. apomorphine; administered SubQ)---> newer, more specific, better side effects

MOA of MAO-B inhibitor

**Treatment for PD

*** selegiline, rasagiline

MOA

1. Inhibits dopamine metabolism, prolong L-dopa effects

2. Neuroprotective effects

MOA of Amantadine

**Treatment for PD

1. Stimulate dopamine release, blocks dopamine re-uptake, blocks cholinergic and glutaminergic receptors

2. Most useful for dyskinesias

3. Short-lives

4. Significant AE --> insomnia, agitation, hallucination, restlessness

What drug may provide some preventative effects if used early?

a. MAO-B inhibitor

b. L-Dopa

c. Amantadine

c. anticholinergic drug

Answer A.

Don't get confused with anticholinergic drug, which is more useful in mild or early disease.

AE of L-Dopa (early)

Early

AE of L-dopa (Late stage)

Given Dopamine back

 L-dopa

 Maximizing L-dopa delivery to the  brain?

What causes Alzheimer's disease?

(AD)

** Amount of Ach is decreased; causing Alzheimer's 

** most common cause of dementia

1. Manifest clinically as progressive memmory loss

2. Initiated by amyloid acculation

    - Senile plaque and neurofibrillary tangles

    - Inflammatory response

    - Oxidative injuries & free radical formation

    - Neuronal loss in cortical and subcortical regions

1. Dietary supplements: Vit. E, gingko (not consistently effective)

2. Prevention: epidemiology supports NSAIDs, statin, curcumin, hormone replacement, fish oil

3. Drug in development: focused on inhibition of beta-amyloid synthesis.

**Memantine (Namenda)**

MOA

• Blocks N-methyl-D-aspartate (NMDA) receptor ion channels
• Inhibits calcium influx into neurons caused by excessive glutamate signaling --> reduce noise in learnign &memeory processes, prevent neurotoxiciy associated with excessive calcium influx
• Better toleranted drug than AChe-Is
• Most common AE --> lightheadache, confusion, headache

MOA of "Tracrine and donepezil"

Tacrine & donepezil are centrally acting reversible cholinesterase inhibitors, leading to elevated Ach levels in the brain. The action slows the neoronal degradation that occurs in Alzheimer's disease

Name two limitaitons to these drugs as AD therapy